Primary Cutaneous

NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®)
Primary Cutaneous
Lymphoma
Version 2.2022 — June 8, 2022
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Version 2.2022, 06/08/22 © 2022 National Comprehensive Cancer Network® (NCCN®), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.
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Table of Contents
Primary Cutaneous Lymphoma Discussion
*Steven M. Horwitz, MD/Chair † Þ Ahmad Halwani, MD ‡ Saurabh A. Rajguru, MD † ‡

Memorial Sloan Kettering Cancer Center Huntsman Cancer Institute University of Wisconsin
at the University of Utah Carbone Cancer Center
*Stephen Ansell, MD, PhD/Vice-Chair ‡
Mayo Clinic Cancer Center Bradley M. Haverkos, MD, MPH, MS † *Sima Rozati, MD, PhD ϖ
University of Colorado Cancer Center The Sidney Kimmel Comprehensive
Weiyun Z. Ai, MD, PhD † ‡ Cancer Center at Johns Hopkins
UCSF Helen Diller Family Richard T. Hoppe, MD §
Comprehensive Cancer Center Stanford Cancer Institute Jonathan Said, MD ≠
UCLA Jonsson Comprehensive Cancer Center
Jeffrey Barnes, MD, PhD † Eric Jacobsen, MD †
Massachusetts General Hospital Dana-Farber/Brigham and Women's Aaron Shaver, MD, PhD ≠
Cancer Center Cancer Center Vanderbilt-Ingram Cancer Center
Stefan K. Barta, MD, MRCP, MS † ‡ Deepa Jagadeesh, MD, MPH † ‡ Lauren Shea, MD ‡
Case Comprehensive Cancer Center/ O'Neal Comprehensive Cancer Center at UAB
Abramson Cancer Center
at the University of Pennsylvania University Hospitals Seidman Cancer Michi M. Shinohara, MD ϖ ≠
Center and Cleveland Clinic Taussig Fred Hutchinson Cancer Research Center/
Jonathan Brammer, MD ‡ Seattle Cancer Care Alliance
Cancer Institute
The Ohio State University Comprehensive
Cancer Center - James Cancer Hospital *Allison Jones, MD ϖ Lubomir Sokol, MD, PhD † ‡ Þ
and Solove Research Institute St. Jude Children's Research Hospital/The Moffitt Cancer Center
University of Tennessee Health Science Center *Carlos Torres-Cabala, MD ≠
Mark W. Clemens, MD ʘ
The University of Texas Avyakta Kallam, MD, MBBS Þ The University of Texas
MD Anderson Cancer Center Fred & Pamela Buffett Cancer Center MD Anderson Cancer Center
Ahmet Dogan, MD, PhD ≠ *Youn H. Kim, MD ϖ † Ryan Wilcox, MD, PhD † ‡
Memorial Sloan Kettering Cancer Center Stanford Cancer Institute University of Michigan
Rogel Cancer Center
Francine Foss, MD † ‡ ξ Kiran Kumar, MD, MBA §
Yale Cancer Center/Smilow Cancer Hospital UT Southwestern Simmons Peggy Wu, MD, MPH ϖ
Comprehensive Cancer Center UC Davis Comprehensive Cancer Center
*Paola Ghione, MD ‡
Roswell Park Comprehensive Cancer Center *Neha Mehta-Shah, MD, MSCI † ‡ Jasmine Zain, MD † ‡
Siteman Cancer Center at Barnes- City of Hope National Medical Center
Aaron M. Goodman, MD ‡ ξ NCCN
Jewish Hospital and Washington
UC San Diego Moores Cancer Center Mary Dwyer, MS
University School of Medicine
Joan Guitart, MD ≠ ϖ Hema Sundar, PhD
Elise A. Olsen, MD ϖ †
Robert H. Lurie Comprehensive Cancer ξ Bone marrow ≠ Pathology
Duke Cancer Institute
Center of Northwestern University transplantation ʘ Plastic surgery
ϖ Dermatology § Radiotherapy/
Continue ‡ Hematology/ Radiation oncology
NCCN Guidelines Panel Disclosures Hematology oncology * Discussion Writing
Þ Internal medicine Committee Member
† Medical oncology

Table of Contents
NCCN Primary Cutaneous Lymphomas Panel Members

Summary of the Guidelines Updates Clinical Trials: NCCN believes that
the best management for any patient
Primary Cutaneous B-Cell Lymphomas Primary Cutaneous CD30+ T-Cell with cancer is in a clinical trial.
• Diagnosis and Workup (CUTB-1) Lymphoproliferative Disorders Participation in clinical trials is
• Primary Cutaneous Marginal Zone Lymphoma (CUTB-2) • Overview and Definition (PCTLD/INTRO-1) especially encouraged.
• Primary Cutaneous Follicle Center Lymphoma (CUTB-2) • Diagnosis (PCTLD-1) Find an NCCN Member Institution:
• TNM Classification of Cutaneous Lymphoma other than • Workup (PCTLD-2)
MF/SS (CUTB-A) https://www.nccn.org/home/member-
• Primary Cutaneous ALCL (PCTLD-3)
• Treatment References (CUTB-B) • Lymphomatoid Papulosis (PCTLD-4) institutions.
Mycosis Fungoides/Sézary Syndrome (MF/SS) • Therapy References (PCTLD-A) NCCN Categories of Evidence and
• Overview of Definition and Diagnosis (MFSS/INTRO-1) Consensus: All recommendations
• General Principles (MFSS/INTRO-2) Principles of Radiation Therapy (PCLYM-A) are category 2A unless otherwise
• Diagnosis (MFSS-1) Principles of Molecular Analysis in T-Cell specified.
• Workup (MFSS-2)
Lymphomas (PCLYM-B) See NCCN Categories of Evidence
• TNMB Classification and Staging (MFSS-3)
• Clinical Staging (MFSS-4) Supportive Care for Patients With Cutaneous and Consensus.
• Stage IA (Limited Skin Involvement Alone, <10% BSA) Lymphomas (PCLYM-C) NCCN Categories of Preference:
(MFSS-6) All recommendations are considered
• Stage IB (Skin Only Disease with ≥10% BSA) - Stage IIA appropriate.
(MFSS-7) Use of Immunophenotyping/Genetic Testing
• Stage IIB (Tumor Stage Disease) (MFSS-8) in Differential Diagnosis of Mature B-Cell and See NCCN Categories of
• Stage III (Erythrodermic Disease) (MFSS-10) NK/T-Cell Neoplasms (See NCCN Guidelines Preference.
• Stage IV (MFSS-11) for B-Cell Lymphomas - NHODG-A)
• Large Cell Transformation (LCT) (MFSS-12)
• Suggested Treatment Regimens (MFSS-A) For Primary Cutaneous Diffuse Large B-Cell
• Supportive Care (MFSS-B) Lymphoma, Leg Type (See NCCN Guidelines
for B-Cell Lymphomas - DLBCL)
Classification (ST-1)
The NCCN Guidelines® are a statement of evidence and consensus of the authors regarding their views of currently accepted approaches to
treatment. Any clinician seeking to apply or consult the NCCN Guidelines is expected to use independent medical judgment in the context of individual
clinical circumstances to determine any patient’s care or treatment. The National Comprehensive Cancer Network® (NCCN®) makes no representations
or warranties of any kind regarding their content, use or application and disclaims any responsibility for their application or use in any way. The NCCN
Guidelines are copyrighted by National Comprehensive Cancer Network®. All rights reserved. The NCCN Guidelines and the illustrations herein may not
be reproduced in any form without the express written permission of NCCN. ©2022.

Table of Contents
Updates in Version 2.2022 of the NCCN Guidelines for Primary Cutaneous Lymphomas from Version 1.2022 include:
MS-1
• The discussion section was updated to reflect changes in the algorithm.
Global changes MFSS-6 through MFSS-12
• Suggested treatment regimen references were updated throughout the • Algorithms revised
guidelines. Headers primary treatment, response to therapy, and additional therapy
Primary Cutaneous B-Cell Lymphomas changed to "treatment and response assessment"
CUTB/INTRO-1 Specific treatment recommendations and associated footnotes removed
• Added new page: Principles of Primary Cutaneous B-Cell Lymphomas and directed to the appropriate tables on MFSS-A.
CUTB-1 • Footnote u revised by adding: General Considerations for the Treatment of
• Diagnosis, Useful Patients with MF and SS (MFSS-A 1 of 12).
1st bullet, 2nd sub-bullet revised: Assessment of IgM, IgD, IgA, IgG, MFSS-A - Global changes
IgE,... • Regimens were extensively reorganized and clarified by
• Footnote c added: A multidisciplinary team approach involving Removing previous SYST-CAT A and SYST-CAT B categories
hematology/oncology, dermatology, pathology (with expertise in Separating the regimens by Stage and providing Treatment Considerations
cutaneous lymphoma), and radiation oncology is often optimal for the for each stage
management of patients with CBCL. Combination therapies moved are now listed with each of the stage specific
CUTB-2 recommendations
• Solitary/Regional, Initial therapy, "Excision" was moved to in selected Removed ATRA as a systemic therapy option for all stages
cases. MFSS-A 1 of 12
• Footnote g revised: ...or C/A/P CT with contrast at the end of treatment • Added new page: General Considerations for the Treatment of Patients with
are may be needed to assess response. (also for CUTB-3) MF and SS
• Footnote l added: Small lesions may be excised with minimal non- MFSS-A 3 of 12
disfiguring surgery. (also for PCTLD-3) Removed the following systemic therapy options for Stage IA MF
◊ Brentuximab vedotin
Mycosis Fungoides/Sézary Syndrome ◊ Mogamulizumab
MFSS/INTRO-2 ◊ Romidepsin
• General Principles ◊ Vorinostat
1st bullet revised: ...dermatology, pathology with expertise in cutaneous Removed the following systemic therapy options for Stage IA MF with blood
lymphoma, and... involvement
8th bullet revised: Generally, skin-directed therapies and biologic ◊ Gemcitabine
agents with lower rates of immunosuppression systemic therapy ◊ Liposomal doxorubicin
regimens that can be tolerated for longer durations of therapy with ◊ Pralatrexate
lower rates of cumulative toxicity, less immunosuppression, and/or ◊ Alemtuzumab
higher efficacy are used in earlier lines of therapy. ◊ Pembrolizumab
9th bullet revised: When chemotherapy is required, in general, single MFSS-A 4 of 12
agents are preferred over combination chemotherapy (eg, CHOP), due • For Stage IB/IIA MF with blood involvement, the following regimens changed
to short-lived responses associated with shorter durations of therapy from a category 2A to a category 2B recommendation.
and higher toxicity profiles associated with multiagent regimens. Gemcitabine Alemtuzumab
In patients requiring chemotherapy, single agents are preferred Liposomal doxorubicin Pembrolizumab
over combination chemotherapy, due to the higher toxicity profiles Pralatrexate
associated with multi-agent regimens and the short-lived responses Continued
seen with time-limited combination chemotherapy." UPDATES

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Mycosis Fungoides/Sézary Syndrome Primary Cutaneous CD30+ T-Cell Lymphoproliferative Disorders
MFSS-A 6 of 12 PCTLD-1
• Stage III MF (erythrodermic disease) • Diagnosis, Useful
Added the following as skin-directed therapy options 1st bullet revised: ...perforin, GM1, IRF4/MUM1, EMA, TCRꞵ, TCRδ
◊ Phototherapy as a category 2A recommendation PCTLD-2
◊ TSEBT as a category 2B recommendation • Cutaneous ALCL Workup, Useful
MFSS-A 8 of 12 Bullet moved from essential: Bone marrow aspiration and biopsy...
• Non-Sézary (stage IVA2) or Visceral/solid organ (stage IVB) disease 2nd bullet revised by adding: if contemplating treatments that are
Added mogamulizumab as a category 2A, Other Recommended Regimen contraindicated in pregnancy. (also for LyP)
• Relapsed or refractory disease to multiple prior therapies PCTLD-3
7th bullet revised: Temozolomide for CNS involvement at some NCCN • Footnote s added: Small lesions may be excised with minimal non-disfiguring
Member Institutions surgery.
PCTLD-4
MFSS-B 1 of 2 • Footnote z added: NB-UVB is generally preferred over PUVA.
• Pruritis, treatment, systemic agents
First-line added: pregabalin Principles of Radiation Therapy
Third-line added: systemic steroids PCLYM-A 1 of 3
• Infections • Link added: See NCCN Guidelines for Hodgkin Lymphoma - Radiation Dose
Ulcerated and necrotic tumors, sub-bullet revised by adding: Ulcer will Constraints.
not heal unless disease is treated. Consider RT beam if feasible.
Supportive Care
PCLYM-C
• Adverse events associated with mogamulizumab
Added: Drug Eruption: Mogamulizumab has been associated with a drug
eruption that can clinically mimic CTCL. Skin biopsy is recommended
to distinguish progression of disease versus drug eruption (Chen L, et
al JAMA Dermatology 2019;155:968-971; Hirotsu K, et al JAMA Dermatol
2021;157:700-707).
UPDATES

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Primary Cutaneous B-Cell Lymphomas Discussion
PRINCIPLES FOR PRIMARY CUTANEOUS B-CELL LYMPHOMAS (PCBCL)

Overview & Definition
Three subtypes of PCBCL:
1. Primary cutaneous follicle center lymphoma (PCFCL)
• Most common subtype of PCBCL (57%),1,2 located primarily in the scalp, face, forehead, and trunk, usually with indolent course and
excellent prognosis (5-year overall survival [OS] rate is >95%).
• Typically presents as solitary, firm, and pink to violaceous papules, nodules, plaques, or tumors. Multifocal skin lesions are seen in 15%
of cases.1,2 Ulceration is rare.
• Dissemination to extracutaneous sites is extremely uncommon; cutaneous recurrences occur near the initial site in approximately 30%
of cases.
2. Primary cutaneous marginal zone lymphoma (PCMZL)
• Second most common subtype of PCBCL (24%–31%)1,2 with distribution primarily on the trunk, upper extremities, and head. Typically
presents as solitary or multiple erythematous to violaceous papules, small nodules, plaques, or tumors with indolent course and
excellent prognosis (5-year survival rate is 99%).
• Relapses in the skin occur in 50% of patients.
3. Primary cutaneous diffuse large B cell lymphoma (PCDLBCL, leg type)
• The rarest subtype of PCBCL (11%–19%), constituting 4% of all primary cutaneous lymphomas. It is distributed mostly to the leg, but
not uncommonly (10%–15%) can be found in other sites.1,2
• Typical clinical presentation is red to bluish plaques or tumors located on one or both legs that can ulcerate.
• It is usually aggressive and associated with a poor prognosis (high frequency of extracutaneous relapses) (5-year OS rate is 50%).3,4
• Multiple skin lesions, inactivation of CDKN2A, and MYD88 L265P associated with inferior prognosis.
Diagnosis
• PCFCL: punch biopsy/incision/excision of skin lesion preferred to shave biopsy
Immunophenotype – cells express CD20, CD79a, and BCL6; surface Ig is negative. CD10 can be negative in cases with diffuse growth
pattern. BCL2 is usually negative, or minimally expressed.
When CD10 and BCL2 are strongly expressed, or BCL2 is rearranged, consider a nodal FL with secondary skin involvement.
• PCMZL: punch biopsy/incision/excision of skin lesion preferred to shave biopsy
Immunophenotype – cells are negative for CD10 and BCL6, but are often positive for BCL2. IgG4 can be expressed in about a third of cases.
Can be divided into 2 groups with different prognosis based on the Ig heavy chain rearrangement: 1) CXCR3-negative and Ig class-switched
subtype (IgG, IgA, and IgE), characterized by nodular infiltrates of plasma cells; and 2) a less common subtype that is CXCR3-positive
and IgM positive (non class-switched) which may have extracutaneous extension.5-8 IgG class-switched subtype is a clonal chronic
lymphoproliferative disorder (LPD), with indolent course.8,9
• PCDLBCL, leg type: punch biopsy/incision/excision of skin lesion preferred to shave biopsy
Immunophenotype – cells express CD20, CD79a, monotypic immunoglobulins, BCL2 (strong), IRF/MUM1, FOXP1, and MYC. CD10 staining is
usually negative.
Gene expression profiling: PCDLBCL, leg type has been demonstrated to be always activated B-cell (ABC) subtype. Germinal center B-cell
(GCB) subtype should raise concern for PCFCL, even if large cells are present.10,11
FISH: frequently shows translocations of MYC, BCL6, and IGH genes.
Note: All recommendations are category 2A unless otherwise indicated. Continued

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged.
CUTB/INTRO-1

Table of Contents
PRINCIPLES FOR PRIMARY CUTANEOUS B-CELL LYMPHOMAS (PCBCL)

General Principles
• PCFCL, PCMZL: If the pathology or clinical presentation is not typical, complete staging with chest/abdominal/pelvic CT and/or PET/CT
scan to rule out systemic involvement. Low-dose localized radiation therapy, topical or intralesional steroids, or observation are excellent
treatment options.
• PCDLBCL, leg type: Complete staging with PET/CT scan. Treat with chemoimmunotherapy and localized radiation therapy. (See NCCN
Guidelines for B-Cell Lymphomas - DLBCL)
1 Zinzani PL, Quaglino P, Pimpinelli N, et al. Prognostic factors in primary cutaneous B-cell lymphoma: the Italian Study Group for Cutaneous Lymphomas. J Clin Oncol
2006;24:1376-1382.
2 Senff NJ, Hoefnagel JJ, Jansen PM, et al. Reclassification of 300 primary cutaneous B-cell lymphomas according to the new WHO-EORTC classification for cutaneous
lymphomas: comparison with previous classifications and identification of prognostic markers. J Clin Oncol 2007;25:1581-1587.
3 Grange F, Bekkenk MW, Wechsler J, et al. Prognostic factors in primary cutaneous large B-cell lymphomas: a European multicenter study. J Clin Oncol 2001;19:3602-
3610.
4 Grange F, Beylot-Barry M, Courville P, et al. Primary cutaneous diffuse large B-cell lymphoma, leg type: clinicopathologic features and prognostic analysis in 60 cases.
Arch Dermatol 2007;143:1144-1150.
5 van Maldegem F, van Dijk R, Wormhoudt TA, et al. The majority of cutaneous marginal zone B-cell lymphomas expresses class-switched immunoglobulins and develops in
a T-helper type 2 inflammatory environment. Blood 2008;112:3355-3361.
6 Edinger JT, Kant JA, Swerdlow SH. Cutaneous marginal zone lymphomas have distinctive features and include 2 subsets. Am J Surg Pathol 2010;34:1830-1841.
7 Kogame T, Takegami T, Sakai TR, et al. Immunohistochemical analysis of class-switched subtype of primary cutaneous marginal zone lymphoma in terms of inducible
skin-associated lymphoid tissue. J Eur Acad Dermatol Venereol. 2019;33:e401-e403.
8 Carlsen ED, Swerdlow SH, Cook JR, Gibson SE. Class-switched primary cutaneous marginal zone lymphomas are frequently IgG4-positive and have features distinct
from IgM-positive cases. Am J Surg Pathol 2019;43:1403-1412.
9 Gibson SE, Swerdlow SH. How I diagnose primary cutaneous marginal zone lymphoma. Am J Clin Pathol 2020;154:428-449.
10 Hoefnagel JJ, Dijkman R, Basso K, et al. Distinct types of primary cutaneous large B-cell lymphoma identified by gene expression profiling. Blood 2005;105:3671-3678.
11 Menguy S, Beylot-Barry M, Parrens M, et al. Primary cutaneous large B-cell lymphomas: relevance of the 2017 World Health Organization classification:
clinicopathological and molecular analyses of 64 cases. Histopathology 2019;74:1067-1080.
Note: All recommendations are category 2A unless otherwise indicated.

CUTB/INTRO-2

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DIAGNOSISa WORKUPc
ESSENTIAL:
• Review of all slides with at least one paraffin block
representative of the tumor should be done by a ESSENTIAL:d Primary Cutaneous
pathologist with expertise in the diagnosis of primary • History and physical exam, including complete Marginal Zone
cutaneous B-cell lymphoma. Rebiopsy if consult skin exam Lymphoma (PCMZL)
material is nondiagnostic. • CBC with differential (CUTB-2)
• Adequate biopsy (punch, incisional, excisional) of • Comprehensive metabolic panel
clinical lesions • LDH
• Adequate immunophenotyping to establish diagnosisb • Chest/abdominal/pelvic CT with contrast and/
IHC panel may include: CD20, CD3, CD10, BCL2, or PET/CT scan (may be omitted if clinically Primary Cutaneous
BCL6, IRF4/MUM1 indicated) Follicle Center
• Pregnancy testing in patients of childbearing Lymphoma (PCFCL)
USEFUL IN CERTAIN CIRCUMSTANCES: potential (if chemotherapy or RT planned) (CUTB-2)
• Additional immunohistochemical studies to establish
lymphoma subtype USEFUL IN SELECTED CASES:
IHC panel may include: Ki-67, CD5, CD43, CD21, • Bone marrow biopsye Primary Cutaneous
CD23, cyclin D1, kappa/lambda (IHC or ISH) • Peripheral blood flow cytometry, if CBC Diffuse Large B-Cell
Assessment of IgM, IgD, IgA, IgG, IgE, and FOXP1 demonstrates lymphocytosis Lymphoma (PC-
DLBCL), Leg Type
expression (to further help in distinguishing PC- • SPEP/quantitative immunoglobulins for PCMZL
(See NCCN Guidelines
DLBCL, leg type from PCFCL) • HIV testing for B-Cell Lymphomas
• EBER-ISH • Hepatitis B and C testingf - DLBCL)
• Cytogenetics (FISH and karyotype): t(14;18) if systemic • Discussion of fertility and sperm banking, if
FL is suspected fertility-impacting therapy is planned
• If adequate biopsy material available, flow cytometry
or IgH gene rearrangement studies can be useful in
determining B-cell clonality
a For d Rule out drug-induced cutaneous lymphoid hyperplasia.
non-cutaneous extranodal B-cell lymphomas, see Nongastric MALT Lymphoma in
e Often reserved for patient with unexplained cytopenias or if there is clinical
the NCCN Guidelines for B-Cell Lymphomas. A germinal (or follicle) center phenotype
and large cells in a skin lesion is not equivalent to DLBCL but is consistent with primary suspicion of other subtypes (eg, PC-DLBCL, leg type).
f Hepatitis B testing is indicated because of the risk of reactivation with
cutaneous germinal/follicle center lymphoma.
b See Use of Immunophenotyping/Genetic Testing in Differential Diagnosis of Mature immunotherapy + chemotherapy. See monoclonal antibody and viral
B-Cell and NK/T-Cell Neoplasms (See NCCN Guidelines for B-Cell Lymphomas). reactivation in the NCCN Guidelines B-Cell Lymphomas. Tests include
c A multidisciplinary team approach involving hematology/oncology, dermatology, hepatitis B surface antigen and core antibody for a patient with no risk factors.
pathology (with expertise in cutaneous lymphoma), and radiation oncology is often For patients with risk factors or previous history of hepatitis B, add e-antigen.
optimal for the management of patients with PCBCL. If positive, check viral load and consult with gastroenterologist.

CUTB-1

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PRIMARY CUTANEOUS MARGINAL ZONE LYMPHOMA OR FOLLICLE CENTER LYMPHOMAg

STAGEh INITIAL THERAPYi RESPONSE/ADDITIONAL THERAPY For PCFCL,
manage as
Follicular
Regional Lymphoma in the
Local ISRT (preferred)j NCCN Guidelines
Relapsed or for B-Cell
Responseg Observe progressive Generalized disease Lymphomas (see
In selected cases:
diseaseg (extracutaneous FOLL-4)
Observation k
disease) or
or
Solitary/regional, For PCMZL,
Excisionl
T1–2 Generalized manage as Nodal
or
disease (skin Marginal Zone
Skin-directed
See Generalized Lymphoma in the
therapiesm Refractory only)
NCCN Guidelines
or disease (skin only),
diseaseg T3 (CUTB-3)
for B-Cell
Intralesional steroids Lymphomas (see
NODE-2)
See Generalized
Generalized disease (skin only),
disease (skin only), See CUTB-3 T3 (CUTB-3)
T3
For PCFCL, manage as Follicular
Lymphoma in the NCCN Guidelines for
B-Cell Lymphomas (see FOLL-4)
Extracutaneous or
disease For PCMZL, manage as Nodal Marginal
Zone Lymphoma in the NCCN Guidelines
for B-Cell Lymphomas (see NODE-2)
g Additional imaging studies during the course of treatment are not needed. PET/CT (strongly preferred) or C/A/P CT with contrast at the end of treatment may be
needed to assess response. This can be repeated if there is clinical suspicion of progressive disease.
h See TNM Classification of Cutaneous Lymphoma other than MF/SS (CUTB-A).
i See Treatment References (CUTB-B).
j Local ISRT is the preferred initial treatment, but not necessarily the preferred treatment for relapse. See Principles of Radiation Therapy (PCLYM-A).
k When RT or surgical treatment is neither feasible nor desired.
l Small lesions may be excised with minimal non-disfiguring surgery.
m There are case reports showing efficacy of topicals, which include steroids, imiquimod, nitrogen mustard, and bexarotene (useful in pediatric patients).

CUTB-2

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PRIMARY CUTANEOUS MARGINAL ZONE LYMPHOMA OR FOLLICLE CENTER LYMPHOMAg

STAGEh INITIAL THERAPYi RESPONSE/ADDITIONAL THERAPY
For PCFCL,
Generalized disease manage as
(skin only) Follicular
Observationn Relapsed or Lymphoma in the
or NCCN Guidelines
Responseg Observe progressive
Skin-directed therapiesm diseaseg
for B-Cell
or Lymphomas (see
Generalized disease
Local ISRTj (extracutaneous
FOLL-4)
Generalized disease or
or disease)
(skin only), T3 For PCMZL,
Intralesional steroids
or manage as Nodal
Rituximabo,p Refractory Alternate regimen not Marginal Zone
or diseaseg used for initial therapy Lymphoma in the
Other systemic therapyq NCCN Guidelines
for B-Cell
Lymphomas (see
NODE-2)
g Additional imaging studies during the course of treatment are not needed. PET/
CT (strongly preferred) or C/A/P CT with contrast at the end of treatment may be o See monoclonal antibody and viral reactivation (See NCCN Guidelines B-Cell
needed to assess response. This can be repeated if there is clinical suspicion of Lymphomas).
progressive disease. p Rituximab and hyaluronidase human injection for subcutaneous use may be
h See TNM Classification of Cutaneous Lymphoma other than MF/SS (CUTB-A). substituted for rituximab after patients have received the first full dose of rituximab
i See Treatment References (CUTB-B). by intravenous infusion. This substitution cannot be made for rituximab used
j Local ISRT is the preferred initial treatment, but not necessarily the preferred in combination with ibritumomab tiuxetan. An FDA-approved biosimilar is an
treatment for relapse. See Principles of Radiation Therapy (PCLYM-A). appropriate substitute for rituximab.
m There are case reports showing efficacy of topicals, which include steroids, q In rare circumstances for very extensive or refractory disease, other combination
imiquimod, nitrogen mustard, and bexarotene (useful in pediatric patients). chemotherapy regimens listed in NCCN Guidelines for B-Cell Lymphomas,
n Considered appropriate in asymptomatic patients. FOLL-B are used.

CUTB-3

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TNM CLASSIFICATION OF CUTANEOUS LYMPHOMA OTHER THAN MF/SSa,b
T
T1 Solitary skin involvement
T1a: a solitary lesion <5 cm diameter
T1b: a solitary >5 cm diameter
T2 Regional skin involvement: multiple lesions limited to 1 body region or 2 contiguous body regionsb
T2a: all-disease-encompassing in a <15-cm-diameter circular area
T2b: all-disease-encompassing in a >15- and <30-cm-diameter circular area
T2c: all-disease-encompassing in a >30-cm-diameter circular area
T3 Generalized skin involvement
T3a: multiple lesions involving 2 noncontiguous body regionsb
T3b: multiple lesions involving ≥3 body regionsb
N
N0 No clinical or pathologic lymph node involvement
N1 Involvement of 1 peripheral lymph node regionc that drains an area of current or prior skin involvement
N2 Involvement of 2 or more peripheral lymph node regionsc or involvement of any lymph node region that
does not drain an area of current or prior skin involvement
N3 Involvement of central lymph nodes
M
M0 No evidence of extracutaneous non-lymph node disease
M1 Extracutaneous non-lymph node disease present
a This work was originally published in Blood. Kim YH, Willemze R, Pimpinell Ni, et al, for the ISCL and the EORTC. TNM classification system for primary cutaneous
lymphomas other than mycosis fungoides and Sézary syndrome: A proposal of the International Society for Cutaneous Lymphomas (ISCL) and the Cutaneous Lymphoma
Task Force of the European Organization of Research and Treatment of Cancer (EORTC) Blood 2007;110:479-484. © The American Society of Hematology.
b For definition of body regions, see Body Regions for the Designation of T (Skin Involvement) Category (CUTB-A 2 of 2).
c Definition of lymph node regions is consistent with the Ann Arbor system: Peripheral sites: antecubital, cervical, supraclavicular, axillary, inguinal-femoral, and
popliteal. Central sites: mediastinal, pulmonary hilar, paraortic, and iliac.

CUTB-A
Version 2.2022, 06/08/22 © 2022 National Comprehensive Cancer Network (NCCN ), All rights reserved. NCCN Guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.
® ® ®
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BODY REGIONS FOR THE DESIGNATION OF T (SKIN INVOLVEMENT) CATEGORYa,d,e
a This work was originally published in Blood. Kim YH, Willemze R, Pimpinell Ni, et al, for the ISCL and the EORTC. TNM classification system for primary cutaneous
lymphomas other than mycosis fungoides and Sézary syndrome: A proposal of the International Society for Cutaneous Lymphomas (ISCL) and the Cutaneous Lymphoma
Task Force of the European Organization of Research and Treatment of Cancer (EORTC) Blood 2007;110:479-484. © The American Society of Hematology.
d Left and right extremities are assessed as separate body regions. The designation of these body regions is based on regional lymph node drainage patterns.
e Definition of body regions: Head and neck: inferior border—superior border of clavicles, T1 spinous process. Chest: superior border—superior border of clavicles; inferior
border—inferior margin of rib cage; lateral borders—midaxillary lines, glenohumeral joints (inclusive of axillae). Abdomen/genital: superior border—inferior margin of rib
cage; inferior border—inguinal folds, anterior perineum; lateral borders—mid-axillary lines. Upper back: superior border—T1 spinous process; inferior border—inferior
margin of rib cage; lateral borders—mid-axillary lines. Lower back/buttocks: superior border—inferior margin of rib cage; inferior border—inferior gluteal fold, anterior
perineum (inclusive of perineum); lateral borders—midaxillary lines. Each upper arm: superior borders—glenohumeral joints (exclusive of axillae); inferior borders—
ulnar/radial-humeral (elbow) joint. Each lower arm/hand: superior borders—ulnar/radial-humeral (elbow) joint. Each upper leg (thigh): superior borders—inguinal folds,
inferior gluteal folds; inferior borders—mid-patellae, midpopliteal fossae. Each lower leg/foot: superior borders—mid-patellae, mid-popliteal fossae.

CUTB-A
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2 OF 2

Table of Contents
TREATMENT REFERENCES
Topicals Chemotherapy/Chemoimmuotherapy
Topical/intralesional corticosteroids Bekkenk MW, Vermeer MH, Geerts ML, et al. Treatment of multifocal primary
Bekkenk MW, Vermeer MH, Geerts ML, et al. Treatment of multifocal primary cutaneous B-cell lymphoma: a clinical follow-up study of 29 patients. J Clin Oncol
cutaneous B-cell lymphoma: a clinical follow-up study of 29 patients. J Clin Oncol 1999;17:2471-2478.
1999;17:2471-2478. Brice P, Cazals D, Mounier N, et al. Primary cutaneous large-cell lymphoma:
Perry A, Vincent BJ, Parker SR. Intralesional corticosteroid therapy for primary analysis of 49 patients included in the LNH87 prospective trial of
cutaneous B-cell lymphoma. Br J Dermatol 2010;163:223-225. polychemotherapy for high-grade lymphomas. Groupe d'Etude des Lymphomes
Topical nitrogen mustard de l'Adulte. Leukemia 1998;12:213-219.
Bachmeyer C, Orlandini V, Aractingi S. Topical mechlorethamine and clobetasol Hoefnagel JJ, Vermeer MH, Jansen PM, et al. Primary cutaneous marginal zone
in multifocal primary cutaneous marginal zone-B cell lymphoma. B J Dermatol B-cell lymphoma: Clinical and therapeutic features in 50 cases. Arch Dermatol
2006;154:1207-1209. 2005;141:1139-1145.
Topical bexarotene Grange F, Beylot-Barry M, Courville P, et al. Primary cutaneous diffuse large B-cell
Trent JT, Romanelli P, Kerdel FA. Topical targretin and intralesional interferon alfa lymphoma, leg type: clinicopathologic features and prognostic analysis in 60
for cutaneous lymphoma of the scalp. Arch Dermatol 2002;138:1421-1423. cases. Arch Dermatol 2007;143:1144-1150.
Topical imiquimod Grange F, Joly P, Barbe C, et al. Improvement of survival in patients with primary
Coors EA, Schuler G, Von Den Driesch P. Topical imiquimod as treatment for cutaneous diffuse large B-cell lymphoma, leg type, in France. JAMA Dermatol
different kinds of cutaneous lymphoma. Eur J Dermatol 2006;16:391-393. 2014;150:535-541.
Stavrakoglou A, Brown VL, Coutts I. Successful treatment of primary cutaneous Rijlaarsdam JU, Toonstra J, Meijer OW, Noordijk EM, Willemze R. Treatment of
follicle centre lymphoma with topical 5% imiquimod. Br J Dermatol 2007;157:620- primary cutaneous B-cell lymphomas of follicle center cell origin: A clinical follow-
622. up study of 55 patients treated with radiotherapy or polychemotherapy. J Clin
Oncol 1996;14:549-555.
Rituximab Senff NJ, Noordijk EM, Kim YH, et al. European Organization for Research
Morales AV, Advani R, Horwitz SM, et al. Indolent primary cutaneous B-cell and Treatment of Cancer and International Society for Cutaneous Lymphoma
lymphoma: experience using systemic rituximab. J Am Acad Dermatol consensus recommendations for the management of cutaneous B-cell
2008;59:953-957. lymphomas. Blood 2008;112:1600-1609.
Heinzerling LM, Urbanek M, Funk JO, et al. Reduction of tumor burden and Vermeer MH, Geelen FA, van Haselen CW, et al. Primary cutaneous large B-cell
stabilization of disease by systemic therapy with anti-CD20 antibody (rituximab) lymphomas of the legs. A distinct type of cutaneous B-cell lymphoma with an
in patients with primary cutaneous B-cell lymphoma. Cancer 2000;89:1835-1844. intermediate prognosis. Dutch Cutaneous Lymphoma Working Group. Arch
Valencak J, Weihsengruber F, Rappersberger K, et al. Rituximab monotherapy for Dermatol 1996;132:1304-1308.
primary cutaneous B-cell lymphoma: Response and follow-up in 16 patients. Ann
Palliative low-dose RT
Oncol 2009;20:326-330.
Neelis KJ, Schimmel EC, Vermeer MH, et al. Low-dose palliative radiotherapy for
Senff NJ, Noordijk EM, Kim YH, et al. European Organization for Research
cutaneous B- and T-cell lymphomas. Int J Radiat Oncol Biol Phys 2009;74:154-
and Treatment of Cancer and International Society for Cutaneous Lymphoma
158.
consensus recommendations for the management of cutaneous B-cell
lymphomas. Blood 2008;112:1600-1609.
Heinzerling L, Dummer R, Kempf W, Schmid MH, Burg G. Intralesional therapy
with anti-CD20 monoclonal antibody rituximab in primary cutaneous B-cell
lymphoma. Arch Dermatol 2000;136:374-378.

CUTB-B

Table of Contents
Mycosis Fungoides/Sezary Syndrome Discussion
PRINCIPLES FOR MYCOSIS FUNGOIDES/SÉZARY SYNDROME

Definition
• Mycosis fungoides (MF)
MF is the most common cutaneous T-cell lymphoma (CTCL) and many clinicopathologic variants of MF have been described.a
Most patients with MF exhibit an indolent clinical course with intermittent, stable, or slow progression of the lesions.
Extracutaneous involvement may be seen in advanced stages, with involvement of lymph nodes, blood, or less commonly other organs.a
• Sézary syndrome (SS)
SS is closely related to MF but has unique characteristics. SS is rare, accounting for less than 5% of cutaneous lymphomas and
predominantly affects older individuals.
SS is characterized by the presence of atypical T cells (Sézary cells) in skin causing diffuse erythema (erythroderma) and significant
blood involvement with abnormal T cells (>1000 abnormal cells/uL) defined as Sézary cells by cytopathologic assessment or flow
cytometry (abnormal subsets including but not limited to CD4+CD7- or CD4+CD26- cells).b
SS is thought to arise from thymic memory T cells, while skin resident effector memory T cells are the cells of origin of MF. This supports
the contention that SS is a process distinct from MF.c Cases presenting clinically as an overlap of these two conditions exist.
Diagnosis
• The histopathologic findings of MF, even in cases showing classic features, need to be correlated with clinical presentation in order to
reach a definitive diagnosis.d
• Patch lesions are often difficult for conclusive diagnosis; thus, in some instances multiple skin biopsies may be necessary for diagnosis.
Stopping skin-directed therapy for 2–3 weeks or longer to individual lesions before obtaining a skin biopsy is advisable and may aid in
diagnosis.a
• Awareness of specific clinicopathologic variants may aid in accurate diagnosis:
Lesions may be hyper- or hypopigmented.
Folliculotropic MF (FMF) may present as folliculocentric papules or nodules or areas of alopecia in any hair-bearing area of the body.
Unilesional, pagetoid reticulosis and CD8+ MF variants tend to be associated with an indolent course.
Granulomatous slack skin is rare and presents with redundant skin resembling cutis laxa on flexural areas.
• The tumor cells are usually CD3+, CD4+, and CD8-, although CD8+ variants are not uncommon.
• Large-cell transformation (LCT) of MF is defined histologically as greater than 25% of the tumor cells displaying large size. CD30
expression may be seen but is not included in the definition of LCT.
• The histopathologic findings of SS in skin are generally similar to, but may be more subtle than those seen in MF. Correlation with clinical
and laboratory findings in blood is essential for a definitive diagnosis.
See General Principles (MFSS/INTRO-2)
a Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood 2016;127:2375-2390.
b Olsen E, Whittaker S, Kim YH, et al. J Clin Oncol 2011;29:2598-2607.
c Campbell JJ, Clark RA, Watanabe R, Kupper TS. Sezary syndrome and mycosis fungoides arise from distinct T-cell subsets: a biologic rationale for their distinct clinical
behaviors. Blood 2010;116:767-771.
d Pimpinelli N, Olsen EA, Santucci M, et al. Defining early mycosis fungoides. J Am Acad Dermatol 2005;53:1053-1063.

MFSS/INTRO-1

Table of Contents
PRINCIPLES FOR MYCOSIS FUNGOIDES/SÉZARY SYNDROME

General Principles
• A multidisciplinary team approach involving hematology/oncology, dermatology, pathology with expertise in cutaneous lymphoma, and
radiation oncology is often optimal for the management of patients with MF/SS, particularly those with advanced disease.
• Given the rarity of the disease, it is preferred that treatment or consultation occur at centers with expertise in the management of CTCL.
• Evaluation by a pathologist at a referral center is recommended.
• FMF and LCT are histologic features that can occur irrespective of stage.
• Recent studies have reported that FMF presents with two distinct patterns of clinicopathologic features with different prognostic
implications (early stage and advanced stage); in a subgroup of patients with early skin-limited disease, FMF has an indolent disease
course and a favorable prognosis.e,f,g Treatment may require skin-directed therapy that reaches the subcutaneous tissue (eg, psoralen
plus ultraviolet A [PUVA], involved-site RT [ISRT]) or the addition of systemic therapy as used in stages I–IIB for patients with disease not
responding to skin-directed therapy alone.
• The incidence of LCT is strongly dependent on the disease stage at diagnosis.h,i LCT often but not always corresponds to a more aggressive
growth rate requiring systemic therapies (see MFSS-12).
• Goals of therapy should be individualized but often include:
Attain adequate response in order to reduce and control symptoms and minimize risk of progression.
Most treatments for MF/SS do not result in durable remissions off of treatment.
Therapies with lower side-effect profiles and an absence of cumulative toxicity are often given in an ongoing or maintenance fashion to
improve and maintain disease control and quality of life.
Other than allogeneic hematopoietic cell transplant (HCT), therapies are not given with curative intent.
• Generally, skin-directed therapies and systemic therapy regimens that can be tolerated for longer durations of therapy with lower rates of
cumulative toxicity, less immunosuppression, and/or higher efficacy are used in earlier lines of therapy.
• In patients requiring chemotherapy, single agents are preferred over combination chemotherapy, due to the higher toxicity profiles
associated with multi-agent regimens and the short-lived responses seen with time-limited combination chemotherapy.
• Responses can vary between the different compartments (ie, skin, blood, lymph nodes). Unlike other non-Hodgkin lymphoma subtypes,
response criteria for MF/SS have not been demonstrated to correlate with prognosis. Often decisions to continue or switch therapy are on a
clinical basis.
• Disease relapse after discontinuation of therapy may respond to re-treatment with previous therapy.
• Partial responses with suboptimal quality of life should be treated with other or additional primary treatment options.
• Use of supportive care measures to minimize risk of skin infections and treat pruritus is an important part of disease and symptom control
(see MFSS-B).
e Hodak E, Amitay-Laish I, Atzmony L, et al. New insights into folliculotropic mycosis fungoides (FMF): A single-center experience. J Am Acad Dermatol 2016;75:347-355.
f van Santen S, Roach RE, van Doorn R, et al. Clinical staging and prognostic factors in folliculotropic mycosis fungoides. JAMA Dermatol 2016;152:992-1000.
g van Santen S, van Doorn R, Neelis KJ, et al. Recommendations for treatment in folliculotropic mycosis fungoides: report of the Dutch Cutaneous Lymphoma Group. Br J
Dermatol 2017;177:223-228.
h VergierB, de Muret A, Beylot-Barry M, et al. Transformation of mycosis fungoides: clinicopathological and prognostic features of 45 cases. French Study Group of
Cutaneious Lymphomas. Blood 2000;95:2212-2218.
i Arulogun SO, Prince HM, Ng J, et al. Long-term outcomes of patients with advanced-stage cutaneous T-cell lymphoma and large cell transformation. Blood
2008;112:3082-3087.

MFSS/INTRO-2

Table of Contents
DIAGNOSISa
ESSENTIAL:
• Biopsy of suspicious skin sites
Multiple biopsies may be necessary to capture the pathologic variability of disease at diagnosis
• Review of all slides with at least one paraffin block representative of the tumor should be done by a pathologist
with expertise in the diagnosis of CTCLs. Rebiopsy if consult material in conjunction with the clinical picture is
nondiagnostic.b
• IHC panel of skin biopsy may include:c,d,e
CD2, CD3, CD4, CD5, CD7, CD8, CD20, CD30
• Molecular analysis to detect clonal T-cell receptor (TCR) gene rearrangements or other assessment
of clonalitya,f
USEFUL UNDER CERTAIN CIRCUMSTANCES:
• Assessment of peripheral blood for Sézary cells (in extensive skin disease where skin biopsy is not diagnostic in See Workup
extensive patch or erythrodermic skin disease and/or strongly suggestive but not diagnostic of advanced-stage disease) (MFSS-2)
including:
Flow cytometry and molecular analysis to assess and quantitate an expanded T-cell population with aberrant
phenotype.a,g See MFSS-3 for specifics.
Sézary cell preparation is less useful than flow cytometry due to the subjective nature of the process but can be useful
where flow cytometry is not available.
• IHC panel of skin biopsy may include:b,c
CD25, CD56, TIA1, granzyme B, TCRß, TCRẟ; CXCL13, inducible T-cell co-stimulator (ICOS), and PD-1
• Biopsy of enlarged lymph nodes or suspected extracutaneous sites (if biopsy of skin is not diagnostic). Excisional or
incisional biopsy is preferred over core needle biopsy. A fine-needle aspiration (FNA) biopsy alone is not sufficient for
the initial diagnosis of lymphoma. A core needle biopsy is not optimal but can be used under certain circumstances. In
certain circumstances, when a lymph node is not easily accessible for excisional or incisional biopsy, a combination of
core needle biopsy and FNA biopsy in conjunction with appropriate ancillary techniques may be sufficient for diagnosis.
Rebiopsy if consult material is nondiagnostic.
• Assessment of HTLV-1/2h by serology or other methods is encouraged as results can impact therapy.
e Typical immunophenotype: CD2+, CD3+, CD5+, CD7-, CD4+, CD8- (rarely CD8+),
a See Principles of Molecular Analysis in Cutaneous Lymphomas (PCLYM-B). CD30-/+ cytotoxic granule proteins negative.
b Presence of transformation or areas of folliculotropism may have important f Clonal TCR gene rearrangements alone are not sufficient for diagnosis, as these
implications for selection of therapy and outcome and should be included in can also be seen in patients with non-malignant conditions. Results should be
pathology reports. interpreted in the context of overall presentation. See Principles of Molecular
c Clinically suspicious and histologically non-diagnostic cases. Pimpinelli N, Analysis in Cutaneous Lymphomas (PCLYM-B).
et al. J Am Acad Dermatol 2005;53:1053-1063. g CD3, CD4, CD7, CD8, CD26 to assess for expanded CD4+ cells with increased
d See Use of Immunophenotyping/Genetic Testing in Differential Diagnosis of CD4/CD8 ratio or with abnormal immunophenotype, including loss of CD7 or CD26.
Mature B-Cell and NK/T-Cell Neoplasms (See NCCN Guidelines for B-Cell h See map for prevalence of HTLV-1/2 by geographic region. HTLV-1 has been
Lymphomas). described in patients in non-endemic areas.

MFSS-1

Table of Contents
WORKUP
ESSENTIAL:
• History and complete physical examination:
Complete skin examination: assessment of % body surface area (BSA) (palm plus digits ≈1% BSA) and type of skin
lesion (ie, patch/plaque, tumor, erythroderma)
Palpation of peripheral lymph node regions
Palpation for organomegaly/masses
• Laboratory studies:i
CBC with differential and determination of absolute lymphocyte count
Flow cytometric studies to assess and quantitate an expanded T-cell population with aberrant phenotype (optional
for T1j) (see MFSS-3)
◊ Recommended for any patient with T2–4 skin classification, any suspected extracutaneous disease including
adenopathy
Clonal TCR gene rearrangement in peripheral blood lymphocytes if blood involvement suspecteda
Comprehensive metabolic panel For TNMB
LDH Classification, see
• Imaging studies: MFSS-3
C/A/P CT with contrast or integrated whole body PET/CTk for T3 or T4 (arms/legs included when disease assessment and
of entire body is needed) For Clinical Staging
of MF and SS, see
USEFUL IN SELECTED CASES: MFSS-4
• Bone marrow biopsy in patients with unexplained hematologic abnormality
• Biopsy of enlarged lymph nodes or suspected extracutaneous sites (if biopsy of skin is not diagnostic). Excisional
or incisional biopsy is preferred over core needle biopsy. An FNA biopsy alone is not sufficient for the initial
diagnosis of lymphoma. A core needle biopsy is not optimal but can be used under certain circumstances. In certain
circumstances, when a lymph node is not easily accessible for excisional or incisional biopsy, a combination of core
needle biopsy and FNA biopsy in conjunction with appropriate ancillary techniques may be sufficient for diagnosis.
Rebiopsy if consult material is nondiagnostic.
• Rebiopsy skin if suspicious of LCT or folliculotropism and not previously confirmed pathologically
• C/A/P CT with contrast or integrated whole body PET/CTk for ≥T2b or large-cell transformed or FMF, or with palpable
adenopathy or abnormal laboratory studies; consider for T2a (patch disease with ≥10% BSA)
• Neck CT with contrast if have not done whole body PET/CT
• Pregnancy testing in patients of childbearing potential if contemplating treatments that are contraindicated in
pregnancyl
• Discussion of fertility and sperm banking, if fertility-impacting therapy is planned
a See Principles of Molecular Analysis in Cutaneous Lymphomas (PCLYM-B).
i Sézary syndrome (B2) is as defined on MFSS-3.
j See Discussion for when Sézary flow cytometric study is appropriate in T1 disease.
k Patients with cutaneous lymphomas have extranodal disease, which may be inadequately imaged by CT. PET scan may be preferred in these instances.
l Many skin-directed and systemic therapies are contraindicated or of unknown safety in pregnancy. Refer to full prescribing information for individual drugs.

MFSS-2

Table of Contents
TNMB TNMB Classification and Staging of Mycosis Fungoides and Sézary Syndromem,n Clinical Staging of MF and SS (MFSS-4)
Skin T1 Limited patches,o papules, and/or plaquesp covering <10% of the skin surface
T2 Patches, papules,o and/or plaqueso covering ≥10% of the skin surface
T2a Patch only
T2b Plaque ± patch
T3 One or more tumorsq (≥1 cm in diameter)
T4 Confluence of erythema ≥80% body surface area
Node N0 No abnormal lymph nodes; biopsy not required NCI Lymph Node Classification on MFSS-5
N1 Abnormal lymph nodes; histopathology Dutch Gr 1 or NCI LN 0-2 Dutch Criteria for Lymph Nodes on MFSS-5
N2 Abnormal lymph nodes; histopathology Dutch Gr 2 or NCI LN 3
N3 Abnormal lymph nodes; histopathology Dutch Gr 3-4 or NCI LN 4
NX Abnormal lymph nodes; no histologic confirmation
Visceral M0 No visceral organ involvement
M1 Visceral involvement (must have pathology confirmation and organ involved should be specified)
MX Abnormal visceral site; no histologic confirmation
Blood B0 Absence of significant blood involvement: ≤5% of peripheral blood lymphocytes or <250/mcL are atypical (Sézary) cells or <15% CD4+/
CD26- or CD4+/CD7- cells of total lymphocytes
B1 Low blood tumor burden: >5% of peripheral blood lymphocytes are atypical (Sézary) cells or >15% CD4+CD26- or CD4+CD7- of total
lymphocytes but do not meet the criteria of B0 or B2
B2 High blood tumor burden: ≥1000/mcL Sézary cellsn determined by cytopathology or ≥1000 CD4+CD26- or CD4+CD7- cells/uL or other
abnormal subset of T lymphocytes by flow cytometry with clone in blood same as that in skin. Other criteria for documenting high blood
tumor burden in CD4+ MF/SS include CD4+/CD7- cells ≥40% and CD4+CD26- cells ≥30%.
m Adapted from Olsen E, et al. Blood 2007;110:1713-1722 and Olsen E, et al. J Clin Oncol 2011;29:2598-2607.
n Sézary syndrome is defined by B2 blood involvement and a clonal rearrangement of TCR in the blood (clones should be relevant to clone in the skin).
o Patch = Any size skin lesion without significant elevation or induration. Presence/absence of hypo- or hyperpigmentation, scale, crusting, and/or poikiloderma should
be noted.
p Plaque = Any size skin lesion that is elevated or indurated. Presence or absence of scale, crusting, and/or poikiloderma should be noted. Histologic features such as
folliculotropism or LCT (≥25% large cells), CD30+ or CD30-, and clinical features such as ulceration are important to document.
q Tumor = at least one >1 cm diameter solid or nodular lesion with evidence of depth and/or vertical growth. Note total number of lesions, total volume of lesions, largest
size lesion, and region of body involved. Also note if histologic evidence of LCT has occurred. Phenotyping for CD30 is encouraged.

MFSS-3

Table of Contents
Clinical Staging of MF and SSr
Clinical Stages T (Skin) N (Node) M (Visceral) B (Blood Involvement) Guidelines Page
T1
IA (Patches, papules, and/or plaques
(Limited skin involvement) N0 M0 B0 or B1 MFSS-6
covering <10% body surface area
[BSA])
IB T2
(Skin only disease) (Patches, papules, and/or plaques N0 M0 B0 or B1 MFSS-7
covering ≥10% BSA)
IIA T1–2 N1–2 M0 B0 or B1 MFSS-7
IIB T3
(Tumor stage disease) (One or more tumors [≥1 cm in N0–2 M0 B0 or B1 MFSS-8
diameter])
IIIA T4 N0–2 M0 B0 MFSS-10
(Erythrodermic disease) (Confluence of erythema ≥80% BSA)
IIIB T4 N0–2 M0 B1 MFSS-10

(Erythrodermic disease) (Confluence of erythema ≥80% BSA)
IVA1 (Sézary syndrome) T1–4 N0–2 M0 B2 MFSS-11
IVA2 (Sézary syndrome or T1–4 N3 M0 B0 or B1 or B2 MFSS-11

Non-Sézary)
IVB (Visceral disease) T1–4 N0–3 M1 B0 or B1 or B2 MFSS-11
Large-cell transformation (LCT)t MFSS-12

r Olsen E, et al. Blood 2007;110:1713-1722.
s Folliculotropism is a histologic feature that canoccur irrespective of stage. Histologic evidence of FMF is associated with higher risk of disease progression. In selected
cases or inadequate response, consider primary treatment for stage IIB (tumor stage disease).
t LCT is a histologic feature that can occur irrespective of clinical stage. LCT often but not always corresponds to a more aggressive growth rate requiring systemic therapies.
For TNMB Classification,

Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. see MFSS-3
MFSS-4

Table of Contents
LYMPH NODE CLASSIFICATION IN MF AND SS
NCI-VA Lymph Node Classification

LN0: no atypical lymphocytes
LN1: occasional and isolated atypical lymphocytes (not arranged in clusters)
LN2: many atypical lymphocytes or in 3–6 cell clusters
LN3: aggregates of atypical lymphocytes; nodal architecture preserved
LN4: partial/complete effacement of nodal architecture by atypical lymphocytes or frankly neoplastic cells
Clendenning WE, Rappaport HW. Report of the Committee on Pathology of Cutaneous T Cell Lymphomas.
Cancer Treat Rep 1979;63:719-724.
Dutch Criteria for Lymph Nodes

Grade 1: Dermatopathic lymphadenopathy
Grade 2: Early involvement by mycosis fungoides (presence of cerebriform nuclei >7.5 micrometers)
Grade 3: Partial effacement of lymph node architecture; many atypical cerebriform mononuclear cells
Grade 4: Complete effacement of lymph node architecture
Scheffer E, Meijer CJLM, van Vloten WA. Dermatopathic lymphadenopathy and lymph node
involvement in mycosis fungoides. Cancer 1980;45:137-148.

MFSS-5

Table of Contents
STAGEu TREATMENT AND RESPONSE ASSESSMENT

(MFSS-3 and
MFSS-4)
Relapse with T1 skin disease
CR/PRx
Relapse with
>stage IA disease Treatment based on clinical
Stage IA
See Table 1: Stage IA MF stage. See MFSS-4 for
(limited skin
(Limited skin involvement appropriate clinical stage
involvement alone,
alone; <10% BSA) Progression to >stage
<10% BSA)v,w
IA on skin-directed
therapies
Inadequate or Manage as Stage IB–IIA MF
response Refractory disease (see MFSS-7)
to multiple previous or
therapies Consider RT if not
or previously usedy
Persistent T1 skin or
disease Clinical trial
u See Principles for Mycosis Fungoides/Sézary Syndrome (MFSS/INTRO-1) and General Considerations for the Treatment of Patients with MF and SS (MFSS-A 1 of 12).
v In rare cases of confirmed unilesional MF, RT has been shown to provide long-term remission.
w Rebiopsy if LCT is suspected; if histologic evidence of LCT, see MFSS-12.
x Patients with disease achieving a clinical benefit and/or those with disease responding to primary treatment should be considered for maintenance or tapering of
regimens to optimize response duration.
y See Principles of Radiation Therapy (PCLYM-A).

MFSS-6

Table of Contents
STAGEu TREATMENT AND RESPONSE ASSESSMENTz

(MFSS-3 and MFSS-4)
Relapse with low skin
disease burden
Lower skin CR/PRx Relapse with high skin disease burden (see below)
disease See Table 2: Stage IB MF Treatment based on
burden (eg, (skin only disease with clinical stage. See
predominantly ≥10% BSA) – Stage IIA MF Progression to >stage IB–IIA
MFSS-4 for appropriate
patch disease) clinical stage
Inadequate
response
Stage IB (skin High skin disease burden (see below)
only disease
with ≥10% BSA) Relapse with T1–T2 disease
- Stage IIAw
CR/PRx
Treatment based on
Higher skin Relapse with >stage IB–IIA disease clinical stage. See
disease
See Table 2: Stage IB MF MFSS-4 for appropriate
burden (eg, Progression to >stage IB–IIA
(skin only disease with clinical stage
predominantly or
≥10% BSA) – Stage IIA MF
plaque Clinical trial
disease) or
Refractory disease to multiple TSEBTy (if not previously
Inadequate administered)
response previous therapies
or
or Manage as Stage IIB
- Generalized Tumor
Persistent T1–T2 skin disease Lesions (see MFSS-9).
z Imaging indicated when suspicious of clinical extracutaneous disease with modalities used in workup.

MFSS-7

Table of Contents

(MFSS-3 and
MFSS-4)
Relapse
• T1–2 limited tumor lesions See Table 1 or
See Table 2)
CR/PRx • T3 limited tumor lesions
Relapse with >stage IIB

Treatment based on
Limited tumor See Table 3: Stage IIB MF disease
clinical stage. See
lesions (Tumor stage disease)
Progression >stage IIB MFSS-4 for appropriate
disease clinical stage
or
Inadequate Refractory disease Manage as Stage IIB
Stage IIB to multiple previous - Generalized Tumor
(tumor stage response
therapies Lesions (see MFSS-9).
disease)w or
Persistent T1–T3 limited
tumor lesions
Generalized
See MFSS-9
tumor lesions

MFSS-8

Table of Contents

(MFSS-3 and
MFSS-4)
Relapse:
• T1–2 (See Table 1 or See Table 2)
• T3
CR/PRx
Relapse with >stage IIB Treatment based on
Stage IIB Generalized See Table 3: Stage IIB MF disease clinical stage. See
(tumor stage tumor (Tumor stage disease) MFSS-4 for appropriate
disease)w lesions Progression >stage IIB clinical stage
disease See Table 6 - Suggested
or regimens for MF with Large-
Inadequate Refractory disease Cell Transformation (LCT) or
response to multiple previous Table 7 - Relapsed/Refractory
therapies Disease Requiring Systemic
or Therapy
Persistent T1–T3 or
generalized tumor lesions Clinical trial
or
Consider allogeneic HCTaa
w Rebiopsy if LCT is suspected, if histologic evidence of LCT, see MFSS-12.
x Patients with disease achieving a clinical benefit and/or those with disease responding to primary treatment should be considered formaintenance or tapering of
aa Allogeneic HCT is associated with better outcomes in patients with disease responding to primary treatment prior to transplant. See Discussion for further details.

MFSS-9

Table of Contents

(MFSS-3 and
MFSS-4)
Relapse
CR/PRx
Relapse with >stage III

Stage III See Table 4: Stage III MF See MFSS-11
(erythrodermic (Erythrodermic Disease) Progression with
disease)w
>stage III
or Clinical trial
Inadequate or
response See Table 6 - Suggested Regimens
Refractory disease
to multiple for MF with Large-Cell Transformation
previous therapies (LCT) or Table 7 - Relapsed/Refractory
Disease Requiring Systemic Therapy
or or
Consider allogeneic HCT,aa as
Persistent disease appropriate
x Patients with disease achieving a clinical benefit and/or those with disease responding to primary treatment should be considered formaintenance or tapering of

MFSS-10

Table of Contents
STAGEu TREATMENT AND RESPONSE ASSESSMENTbb

(MFSS-3 and
MFSS-4)
Clinical trial
or
Sézary CR/PRx Relapse See Table 7: Suggested
syndrome Regimens for Relapsed/
(stage See Table 5: Sézary syndrome Persistent disease Refractory Disease Requiring
(Stage IVA1 or IVA2) or Systemic Therapy
IVA1 or Inadequate
IVA2) Refractory disease or
response to multiple previous Consider allogeneic HCTaa
therapies as appropriate
Stage IVw Retreat with

primary treatment
or
Repeat Clinical trial
CR/PRx Relapse or
Non-Sézary imaging Consider allogeneic HCT,aa
(stage IVA2) See Table 6: Suggested with as appropriate
or regimens for Non- modalities Clinical trial
Visceral Sézary (stage IVA2) or used in Refractory or
(stage IVB) Visceral/solid organ workup disease to See Table 7: Suggested
disease (stage IVB) disease (frequency multiple
Inadequate Regimens for Relapsed/
(solid organ) as clinically response previous Refractory Disease Requiring
indicated)bb therapies Systemic Therapy
or or
Persistent Consider allogeneic HCTaa
See Supportive Care for disease as appropriate
Patients MF/SS (MFSS-B)
u See Principles for Mycosis Fungoides/Sézary Syndrome (MFSS/INTRO-1) and

General Considerations for the Treatment of Patients with MF and SS (MFSS-A
1 of 12). aa Allogeneic HCT is associated with better outcomes in patients with disease
w Rebiopsy if LCT is suspected; if histologic evidence of LCT, see MFSS-12. responding to primary treatment prior to transplant. See Discussion for further details.
x Patients with disease achieving a clinical benefit and/or those with disease bb If disease in lymph nodes and/or viscera or suspicious of disease progression,
responding to primary treatment should be considered for maintenance or imaging indicated with modalities used in workup as clinically indicated based on
tapering of regimens to optimize response duration. distribution of disease.

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(MFSS-3 and
MFSS-4) • See Table 6 - Suggested
Regimens for MF with Large-Cell
CR/PRx Relapse Transformation (LCT) or Table
Consider RT to lesions 7 - Relapsed/Refractory Disease
with LCTy Requiring Systemic Therapy
Limited
and Refractory disease and concurrent management of
cutaneous
Concurrent management to multiple previous co-existing disease based on
lesions with LCT Inadequate
of co-existing disease therapies clinical stage (See MFSS-4)
based on clinical stage response • Consider allogeneic HCT,aa as
or
Persistent disease appropriate
• Clinical trial
LCT
Retreat with
primary treatment
or
Repeat Clinical trial
imaging CR/PRx Relapse or
Generalized with Consider allogeneic HCT,aa
See Table 6 - as appropriate
cutaneous or modalities
Suggested Regimens Refractory
extracutaneous used in Clinical trial
for MF with Large-Cell disease to
lesions with workup or
Transformation (LCT) multiple
LCT (frequency See Table 7 - Suggested Regimens
Inadequate previous
as clinically for Relapsed/Refractory Disease
response therapies
indicated) Requiring Systemic Therapy
or
or
See Supportive Care for
Persistent Consider allogeneic HSTaa as
Patients MF/SS (MFSS-B)
disease appropriate
u See Principles for Mycosis Fungoides/Sézary Syndrome (MFSS/INTRO-1) and General Considerations for the Treatment of Patients with MF and SS (MFSS-A 1 of
12).

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GENERAL CONSIDERATIONS FOR THE TREATMENT OF PATIENTS WITH MF AND SS

• Generally, skin-directed therapies and systemic therapy regimens that can often be tolerated for longer durations of therapy with lower rates
of cumulative toxicity, less immunosuppression, and/or higher efficacy are used in earlier lines of therapy before moving on to treatment
options that carry a higher risk of cumulative toxicity and/or immunosuppression.
• Therapies with lower side effect profiles and an absence of cumulative toxicity are often given in an ongoing or maintenance fashion to
improve and maintain disease control and quality of life.
• Systemic therapy is often combined with skin-directed therapy to maximize clinical responses in the skin compartment and to provide
additive efficacy without cumulative toxicities.
• Bexarotene, brentuximab vedotin, mogamulizumab, vorinostat, and romidepsin are approved by the U.S. Food and Drug Administration
(FDA) for the treatment of MF and SS. Other systemic therapies such as interferons (alfa and gamma), methotrexate, and other retinoids
(acitretin and isotretinoin) also offer clinical benefit but have only been evaluated in small studies.
• The optimal treatment for any patient at any given time is often individualized based on symptoms of disease, route of administration,
toxicities, and overall goals of therapy. Use of supportive care measures to minimize risk of skin infections and treat pruritus is an important
part of disease and symptom control (see MFSS-B).

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SUGGESTED REGIMENS: SKIN-DIRECTED THERAPIES
SKIN-LIMITED/LOCAL TREATMENT CONSIDERATIONS

(FOR LIMITED/LOCALIZED SKIN INVOLVEMENT)
• Local radiation (ISRT) 1. Skin-directed therapies can be used alone or in combination with other skin-directed
8–12 Gy; 24–30 Gy for unilesional presentation therapies.
• Phototherapy 2. Cumulative dose of UV, in particular PUVA, is associated with increased risk of UV-
UVB, Narrowband UVB (NB-UVB) associated skin neoplasms; thus, phototherapy use should be balanced against these
• Topical corticosteroids risks in patients with a history of extensive squamoproliferative skin neoplasms or basal
cell carcinomas or who have had melanoma.
• Topical imiquimod
• Topical mechlorethamine (nitrogen mustard) 3. TSEBT, and in certain cases PUVA or UVA1 may be considered for widespread thicker
plaques or tumors.
• Topical retinoids (bexarotene, tazarotene)
• Topical carmustine (category 2B) 4. RT (24–30 Gy) for unilesional lesions is given as monotherapy with curative intent. Low-
dose RT (8–12 Gy) is given with palliative intent (usually as combined modality therapy).
SKIN-GENERALIZED Some Member Institutions are exploring the use of lower dose options (eg, 4 Gy).
(FOR GENERALIZED SKIN INVOLVEMENT) 5. Optimal use of topical steroids is often dependent on lesion type and location of disease.
• Phototherapy This is best done in consultation with a dermatologist or physician with experience in
UVB or NB-UVB the use of topical steroids. In general, high-potency steroids may be less well-tolerated
intertriginous body areas or other areas such as the face. Potency of steroid and extent/
PUVA duration of skin treated can result in systemic absorption and/or skin atrophy.
UVA1 (if available)
6. Topical imiquimod can be considered (often in consultation with a dermatologist or
• Topical corticosteroids physician with experience in its safety and use) for areas with few patches/plaques/small
• Topical mechlorethamine (nitrogen mustard) tumors that are recalcitrant to treatment or on sun-damaged skin such as forearms, scalp,
• TSEBT (12–36 Gy) and face.
7. Topical mechlorethamine use, in particular gel preparation, can be complicated by
dermatitis and can result in skin irritation when used on face and intertriginous body
areas. Consider initiating at less than daily use to dermine tolerability. Slowly increase the
application of topical mechlorethamine to once daily five times per week.
8. Topical retinoids can cause skin irritation including redness, peeling, and dermatitis when
used on face and intertriginous body areas.
9. It is common practice to follow TSEBT with systemic therapies to maintain response.
There is limited safety data for the use of TSEBT in combination with systemic retinoids,
HDAC inhibitors (such as vorinostat or romidepsin), or mogamulizumab, or combining
phototherapy with vorinostat or romidepsin.

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TABLE 1: STAGE IA MF (Limited skin involvement alone; <10% BSA) - MFSS-6a,b
TREATMENT CONSIDERATIONS
SUGGESTED REGIMENS
(SEE ALSO GENERAL CONSIDERATIONS ON MFSS-A [1 of 12])
• Skin-directed therapies (alone or in combination with
other skin-directed therapies) [See Skin-Limited/Local (for 1. Stage IA MF most often can be treated with skin-directed therapies (alone or in
limited/localized skin involvement, MFSS-A 2 of 12)] combination with other skin-directed therapies).
OR 2. In patients with histologic evidence of FMF, skin disease may be less responsive
• Skin-directed therapy (Skin-Limited/Local) in to topical therapies.
combination with systemic therapy (in selected cases) 3. Systemic therapies (single agents or combination therapies) should be reserved
for patients with blood involvement or for whom skin-directed therapies do not
provide sufficient disease control or who have disease that is not amenable to
Preferred Regimens (alphabetical order) skin-directed therapy (eg, in regions where topical therapies are difficult to apply
• Systemic therapy + skin-directed therapy regularly).
Bexarotene
Interferon alfab 4. Alternative retinoids (acitretin or isotretinoin) could be considered in place of
bexarotene.
Methotrexate
• Combination therapy 5. In stage IA, ECP is primarily reserved for the uncommon stage IA patients with
Phototherapy + interferonb or retinoid low level blood involvement (B1).
6. Patients with disease achieving a clinical benefit and/or those with disease
Useful in Certain Circumstances (alphabetical order) responding to primary treatment should be considered for maintenance or
• Systemic therapy + skin-directed therapy tapering of regimens to optimize response duration.
Acitretin
Extracorporeal photopheresis (ECP)
Interferon gamma-1b
Isotretinoin
• Combination therapy
Phototherapy + ECP

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TABLE 2: STAGE IB MF (skin only disease with ≥10% BSA) – STAGE IIA MF - MFSS-7a,b,c
SUGGESTED REGIMENS
• Skin-directed therapies (alone or in combination with other skin- 1. Stage IB–IIA MF can be treated with skin-directed therapies (alone or in
directed therapies) combination with other skin-directed therapies).
Lower skin disease burden (eg, predominantly patch
Limited patches/plaques: Skin-directed therapy can be considered as
disease): Skin-Limited/Local (for limited/localized skin monotherapy.
involvement) Extensive skin involvement: Phototherapy may be given alone or in
Higher skin disease burden (eg, predominantly plaque combination with other skin-directed therapies. TSEBT maybe given alone or
disease): Skin-Generalized (for generalized skin involvement) in combination with topical corticosteroids.
OR 2. In patients with histologic evidence of FMF, skin disease may be less
• Systemic therapy + skin-directed therapy OR combination responsive to topical therapies.
therapies (in selected cases) 3. Systemic therapies (single agents or combination therapies) should be
considered for patients with extensive skin involvement, higher skin disease
Preferred Regimens (alphabetical order) burden, predominantly plaque disease, blood involvement, and/or inadequate
• Systemic therapy + skin-directed therapy response to skin-directed therapy.
Bexarotene 4. In the randomized ALCANZA trial (Prince HM, et al. Lancet 2017;390:555-
Brentuximab vedotin 566), brentuximab vedotin was more effective than methotrexate or
Interferon alfab bexarotene in patients with previously treated MF (≥ stage IB). Patients with
SS were excluded from the ALCANZA trial.
Methotrexate
Mogamulizumab 5. In the randomized MAVORIC trial (Lancet Oncol 2018;19:1192-1204),
mogamulizumab was more effective than vorinostat in patients with previously
Romidepsin treated MF (≥ stage IB) and SS. Responses were higher in patients with blood
Vorinostat involvement (stage III or stage IV disease) than those with stage IIB or stage
• Combination therapy IB/IIA disease. Patients with MF-LCT were excluded from the MAVORIC trial.
Phototherapy + interferonb or retinoid 6. Alternative retinoids (acitretin or isotretinoin) could be considered in place of
bexarotene.
Useful in Certain Circumstances (alphabetical order) 7. In stage IB/IIA, ECP is primarily reserved for patients with low-level blood
• Systemic therapy + skin-directed therapy involvement (B1).
Acitretin Liposomal doxorubicin
8. There is limited safety data for the use of TSEBT in combination with
Alemtuzumab (category 2B) (category 2B) systemic retinoids, HDAC inhibitors (such as vorinostat or romidepsin), or
Gemcitabine (category 2B) Pembrolizumab (category 2B) mogamulizumab, or combining phototherapy with vorinostat or romidepsin.
ECP Pralatrexate (category 2B) 9. Patients with disease achieving a clinical benefit and/or those with disease
Interferon gamma-1b responding to treatment should be considered for maintenance or tapering of
Isotretinoin regimens to optimize response duration.
Phototherapy + ECP
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TABLE 3: STAGE IIB MF (Tumor stage disease)a,b,c

LIMITED TUMOR DISEASE GENERALIZED TUMOR DISEASE
• Local RT and/or skin-directed • TSEBT
therapy OR 1. RT is preferred for limited tumor lesions. Topical therapies alone are
OR • Systemic therapy + skin-directed therapy often inadequate for tumor stage disease.
• Systemic therapy ± local RT OR 2. In patients with histologic evidence of FMF, skin disease may be less
• Combination therapies responsive to topical therapies.
Preferred Regimens
(alphabetical order) Preferred Regimens (alphabetical order) 3. Adjuvant systemic biologic therapy may be considered after TSEBT
• Bexarotene • Systemic therapy + skin-directed therapy for generalized tumor lesions to improve response duration.
• Brentuximab vedotin Bexarotene 4. In the randomized ALCANZA trial (Prince HM, et al. Lancet
• Interferon alfab Brentuximab vedotin 2017;390:555-566), brentuximab vedotin was more effective than
• Methotrexate Gemcitabine methotrexate or bexarotene in patients with previously treated MF (≥
• Mogamulizumab Interferon alfab stage IB). Patients with SS were excluded from the ALCANZA trial.
• Romidepsin Liposomal doxorubicin 5. In the randomized MAVORIC trial (Lancet Oncol 2018;19:1192-1204),
Methotrexate mogamulizumab was more effective than vorinostat in patients with
Other Recommended Mogamulizumab previously treated MF (≥ stage IB) and SS. Responses were higher
Regimens Pralatrexate in patients with blood involvement (stage III or stage IV disease) than
• Vorinostat Romidepsin those with stage IIB or stage IB/IIA disease. Patients with MF-LCT
were excluded from the MAVORIC trial.
Useful in Certain Phototherapy + interferonb or retinoid 6. Alternative retinoids (acitretin or isotretinoin) could be considered in
Circumstances (alphabetical Retinoid + interferon place of bexarotene.
order) Other Recommended Regimens 7. ECP may be more appropriate as systemic therapy in patients with
• Acitretin • Vorinostat some blood involvement (B1 or B2).
• ECP Useful in Certain Circumstances 8. There is limited safety data for the use of TSEBT in combination
• Interferon gamma-1b (alphabetical order) with systemic retinoids, HDAC inhibitors (such as vorinostat or
• Isotretinoin • Systemic therapy + skin-directed therapy romidepsin), or mogamulizumab, or combining phototherapy with
Acitretin vorinostat or romidepsin.
ECP 9. Patients with disease achieving a clinical benefit and/or those
Interferon gamma-1b with disease responding to treatment should be considered for
Isotretinoin maintenance or tapering of regimens to optimize response duration.
Phototherapy + ECP
ECP + interferonb or retinoid
ECP + interferonb + retinoid

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TABLE 4: STAGE III MF (Erythrodermic disease) - MFSS-10a,b,c,d
SUGGESTED REGIMENS
Preferred Regimens (alphabetical order)
• Systemic therapy + skin-directed therapy 1. In the randomized ALCANZA trial (Lancet 2017;390:555-566), brentuximab
Bexarotene vedotin was more effective than methotrexate or bexarotene in patients with
Brentuximab vedotin previously treated MF (≥ stage IB). Patients with SS were excluded from
ECP the ALCANZA trial.
Interferon alfab 2. In the randomized MAVORIC trial (Lancet Oncol 2018;19:1192-1204),
Methotrexate mogamulizumab was more effective than vorinostat in patients with
Mogamulizumab previously treated MF (≥ stage IB) and SS. Responses were higher in
Romidepsin patients with blood involvement (stage III or stage IV disease) than those
• Combination therapy with stage IIB or stage IB/IIA disease. Patients with MF-LCT were excluded
ECP + interferonb or retinoid from the MAVORIC trial.
ECP + interferonb + retinoid 3. Alternative retinoids (acitretin or isotretinoin) could be considered in place
Phototherapy + interferonb or retinoid of bexarotene.
Phototherapy + ECP 4. ECP may be more appropriate as systemic therapy in patients with some
Retinoid + interferonb blood involvement (B1 or B2).
Other Recommended Regimens 5. Phototherapy and TSEBT may be associated with increased toxicity in
• Vorinostat patients with erythroderma and modification is dose/schedule may be
considered.
Useful in Certain Circumstances (alphabetical order) 6. There is limited safety data for the use of TSEBT in combination with
• Systemic therapy + skin-directed therapy systemic retinoids, HDAC inhibitors (such as vorinostat or romidepsin), or
Acitretin mogamulizumab, or combining phototherapy with vorinostat or romidepsin.
Alemtuzumab 7. Patients with disease achieving a clinical benefit and/or those with disease
Gemcitabine responding to treatment should be considered for maintenance or tapering
Interferon gamma-1b of regimens to optimize response duration.
Isotretinoin 8. Patients with erythrodermic disease are at increased risk for secondary
Liposomal doxorubicin infection with skin pathogens and systemic antibiotic therapy should be
Pembrolizumab considered. See MFSS-B.
Pralatrexate
• Skin-directed therapy
Phototherapy
TSEBT (category 2B)

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TABLE 5: SÉZARY SYNDROME (Stage IVA1 or IVA2) - MFSS-11a,b,c,d

SUGGESTED REGIMENS TREATMENT CONSIDERATIONS
Low-Intermediate Burden High Burden (SEE ALSO GENERAL CONSIDERATIONS ON
(eg, ASC <5 K/mm3) (eg, ASC >5 K/mm3) MFSS-A [1 of 12])
Preferred Regimens (alphabetical order) Preferred Regimens (alphabetical order)
• Systemic therapy + skin-directed therapy • Systemic therapy + skin-directed therapy 1. In the randomized ALCANZA trial (Lancet
Bexarotene Mogamulizumab 2017;390:555-566), brentuximab vedotin was
ECP Romidepsin more effective than methotrexate or bexarotene in
Interferon alfab • Combination therapy patients with previously treated MF (≥ stage IB).
Methotrexate Phototherapy + ECP Patients with SS were excluded from the ALCANZA
Mogamulizumab Phototherapy + interferonb or retinoid trial.
Romidepsin ECP + interferonb or retinoid 2. In the randomized MAVORIC trial (Lancet Oncol
Vorinostat ECP + interferonb + retinoids 2018;19:1192-1204), mogamulizumab was more
• Combination therapy Retinoid + interferon effective than vorinostat in patients with previously
ECP + interferonb or retinoid treated MF (≥ stage IB) and SS. Responses were
ECP + interferonb + retinoids Other Recommended Regimens higher in patients with blood involvement (stage III
Phototherapy + ECP (alphabetical order) or stage IV disease) than those with stage IIB or
Phototherapy + interferonb or retinoid • Systemic therapy + skin-directed therapy stage IB/IIA disease. Patients with MF-LCT were
excluded from the MAVORIC trial.
Retinoid + interferon Alemtuzumab
Other Recommended Regimens Bexarotene 3. Alternative retinoids (acitretin or isotretinoin) could
(alphabetical order) Brentuximab vedotin be considered in place of bexarotene.
• Systemic therapy + skin-directed therapy ECP 4. There is limited safety data for the use of TSEBT
Alemtuzumab Gemcitabine in combination with systemic retinoids, HDAC
Brentuximab vedotin Interferon alfab inhibitors (such as vorinostat or romidepsin), or
Liposomal doxorubicin mogamulizumab, or combining phototherapy with
Gemcitabine vorinostat or romidepsin.
Liposomal doxorubicin Methotrexate
Pembrolizumab Pembrolizumab 5. Patients with disease achieving a clinical benefit
Pralatrexate Pralatrexate and/or those with disease responding to treatment
Useful in Certain Circumstances Vorinostat should be considered for maintenance or tapering
(alphabetical order) of regimens to optimize response duration.
• Systemic therapy + skin-directed therapy Useful in Certain Circumstances (alphabetical
Acitretin order)
Interferon gamma-1b • Systemic therapy + skin-directed therapy
Isotretinoin Acitretin
Interferon gamma-1b
Isotretinoin

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TABLE 6: STAGE IV MF (Non-Sézary/Visceral organ disease) AND MF WITH LARGE CELL TRANSFORMATION (MF-LCT)c,d,e
SUGGESTED REGIMENS
Non-Sézary (stage IVA2) or Visceral/Solid (SEE ALSO GENERAL CONSIDERATIONS ON MFSS-A [1 of 12])
MF-LCT (MFSS-12)
Organ (stage IVB) Disease (MFSS-11)
• Systemic therapy ± RT for local control • TSEBT 1. In the MAVORIC trial (Lancet Oncol 2018;19:1192-1204),
OR mogamulizumab was more effective than vorinostat in patients with
Preferred Regimens (alphabetical order) • Systemic therapy + skin directed previously treated MF and SS. Response rates were higher in the
• Brentuximab vedotin therapy blood compartment than in lymph nodes or viscera. Patients with MF-
• Gemcitabine LCT were excluded from the MAVORIC trial.
• Liposomal doxorubicin Preferred Regimens (alphabetical 2. There is limited safety data for the use of TSEBT in combination
• Pralatrexate order) with systemic retinoids, HDAC inhibitors (such as vorinostat or
romidepsin), or mogamulizumab, or combining phototherapy with
• Romidepsin • Brentuximab vedotin vorinostat or romidepsin.
• Gemcitabine
Other Recommended Regimens • Liposomal doxorubicin 3. In patients requiring chemotherapy, single agents are preferred
• Mogamulizumab • Pralatrexate over combination chemotherapy, due to the higher toxicity profiles
• Multiagent chemotherapy regimens associated with multi-agent regimens and the short-lived responses
• Romidepsin seen with time-limited combination chemotherapy.
(See TCEL-B 3 of 7 for regimens listed • Multiagent chemotherapy
for PTCL- NOS) regimens (See TCEL-B 3 of 7 for 4. Multiagent chemotherapy regimens are generally reserved for patients
regimens listed for PTCL-NOS) with relapsed/refractory or extracutaneous disease. Most patients are
treated with multiple single-agent systemic therapies before receiving
multiagent chemotherapy.
Other Recommended Regimens
• Pembrolizumab
TABLE 7: RELAPSED OR REFRACTORY DISEASE TO MULTIPLE PRIOR THERAPIES

SUGGESTED REGIMENS
Useful in Certain Circumstances (alphabetical order by category)
• Alemtuzumab
• Chlorambucil
• Cyclophosphamide
• Etoposide
• Pembrolizumab
• Pentostatin
• Temozolomide for CNS involvement at some NCCN Member Institutions
• Bortezomib (category 2B)
• Multiagent chemotherapy regimens (See TCEL-B 3 of 7 for regimens listed for PTCL-NOS)

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FOOTNOTES
a Laboratory studies for triglycerides, and thyroid function tests (with free thyroxine T4) are recommended for patients receiving bexarotene.
b Interferon alfa (2a and 2b) and peginterferon alfa-2b have been discontinued. Peginterferon alfa-2a may be substituted for other interferon preparations (Schiller M, et
al. J Eur Acad Dermatol Venerol 2017;31:1841-1847).
c In the ALCANZA trial, brentuximab vedotin was associated with superior clinical outcome in patients with previously treated CD30+ MF (CD30 positivity was defined as
CD30 expression in ≥10% of total lymphoid cells). In other clinical studies, clinical responses with BV have been reported across all CD30 expression levels including
negligible CD30 expression.
d Rapid progression has been reported in HTLV-positive patients receiving pembrolizumab. Disease flare is seen in some patients (especially in erythrodermic skin/
Sézary patients) and should be distinguished from disease progression (Khodadoust MS, et al. J Clin Oncol 2020:38:20-28).
e Lower doses of alemtuzumab administered subcutaneously have shown lower incidence of infectious complications. While alemtuzumab is no longer commercially
available, it may be obtained for clinical use. Recommend CMV monitoring or prophylaxis (See PCLYM-C).

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SUGGESTED TREATMENT REGIMENS

Skin-Directed Therapies REFERENCES
Topical corticosteroids UVA1
Zackheim HS, Kashani-Sabet M, Amin S. Topical corticosteroids for mycosis fungoides. Experience in 79 Trovato E, Pellegrino M, Filippi F, et al. Clinical and histological evaluation in patients with mycosis
patients. Arch Dermatol 1998;134:949-954. fungoides treated with UVA1. G Ital Dermatol Venereol 2020;155:306-311.
Zackheim HS. Treatment of patch stage mycosis fungoides with topical corticosteroids. Adışen E, Tektaş V, Erduran F, et al. Ultraviolet A1 phototherapy in the treatment of early mycosis
Dermatol Ther 2003;16:283-287. fungoides. Dermatology 2017;233:192-198.
Nitrogen mustard (mechlorethamine hydrochloride)
Olek-Hrab K, Silny W, Dańczak-Pazdrowska A, et al. Ultraviolet A1 phototherapy for mycosis
Kim YH, Martinez G, Varghese A, Hoppe RT. Topical nitrogen mustard in the management of mycosis
fungoides. Clin Exp Dermatol 2013;38:126-30.
fungoides: Update of the Stanford experience. Arch Dermatol 2003;139:165-173.
Lessin SR, Duvic M, Guitart J, et al. Topical chemotherapy in cutaneous T-cell lymphoma: positive results of a Jang MS, Jang JY, Park JB, et al. Erratum: Folliculotropic mycosis fungoides in 20 Korean cases:
randomized, controlled, multicenter trial testing the efficacy and safety of a novel mechlorethamine, 0.02%, Clinical and histopathologic features and response to ultraviolet A-1 and/or photodynamic therapy.
gel in mycosis fungoides. JAMA Dermatol 2013;149:25-32. Ann Dermatol 2018;30:510.
Local radiation Zane C, Leali C, Airò P, et al. "High-dose" UVA1 therapy of widespread plaque-type, nodular, and
Wilson LD, Kacinski BM, Jones GW. Local superficial radiotherapy in the management of minimal stage IA erythrodermic mycosis fungoides. J Am Acad Dermatol 2001;44:629-633.
cutaneous T-cell lymphoma (Mycosis Fungoides). Int J Radiat Oncol Biol Phys 1998;40:109-115. Total skin electron beam therapy (TSEBT)
Neelis KJ, Schimmel EC, Vermeer MH, et al. Low-dose palliative radiotherapy for cutaneous Chinn DM, Chow S, Kim YH, Hoppe RT. Total skin electron beam therapy with or without adjuvant
B- and T-cell lymphomas. Int J Radiat Oncol Biol Phys 2009;74:154-158. topical nitrogen mustard or nitrogen mustard alone as initial treatment of T2 and T3 mycosis
Thomas TO, Agrawal P, Guitart J, et al. Outcome of patients treated with a single-fraction dose of palliative
fungoides. Int J Radiat Oncol Biol Phys 1999;43:951-958.
radiation for cutaneous T-cell lymphoma. Int J Radiat Oncol Biol Phys 2013;85:747-753.
Ysebaert L, Truc G, Dalac S, et al. Ultimate results of radiation therapy for T1-T2 mycosis
Topical bexarotene
Breneman D, Duvic M, Kuzel T, et al. Phase 1 and 2 trial of bexarotene gel for skin directed treatment of fungoides. Int J Radiat Oncol Biol Phys 2004;58:1128-1134.
patients with cutaneous T cell lymphoma. Arch Dermatol 2002;138:325-332. Hoppe RT, Harrison C, Tavallaee M, et al. Low-dose total skin electron beam therapy as an effective
Heald P, Mehlmauer M, Martin AG, et al. Topical bexarotene therapy for patients with refractory modality to reduce disease burden in patients with mycosis fungoides: results of a pooled analysis
or persistent early stage cutaneous T cell lymphoma: results of the phase III clinical trial. J Am Acad from 3 phase-II clinical trials. J Am Acad Dermatol 2015;72:286-292.
Dermatol 2003;49:801-815. Morris S, Scarisbrick J, Frew J, et al. The results of low-dose total skin electron beam radiation
Tazarotene gel therapy (TSEB) in patients with mycosis fungoides from the UK Cutaneous Lymphoma Group. Int
Apisarnthanarax N, Talpur R, Ward S, et al. Tazarotene 0.1% gel for refractory mycosis fungoides lesions: an J Radiat Oncol Biol Phys 2018;99:627-633.
open-label pilot study. J Am Acad Dermatol 2004;50:600-607.
Topical imiquimod
Deeths MJ, Chapman JT, Dellavalle RP, et al. Treatment of patch and plaque stage mycosis fungoides with
imiquimod 5% cream. J Am Acad Dermatol 2005;52:275-280.
Phototherapy (UVB and PUVA)
Gathers RC, Scherschun L, Malick F, et al. Narrowband UVB phototherapy for early stage mycosis fungoides.
J Am Acad Dermatol 2002;47:191-197.
Querfeld C, Rosen ST, Kuzel TM, et al. Long term follow up of patients with early stage cutaneous T
cell lymphoma who achieved complete remission with psoralen plus UVA monotherapy. Arch Dermatol
2005;141:305-311.
Ponte P, Serrao V, Apetato M. Efficacy of narrowband UVB vs. PUVA in patients with early-stage mycosis
fungoides. J Eur Acad Dermatol Venereol 2010;24:716-721.
Olsen EA, Hodak E, Anderson T, et al. Guidelines for phototherapy of mycosis fungoides and Sézary
syndrome: A consensus statement of the United States Cutaneous Lymphoma Consortium. J Am Acad
Dermatol 2018;74:27-58.
Continued
Clinical Trials: NCCN believes that the best management of any patient with cancer is in a clinical trial. Participation in clinical trials is especially encouraged. MFSS-A
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REFERENCES
Systemic Therapies Awar O, Duvic M. Treatment of transformed mycosis fungoides with intermittent low-dose
Alemtuzumab for Sézary syndrome ± lymph node disease gemcitabine. Oncology 2007;73:130-135.
Lundin J, Hagberg H, Repp R, et al. Phase 2 study of alemtuzumab (anti-CD52 monoclonal antibody) in Interferon
patients with advanced mycosis fungoides/Sezary syndrome. Blood 2003;101:4267-4272. Olsen EA. Interferon in the treatment of cutaneous T-cell lymphoma. Dermatol Ther 2003;16:311-321.
Bernengo MG, Quaglino P, Comessatti A, et al. Low-dose intermittent alemtuzumab in the treatment Kaplan EH, Rosen ST, Norris DB, et al. Phase II study of recombinant human interferon gamma for
of Sezary syndrome: clinical and immunologic findings in 14 patients. Haematologica 2007;92:784- treatment of cutaneous T-cell lymphoma. J Natl Cancer Inst 1990;82:208-212.
794. Liposomal doxorubicin
Gautschi O, Blumenthal N, Streit M, et al. Successful treatment of chemotherapy-refractory Sezary Wollina U, Dummer R, Brockmeyer NH, et al. Multicenter study of pegylated liposomal doxorubicin in
syndrome with alemtuzumab (Campath-1H). Eur J Haematol 2004;72:61-63. patients with cutaneous T-cell lymphoma. Cancer 2003;98:993-1001.
Querfeld C, Mehta N, Rosen ST, et al. Alemtuzumab for relapsed and refractory erythrodermic Quereux G, Marques S, Nguyen J-M, et al. Prospective multicenter study of pegylated liposomal
cutaneous T-cell lymphoma: a single institution experience from the Robert H. Lurie Comprehensive doxorubicin treatment in patients with advanced or refractory mycosis fungoides or Sezary
Cancer Center. Leuk Lymphoma 2009;50:1969-1976. syndrome. Arch Dermatol 2008;144:727-733.
Bortezomib Dummer R, Quaglino P, Becker JC, et al. Prospective international multicenter phase II trial of
Zinzani PL, Musuraca G, Tani M, et al. Phase II trial of proteasome inhibitor bortezomib in patients intravenous pegylated liposomal doxorubicin monochemotherapy in patients with stage IIB, IVA,
with relapsed or refractory cutaneous T-cell lymphoma. J Clin Oncol 2007;25:4293-4297. or IVB advanced mycosis fungoides: final results from EORTC 21012. J Clin Oncol 2012;30:4091-
Brentuximab vedotin 4097.
Kim YH, Tavallaee M, Sundram U, et al. Phase II investigator-initiated study of brentuximab vedotin Methotrexate
in mycosis fungoides and Sezary syndrome with variable CD30 expression level: A multi-institution Zackheim HS, Kashani-Sabet M, Hwang ST. Low-dose methotrexate to treat erythrodermic cutaneous
collaborative project. J Clin Oncol 2015;33:3750-3758. T-cell lymphoma: results in twenty-nine patients. J Am Acad Dermatol 1996;34:626-631.
Prince HM, Kim YH, Horwitz SM, et al. Brentuximab vedotin or physician's choice in CD30-positive Zackheim HS, Kashani-Sabet M, McMillan A. Low-dose methotrexate to treat mycosis fungoides: a
cutaneous T-cell lymphoma (ALCANZA): an international, open-label, randomised, phase 3, retrospective study in 69 patients. J Am Acad Dermatol 2003;49:873-878.
multicentre trial. The Lancet 2018;390:555-566. Mogamulizumab
Extracorporeal photopheresis (ECP) Kim YH, Bagot M, Pinter-Brown L, et al. Mogamulizumab versus vorinostat in previously treated
Talpur R, Demierre MF, Geskin L, et al. Multicenter photopheresis intervention trial in early-stage cutaneous T-cell lymphoma (MAVORIC): An international, open-label, randomised, controlled phase
mycosis fungoides. Clin Lymphoma Myeloma Leuk 2011;11:219-227. 3 trial. Lancet Oncol 2018;19:1192-1204.
Knobler R, Duvic M, Querfeld C, et al. Long-term follow-up and survival of cutaneous T-cell lymphoma Pembrolizumab
patients treated with extracorporeal photopheresis. Photodermatol Photoimmunol Photomed Khodadoust MS, Rook AH, Porcu P, et al. Pembrolizumab in relapsed and refractory mycosis
2012;28:250-257. fungoides and Sezary syndrome: A multicenter phase II study. J Clin Oncol 2020;38:20-28.
Atilla E, Atilla PA, Bozdag SC, et al. Extracorporeal photochemotherapy in mycosis fungoides. Pentostatin
Transfus Clin Biol 2017;24:454-457. Cummings FJ, Kim K, Neiman RS, et al. Phase II trial of pentostatin in refractory lymphomas and
Gao C, McCormack C, van der Weyden C, et al. Prolonged survival with the early use of a novel cutaneous T-cell disease. J Clin Oncol 1991;9:565-571.
Greiner D, Olsen EA, Petroni G. Pentostatin (2'-deoxycoformycin) in the treatment of cutaneous T-cell
extracorporeal photopheresis regimen in patients with Sezary syndrome. Blood 2019;134:1346-1350.
lymphoma. J Am Acad Dermatol 1997;36:950-955.
Gemcitabine
Tsimberidou AM, Giles F, Duvic M, Fayad L, Kurzrock R. Phase II study of pentostatin in advanced
Duvic M, Talpur R, Wen S, et al. Phase II evaluation of gemcitabine monotherapy for cutaneous T-cell
T-cell lymphoid malignancies. Update on an M.D. Anderson Cancer Center Series. Cancer
lymphoma. Clin Lymphoma Myeloma 2006;7:51-58.
2004;100;342-349.
Marchi E, Alinari L, Tani M, et al. Gemcitabine as frontline treatment for cutaneous T-cell lymphoma:
Pralatrexate
phase II study of 32 patients. Cancer 2005;104:2437-2441.
Horwitz SM, Kim YH, Foss F, et al. Identification of an active, well-tolerated dose of pralatrexate in
Zinzani PL, Baliva G, Magagnoli M, et al. Gemcitabine treatment in pretreated cutaneous T-cell
patients with relapsed or refractory cutaneous T-cell lymphoma. Blood 2012;119:4115-4122.
lymphoma: experience in 44 patients. J Clin Oncol 2000;18:2603-2606.
Foss F, Horwitz SM, Coiffier B, et al. Pralatrexate is an effective treatment for relapsed or refractory
Zinzani PL, Venturini F, Stefoni V, et al. Gemcitabine as single agent in pretreated T-cell lymphoma
transformed mycosis fungoides: a subgroup efficacy analysis from the PROPEL study. Clin
patients: evaluation of the long-term outcome. Ann Oncol 2010;21:860-863.
Lymphoma Myeloma Leuk 2012;12:238-243.
Continued
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REFERENCES
Systemic Therapies (continued) Systemic + systemic
Romidepsin Straus DJ, Duvic M, Kuzel T, et al. Results of a phase II trial of oral bexarotene (Targretin) combined with
Piekarz RL, Frye R, Turner M, et al. Phase II multi-institutional trial of the histone deacetylase inhibitor interferon alfa 2b (Intron A) for patients with cutaneous T cell lymphoma. Cancer 2007;109:1799-1803.
romidepsin as monotherapy for patients with cutaneous T-cell lymphoma. J Clin Oncol 2009;27:5410-5417. Talpur R, Ward S, Apisarnthanarax N, et al. Optimizing bexarotene therapy for cutaneous T cell
Whittaker SJ, Demierre MF, Kim EJ, et al. Final results from a multicenter, international, pivotal study of
lymphoma. J Am Acad Dermatol 2002;47:672-684.
romidepsin in refractory cutaneous T-cell lymphoma. J Clin Oncol 2010; 28:4485-4491.
Retinoids Suchin KR, Cucchiara AJ, Gottleib SL, et al. Treatment of cutaneous T-cell lymphoma with combined
Zhang C, Duvic M. Treatment of cutaneous T-cell lymphoma with retinoids. Dermatol Ther 2006;19:264-271. immunomodulatory therapy: a 14-year experience at a single institution. Arch Dermatol 2002;138:1054-
Duvic M, Martin AG, Kim Y, et al. Phase 2 and 3 clinical trial of oral bexarotene (Targretin capsules) for the 1060.
treatment of refractory or persistent early-stage cutaneous T-cell lymphoma. Arch Dermatol 2001;137:581- Raphael BA, Shin DB, Suchin KR, et al. High clinical response rate of Sezary syndrome to
593. immunomodulatory therapies: prognostic markers of response. Arch Dermatol 2011;147:1410-1415.
Duvic M, Hymes K, Heald P, et al. Bexarotene is effective and safe for treatment of refractory advanced-
stage cutaneous T-cell lymphoma: multinational phase II-III trial results. J Clin Oncol 2001;19:2456-2471.
Temozolomide Allogeneic Hematopoietic Cell Transplant
Tani M, Fina M, Alinari L, et al. Phase II trial of temozolomide in patients with pretreated cutaneous T-cell de Masson A, Beylot-Barry M, Bouaziz J, et al. Allogeneic stem cell transplantation for advanced
lymphoma. Haematologica 2005;90:1283-1284. cutaneous T-cell lymphomas: a study from the French Society of Bone Marrow Transplantation and
Querfeld C, Rosen ST, Guitart J, et al. Multicenter phase II trial of temozolomide in mycosis fungoides/sezary French Study Group on Cutaneous Lymphomas. Haematologica 2014;99:527-534.
syndrome: correlation with O6-methylguanine-DNA methyltransferase and mismatch repair proteins. Clin Duarte R, Boumendil A, Onida F, et al. Long-term outcome of allogeneic hematopoietic cell
Cancer Res 2011;17:5748-5754. transplantation for patients with mycosis fungoides and Sézary syndrome: a European society for blood
Vorinostat and marrow transplantation lymphoma working party extended analysis. J Clin Oncol 2014;32:3347-
Duvic M, Talpur R, Ni X, et al. Phase 2 trial of oral vorinostat (suberoylanilide hydroxamic acid, SAHA) for
3348.
refractory cutaneous T-cell lymphoma (CTCL). Blood 2007;109:31-39.
Olsen EA, Kim YH, Kuzel TM, et al. Phase IIb multicenter trial of vorinostat in patients with persistent, Duarte RF, Schmitz N, Servitje O, Sureda A. Haematopoietic stem cell transplantation for patients with
progressive, or treatment refractory cutaneous T-cell lymphoma. J Clin Oncol 2007;25:3109-3115. primary cutaneous T-cell lymphoma. Bone Marrow Transplant 2008;41:597-604.
Duvic M, Olsen EA, Breneman D, et al. Evaluation of the long-term tolerability and clinical benefit of Hosing C, Bassett R, Dabaja B, et al. Allogeneic stem-cell transplantation in patients with cutaneous
vorinostat in patients with advanced cutaneous T-cell lymphoma. Clin Lymphoma Myeloma 2009;9:412-416. lymphoma: updated results from a single institution. Ann Oncol 2015;26:2490-2495.
Combination Therapies Iqbal M, Reljic T, Ayala E, et al. Efficacy of allogeneic hematopoietic cell transplantation in cutaneous
Skin-directed + systemic T-cell lymphoma: Results of a systematic review and meta-analysis. Biol Blood Marrow Transplant
Rupoli S, Goteri G, Pulini S, et al. Long term experience with low dose interferon alpha and PUVA in the 2020;26:76-82.
management of early mycosis fungoides. Eur J Haematol 2005;75:136-145. Johnson WT, Mukherji R, Kartan S, et al. Allogeneic hematopoietic stem cell transplantation in advanced
Kuzel T, Roenigk H Jr, Samuelson E, et al. Effectiveness of interferon alfa-2a combined with phototherapy stage mycosis fungoides and Sezary syndrome: a concise review. Chin Clin Oncol 2019;8:12.
for mycosis fungoides and the Sézary syndrome. J Clin Oncol 1995;13:257-263. Lechowicz M, Lazarus H, Carreras J, et al. Allogeneic hematopoietic cell transplantation for mycosis
McGinnis K, Shapiro M, Vittorio C, et al. Psoralen plus long wave UV A (PUVA) and bexarotene therapy: fungoides and Sezary syndrome. Bone Marrow Transplant 2014;49:1360-1365.
An effective and synergistic combined adjunct to therapy for patients with advanced cutaneous T cell Wu PA, Kim YH, Lavori PW, et al. A meta-analysis of patients receiving allogeneic or autologous
lymphoma. Arch Dermatol 2003;139:771-775. hematopoietic stem cell transplant in mycosis fungoides and Sezary syndrome. Biol Blood Marrow
Wilson LD, Jones GW, Kim D, et al. Experience with total skin electron beam therapy in combination with Transplant 2009;15:982-990.
extracorporeal photopheresis in the management of patients with erythrodermic (T4) mycosis fungoides. J
Am Acad Dermatol 2000;43:54-60.
Stadler R, Otte H-G, Luger T, et al. Prospective randomized multicenter clinical trial on the use of interferon
alpha -2a plus acitretin versus interferon alpha -2a plus PUVA in patients with cutaneous T-cell lymphoma
stages I and II. Blood 1998;92:3578-3581.

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SUPPORTIVE CARE FOR PATIENTS WITH MF/SS

Collaboration with dermatologist for supportive care is essential.
Pruritus Infections
• Assessment • Active or suspected infections
Pruritus should be assessed Cutaneous viral infections
Correlation between sites of disease and localization of pruritus ◊ High risk for skin dissemination of localized viral infections
may be useful in tailoring therapy herpes simplex virus (HSV)/varicella zoster virus (VZV).
For severe or persistent pruritus despite therapeutic response ◊ HSV prophylaxis with acyclovir or equivalent should be
considered for patients with frequent recurrence of HSV
other potential causes for pruritus should be investigated infection.
Erythroderma:
• Treatment ◊ Swab of skin, nares, or other areas for cultures of
Co-management with a dermatologist with expertise in skin care Staphylococcus aureus (S. aureus) infection or colonization
and CTCL ◊ Intranasal mupirocin for S. aureus carriers
Optimized skin-directed and systemic therapy for MF/SS ◊ Oral dicloxacillin or cephalexin
Mild, unscented soaps for bathing are gentle and optimal to ◊ Sulfamethoxazole/trimethoprim, doxycycline, minocycline,
prevent skin dryness or clindamycin if suspected methicillin-resistant
Moisturizers/emollients staphylococcus aureus (MRSA)
Topical steroid application (appropriate strength for body ◊ Vancomycin if no improvement or documented bacteremia
region) ± occlusion1 ◊ Bleach baths [1/2 cup of regular strength bleach (5%–6%) in
full tub of water] or for limited areas, soaks (1 tsp of bleach
Topical over-the-counter preparations
in a gallon of water). Bleach baths should be taken for 5 to 10
Systemic agents minutes two to three times a week maximum followed by tap
◊ First-line water to rinse off the bleach water. Moisturizer should be put
– H1 antihistamines; single agent or combination of on immediately following the bleach bath or soak.
antihistamines from different classes2 Ulcerated and necrotic tumors:
– Gabapentin3,4 ◊ Infection or colonization with Gram-negative rods should be
– Pregabalin considered in addition to the more common gram-positive
◊ Second-line organisms.
– Aprepitant5-8 ◊ Ulcer will not heal unless disease is treated. Consider local
– Mirtazapine4 RT if feasible.
– Selective serotonin reuptake inhibitors (SSRIs)9 • Prophylaxis
◊ Third-line Optimize skin barrier protection with moisturizing of skin
Consider mupirocin to the nares for S. aureus carriers
– Naltrexone10 Diluted bleach baths or soaks (if limited area) as noted above
– Systemic steroids Minimize use of central lines when possible
For patients receiving alemtuzumab, see PCLYM-C
Continued
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SUPPORTIVE CARE FOR PATIENTS WITH MF/SS

REFERENCES
1 Yosipovitch G, Szolar C, Hui XY, Maibach H. High-potency topical corticosteroid rapidly decrease histamine-induced itch but not thermal sensation and pain in
human beings. J Am Acad Dermatol 1996;35:118-120.
2 Eschler D, Klein PA. An evidence-based review of the efficacy of topical antihistamines in the relief of pruritus. J Drugs Dermatol 2010;9:992-997.
3 Matsuda KM, Sharma D, Schonfeld AR, Kwatra SG. Gabapentin and pregabalin for the treatment of chronic pruritus. J Am Acad Dermatol 2018;75:619-625.
4 Demierre MF, Taverna J. Mirtazapine and gabapentin for reducing pruritus in cutaneous T-cell lymphoma. Am Acad Dermatol 2006;55:543-544.
5 Jiménez Gallo D, Albarrán Planelles C, Linares Barrios M, et al. Treatment of pruritus in early-stage hypopigmented mycosis fungoides with aprepitant. Dermatol
Ther 2014;27:178-182.
6 Duval A, Dubertret L. Aprepitant as an antipruritic agent? N Engl J Med 2009;361:1415-1416.
7 Booken N, Heck M, Nicolay JP, et al. Oral apepritant in the therapy of refractory pruritus in erythrodermic cutaneous T-cell lymphomas. Br J Dermatol 2011;164:665–
667.
8 Ladizinski B, Bazakas A, Olsen EA. Aprepitant: A novel neurokinin-1 receptor/substance P antagonist as antipruritic therapy in cutaneous T-cell lymphoma. Am Acad
Dermatol 2012;67:E198-E199.
9 Ständer S, Böckenholt B, Schürmeyer-Horst F, et al. Treatment of chronic pruritus with the selective serotonin re-uptake inhibitors paroxetine and fluvoxamine:
results of an open-labelled, two-arm proof-of-concept study. Acta Derm Venereol 2009;89:45-51.
10 Brune A, Metze D, Luger T, Ständer S. Antipruritic therapy with the oral opioid receptor antagonist naltrexone. Open, non-placebo controlled administration in 133
patients. Hautarzt 2004;55:1130-1136.

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Table of Contents
Primary Cutaneous CD30+ T-Cell Lymphoproliferative Disorders Discussion
OVERVIEW & DEFINITION

• Primary cutaneous CD30+ T-cell lymphoproliferative disorders • Primary cutaneous ALCL (PC-ALCL)
(LPDs) represent a spectrum that includes primary cutaneous Represents about 8% of cutaneous lymphoma cases.a
anaplastic large cell lymphoma (ALCL), lymphomatoid papulosis Unlike systemic ALCL, PC-ALCL typically follows an indolent
(LyP), and “borderline” cases with overlapping clinical and course and although cutaneous relapses are common an excellent
histopathologic features.a,b,c prognosis is usually maintained.d,e
• Clinical correlation with histopathologic features is essential for Histologically characterized by diffuse, cohesive sheets of large
CD30-positive (in >75%) cells with anaplastic, pleomorphic, or
establishing the diagnosis of primary cutaneous CD30+ T-cell
immunoblastic appearance.a
LPDs; diagnosis cannot be made based on pathology review alone. Clinical features typically include solitary or localized nodules or
Differential Diagnosis tumors (often ulcerated); multifocal lesions occur in about 20%
• It is critical to distinguish CD30+ T-cell LPDs from other processes of cases. Extracutaneous disease occurs in about 10% of cases,
involving skin that may express CD30: usually involving regional lymph nodes.a Patches and plaques may
Systemic T-cell lymphomas (eg, ALCL, ATLL, PTCL); also be present and some degree of spontaneous remittance in
lesions may also be seen.
Other CD30+ cutaneous lymphomas such as mycosis fungoides
(MF), especially MF with large-cell transformation (LCT) • Lymphomatoid papulosis (LyP)
Benign disorders such as lymphomatoid drug reactions, LyP is included under the classification system for lymphomas
arthropod bites, viral infections, and others. (WHO-EORTC) but may be best classified as an LPD as it is a
• Lymphomatoid drug reactions have been linked with certain drugs frequently spontaneously regressing process.a
(eg, amlodipine, carbamazepine, cefuroxime, valsartan) and may be LyP has been reported to be associated with other lymphomas
associated with CD30+ atypical large cells in histology. such as MF, PC-ALCL, systemic ALCL, or Hodgkin lymphoma.f,g
• MF and primary cutaneous CD30+ T-cell LPD can coexist in the Lyp is histologically heterogeneous with large atypical anaplastic,
same patient. immunoblastic, or Hodgkin-like cells in a marked inflammatory
background;a several histologic subtypes can be defined based on
evolution of skin lesions.f
Lyp clinical features are characterized by chronic, recurrent,
spontaneously regressing papulonodular (grouped or generalized)
skin lesions.a,f
a Swerdlow SH, Harris NL, Jaffe ES, et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Revised 4th ed. Lyon, France: IARC; 2017.
b Vergier B, et al. Am J Surg Pathol 1998;22:1192-1202.
c Liu HL, et al. J Am Acad Dermatol 2003;49:1049-1058.
d Benner MF, Willemze R. Arch Dermatol 2009;145:1399-1404.
e Woo DK, et al. Arch Dermatol 2009;145:667-674.
f Kempf W, et al. Blood 2011;118:4024-4035.
g Due to overlapping immunophenotype and morphology, need to use caution to not diagnose CD30+ T-cell in lymph nodes as HL (Eberle FC, et al. Amer J Surg Pathol
2012;36:716-725).
See Diagnosis
Note: All recommendations are category 2A unless otherwise indicated. (PCTLD-1)
PCTLD/INTRO-1

Table of Contents
DIAGNOSISa
ESSENTIAL:
• Clinical presentation: see Overview and Definition (PCTLD/INTRO-1)
• Clinical pathologic correlation is essential • Cutaneous ALCL See Workup
• Complete skin examination for evidence of MF • LyP g (PCTLD-2)
• Biopsy of suspicious skin sites
Review of all slides with at least one paraffin block representative of the
tumor should be done by a pathologist with expertise in the diagnosis of
CTCLs. Rebiopsy if consult material in conjunction with the clinical picture is
nondiagnostic.
Biopsy of all types (punch, incisional, or excisional) of clinical lesions present
will aid in final diagnosis.
• Adequate immunophenotyping to establish diagnosisb,c on skin biopsy:
IHC may include: CD3, CD4, CD8, CD20, CD30, CD56, ALKd
USEFUL UNDER CERTAIN CIRCUMSTANCES:

• On skin biopsy, expanded IHC may include: CD2, CD5, CD7, CD25, TIA1,
granzyme B, perforin, IRF4/MUM1, EMA, TCRꞵ, TCRδ
• EBER-ISH
• Molecular analysis to detect clonal TCR gene rearrangements or other
assessment of clonalitya,e See NCCN Guidelines
• FISH: ALK and DUSP22 gene rearrangementsa CD30+ transformed
for Mycosis Fungoides
• Excisional or incisional biopsy of suspicious lymph nodes mycosis fungoides
(MFSS-1)
• Assessment of HTLV-1 serologyf is encouraged as results can impact therapy
a See Principles of Molecular Analysis in Cutaneous Lymphomas (PCLYM-B).

b See Use of Immunophenotyping/Genetic Testing in Differential Diagnosis of Mature B-Cell and NK/T-Cell Neoplasms (See NCCN Guidelines for B-Cell Lymphomas).
c Typical immunophenotype: CD30+ (>75% cells), CD4+ variable loss of CD2/CD5/CD3, CD8+ (<5%) cytotoxic granule proteins positive.
d ALK positivity and t(2;5) translocation is typically absent in PC-ALCL and LyP.
e Clonal TCR gene rearrangements alone are not sufficient for diagnosis, as these can also be seen in patients with non-malignant conditions.
Results should be
interpreted in the context of overall presentation. See Principles of Molecular Analysis in T-Cell Lymphomas (PCLYM-A).
f See map for prevalence of HTLV-1/2 by geographic region. HTLV-1 has been described in patients in non-endemic areas.
g LyP is not considered a malignant disorder; however, there is an association with other lymphoid malignancy (MF or PC-ALCL). Staging studies are done in LyP only if
there is suspicion of systemic involvement by an associated lymphoma.

PCTLD-1

Table of Contents
WORKUP
ESSENTIAL:
• History and complete physical examination including complete skin examination;h
palpation of peripheral lymph node regions;
liver or spleen enlargement Primary
• CBC with differential cutaneous ALCL
• Comprehensive metabolic panel See Primary
• LDH Treatment
• C/A/P CT with contrast or integrated whole body PET/CT (arms/legs included when (PCTLD-3)
disease assessment of entire body is needed)i Cutaneous
• Biopsy suspicious nodes:j,k,l Biopsy of enlarged lymph nodes or suspected extracutaneous ALCL with
Cutaneous sites (if biopsy of skin is not diagnostic). Excisional or incisional biopsy is preferred over core regional node
needle biopsy. An FNA biopsy alone is not sufficient for the initial diagnosis of lymphoma.
ALCL A core needle biopsy is not optimal but can be used under certain circumstances. In certain See NCCN
circumstances, when a lymph node is not easily accessible for excisional or incisional biopsy, Guidelines for
a combination of core needle biopsy and FNA biopsy in conjunction with appropriate ancillary T-Cell
techniques may be sufficient for diagnosis. Rebiopsy if consult material in conjunction with
the clinical picture is nondiagnostic. Systemic ALCL Lymphomas
USEFUL IN SELECTED CASES: - Peripheral
• Bone marrow aspiration and biopsy (optional for solitary C-ALCL or C-ALCL T-Cell
without extracutaneous involvement on imaging) (TCEL-1)
• Pregnancy testing in patients of childbearing potential if contemplating treatments
that are contraindicated in pregnancym
• Discussion of fertility and sperm banking, if fertility-impacting therapy is planned
ESSENTIAL: USEFUL IN SELECTED CASES:
• History and complete physical • Pregnancy testing in patients of childbearing potential if
examination including complete skin contemplating treatments that are contraindicated in pregnancym
examination;h palpation of peripheral • Discussion of fertility and sperm banking, if fertility-impacting See Primary
LyP g lymph node regions; therapy is planned Treatment for
liver or spleen enlargement • C/A/P CT with contrast or integrated whole body PET/CT (arms/ LyP (PCTLD-4)
• CBC with differential legs included when disease assessment of entire body is
• Comprehensive metabolic panel needed)g,i,n (not done for typical LyP)
• LDH • Bone marrow aspiration and biopsy (not done for typical LyP) g,n
g LyP is not considered a malignant disorder; however, there is an association with other k Consider systemic ALCL, regional lymph node involvement with PC-
lymphoid malignancy (MF or PC-ALCL). Staging studies are done in LyP only if there is ALCL, or lymph node involvement with transformed MF.
suspicion of systemic involvement by an associated lymphoma. l Consider PC-ALCL if in draining lymph nodes only.
h Monitoring the size and number of lesions will assist with response assessment.
i Patients with T-cell lymphomas often have extranodal disease, which may be inadequately m Many skin-directed and systemic therapies are contraindicated
imaged by CT. PET scan may be preferred in these instances. or are of unknown safety in pregnancy. Refer to individual drug
j Due to overlapping immunophenotype and morphology, need to use caution to not diagnose information.
CD30+ T-cell in lymph nodes as HL (Eberle F, et al. Amer J Surg Pathol 2012;36:716-725). n Only done to exclude an associated lymphoma.

PCTLD-2

Table of Contents
SUBTYPE EXTENT OF PRIMARY FOLLOW-UPx RELAPSED/REFRACTORY

DISEASE TREATMENTq DISEASE
• Retreat with initial treatment
Observe for if disease confined to skin
Solitary or ISRTr Responsey
recurrence • For multifocal lesions or
grouped or
lesions Surgical excisions ± ISRTr No response/ extracutaneous involvement,
See Multifocal see below
refractory lesions below
Primary disease
cutaneous Preferred regimen
ALCLo • Brentuximab vedotint Observe for
Responsey
recurrence
Other recommended regimens ±
Multifocal skin-directed therapies (see MFSS-A)
lesions • Methotrexate (≤50 mg weekly)
• Systemic retinoidsu • Clinical trial
• Pralatrexate • Treat with same regimen
• Observation, if asymptomatic No response/ (unless refractory or
• Interferonv (category 3) refractory disease intolerant)
• Alternative regimen not used
Preferred regimens for primary treatment
• Brentuximab vedotint ± ISRTr
• ISRTr,w in selected cases • Treat with Systemic Therapies
Cutaneous ALCL with Other recommended regimens Observe for for Large-Cell Transformation
• Brentuximab vedotint + Responsey
regional nodep (N1) (See recurrence (LCT) (Table 6 - Suggested
CHP (cyclophosphamide, Regimens for MF with LCT)
CUTB-A for N definition) doxorubicin, and prednisone)
(excludes systemic ALCL) • Methotrexate ± ISRTr,w No response/
• Pralatrexate ± ISRTr,w refractory disease
• CHOP or CHOEP ± ISRTr,w in
selected cases
o Regression of lesions may occur in up to 44% of cases. w ISRT to include lymph node(s) ± primary skin lesions.
p Biopsy-proven lymphoma in lymph node. x Mycosis fungoides can develop over time; continue to
q See Therapy References (PCTLD-A). conduct thorough skin exam during
r See Principles of Radiation Therapy (PCLYM-A). follow-up.
y Patients with a clinical benefit and/or those with disease responding to primary treatment
s Small lesions may be excised with minimal non-disfiguring surgery.
should be considered for maintenance or tapering of regimens to optimize response
t See Supportive Care for Patients with Cutaneous Lymphomas duration. Relapsed disease often responds well to the same treatment. Partial response
(PCLYMP-C). should be treated with other primary treatment options not received before to improve
u Limited data from case reports (eg, bexarotene). response before moving onto treatment for refractory disease. Patients with disease
v Peginterferon alfa-2a may be substituted for other interferon preparations. relapse or persistent disease after initial primary treatment may be candidates for clinical
Schiller M, et al. J Eur Acad Dermatol Venerol 2017;31:1841-1847. trials.

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SUBTYPE EXTENT OF PRIMARY TREATMENTq FOLLOW-UPbb RELAPSED/REFRACTORY DISEASE

DISEASE
Continue current
Observation Responsey
management
Limited lesions, (preferred)
asymptomatic or
Topical steroids
Alternative regimen not used for
primary treatment
Topical steroids No response/refractory or
or disease Other regimens
Limited lesions,
Phototherapyz or
symptomatic
or Clinical trial
LyP Observation
Clinical trial
Observation (preferred for or
asymptomatic) Observe Observation
or Responsey for or
Methotrexate (10–35 mg weeklyaa) recurrence Retreat with primary
or treatment or treat Refractory
Phototherapyz with alternative disease
Extensive lesions or regimen not
Systemic retinoidsu used for primary
or No response/
treatment
Topical steroids refractory disease
or
Topical mechlorethamine Clinical trial Clinical trial
(nitrogen mustard) or or
q See Therapy References (PCTLD-A).
Alternative regimen not used Brentuximab
t See Supportive Care for Patients with Cutaneous Lymphomas (PCLYMP-C).
u Limited data from case reports (eg, bexarotene).
for primary treatment vedotint
y Patients with a clinical benefit and/or those with disease responding to primary
treatment should be considered for maintenance or tapering of regimens to optimize
response duration. Relapsed disease often responds well to the same treatment. Partial response should be treated with the other primary treatment options not
received before to improve response before moving onto treatment for refractory disease. Patients with disease relapse or persistent disease after initial primary
treatment may be candidates for clinical trials.
z NB-UVB is generally preferred over PUVA.
aa Kempf W, et al. Blood 2011;118:4024-4035.
bb Life-long follow-up is warranted due to high risk for second lymphoid malignancies; continue to conduct thorough skin exam during follow-up.

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THERAPY REFERENCES
Skin-Directed Therapies Systemic Therapies
Topical steroids Brentuximab vedotin
Paul MA, Krowchuk DP, Hitchcock MG, et al. Lymphomatoid papulosis: Duvic M, Tetzlaff MT, Gangar P, et al. Results of a phase II trial of brentuximab vedotin for CD30+
successful weekly pulse superpotent topical corticosteroid therapy in three cutaneous T-cell lymphoma and lymphomatoid papulosis. J Clin Oncol 2015; 33:3759-3765.
pediatric patients. Pediatr Dermatol 1996;13:501-506. Broccoli A, Derenzini E, Pellegrini C, et al. Complete response of relapsed systemic and cutaneous
Phototherapy anaplastic large cell lymphoma using brentuximab vedotin: 2 case reports. Clin Lymphoma Myeloma
Wantzin GL, Thomsen K. PUVA-treatment in lymphomatoid papulosis. Br J Leuk 2013;13:493-495.
Dermatol 1982;107:687-690. Mody K, Wallace JS, Stearns DM, et al. CD30+ cutaneous T cell lymphoma and response to
Topical nitrogen mustard brentuximab vedotin: 2 illustrative cases. Clin Lymphoma Myeloma Leuk 2014;13:319-323.
Vonderheid EC, Tan ET, Kantor AF, et al. Long-term efficacy, curative potential, Desai A, Telang GH, Olszewski AJ. Remission of primary cutaneous anaplastic large cell lymphoma
and carcinogenicity of topical mechloethamine chemotherapy in cutaneous T after a brief course of brentuximab vedotin. Ann Hematol 2013;92:567-568.
cell lymphoma. J Am Acad Dermatol 1989;20:416-428. Brentuximab vedotin + CHP (cyclophosphamide, doxorubicin, and prednisone)
Radiation therapy Horwitz S, O'Connor OA, Pro B, et al. Brentuximab vedotin with chemotherapy for CD30-positive
Million L, Yi EJ, Wu F, et al. Radiation therapy for primary cutaneous anaplastic peripheral T-cell lymphoma (ECHELON-2): a global, double-blind, randomised, phase 3 trial. Lancet
large cell lymphoma: An International Lymphoma Radiation Oncology Group 2019;393:229-240.
Multiinstitutional Experience. Int J Radiat Oncol Biol Phys 2018;95:1454- Interferons
1459. Proctor SJ, Jackson GH, Lennard AL, et al. Lymphotoid papulosis: response to treatment with
Specht L, Dabaja B, Illidge T, et al. Modern radiation therapy for primary recombinant interferon alfa-2b. J Clin Oncol 1992;10:170.
cutaneous lymphomas: field and dose guidelines from the International Schmuch M, Topar G, Illersperger B, et al. Therapeutic use of interferon-alpha for lymphomatoid
Lymphoma Radiation Oncology Group. Int J Radiat Oncol Biol Phys papulosis. Cancer 2000;89:1603-1610.
2015;92:32-39. Methotrexate
Yu JB, McNiff JM, Lund MW, et al. Treatment of primary cutaneous CD30+ Everett MA. Treatment of lymphomatoid papulosis with methotrexate. Br J Dermatol 1984;111:631.
anaplastic large cell lymphoma with radiation therapy. Int J Radiat Oncol Biol Vonderheid EC, Sajjadian A, Kaden ME. Methotrexate is effective for lymphomatoid papulosis and
Phys 2008;70:1542-1545. other primary cutaneous CD30+ lymphoproliferative disorders. J Am Acad Dermatol 1996;34:470-481.
Fujita H, Nagatani T, Miyazawa M, et al. Primary cutaneous anaplastic large cell lymphoma
successfully treated with low-dose methotrexate. Eur J Dermatol 2008;18:360-361.
Pralatrexate
Horwitz SM, Kim YH, Foss F, et al. Identification of an active, well-tolerated dose of pralatrexate in
patients with relapsed or refractory cutaneous T cell lymphoma. Blood 2012;119:4115-4122.
Systemic retinoids
Nakamura S, Hashimoto Y, Nishi K, et al. Primary cutaneous CD30+ lymphoproliferative disorder
successfully treated with etretinate. Eur J Dermatol 2012;22:709-710.
Krathen RA, Ward S, Duvic M. Bexarotene is a new treatment option for lymphomatoid papulosis.
Dermatology 2003;206:142-147.
Wyss M, Dummer R, Dommann SN, et al. Lymphomatoid papulosis: treatment with recombinant
interferon alfa-2a and etretinate. Dermatology 1995;190:288-291.
Sheehy JM, Catherwood M, Pettengeil R, et al. Sustained response of primary cutaneous CD30+
anaplastic large cell lymphoma to bexarotene and photopheresis. Leuk Lymphoma 2009;50:1389-
1391.

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PRINCIPLES OF RADIATION THERAPYa

General Principles
• The general intent of RT is to treat the evident skin disease with adequate margin both circumferentially and in depth.
Target Volumes
• Involved-site radiation therapy (ISRT) for cutaneous lesions:
ISRT is recommended as the appropriate field for treating primary cutaneous lymphomas.
Planning to define the clinical target volume (CTV) may often only require a careful physical exam. However, when the depth of disease is
not evident or when disease extends around curved surfaces, treatment planning may be facilitated by ultrasound imaging or CT-based
simulation and planning. Incorporating other modern imaging like PET and MRI may enhance treatment volume determination in some
cases.
ISRT targets the site of skin involvement. The volume encompasses the clinically evident disease with adequate margins.
The visible or palpable disease defines the gross tumor volume (GTV) and provides the basis for determining the CTV. If using CT-based
planning, delineating tumor boundary with wire for CT simulation will guide treatment volumes. Concerns for questionable subclinical
disease and uncertainties in original imaging accuracy or localization will lead to expansion of the CTV and are determined individually
using clinical judgment but generally include a margin of 1–2 cm both circumferentially and in depth. The CTV need not be expanded into
intact bone.
The planning target volume (PTV) is an additional expansion of the CTV that accounts only for setup variations (see ICRU definitions).
The treatment plan is designed using conventional or 3-D conformal techniques using clinical treatment planning considerations of
coverage and dose reductions for organs at risk (OARs).
• ISRT for nodal disease:
See Principles of Radiation Therapy for T-Cell Lymphomas (Target Volumes: ISRT for nodal disease).
See Principles of Radiation Therapy for B-Cell Lymphomas (Target Volumes: ISRT for nodal disease).
• See NCCN Guidelines for Hodgkin Lymphoma - Radiation Dose Constraints.
a See references on PCLYM-A 3 of 3.

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PRINCIPLES OF RADIATION THERAPYa

General Dose Guidelines: (RT in conventional fraction sizes)
• PCMZL and PCFCL:
Optimal initial management for solitary/regional disease is with 24–30 Gy external beam radiation therapy (EBRT).
◊ Surface margins beyond area of clinically evident disease will vary depending on lesion size and body site and must take into account
dosimetry of the beam being used. Surface margins of 1.0–1.5 cm are generally adequate.
◊ Margins in depth should include the volume at risk for involvement.
◊ Generally, treatment with 6–9 MeV electrons (with surface bolus) provides an adequate depth of treatment. Alternatively, low-energy
x-rays (~100 Kv) may be used.
◊ Doses as low as 4 Gy are used occasionally, but data are limited regarding response and duration.
RT for relapsed disease: 4 Gy EBRT may be adequate.
• MF/SS
Treatment of individual plaques or tumors
◊ Optimal management for individual plaque and tumor lesions is with EBRT, 8–12 Gy; 8 Gy may be given in 1–2 fractions.
◊ For unilesional MF, 24–30 Gy.
◊ Surface margins beyond area of clinically evident disease will vary depending on lesion size and body site and must take into account
dosimetry of the beam being used. Surface margins of 1.0–1.5 cm are generally adequate.
◊ Margins in depth should include the volume at risk for involvement.
◊ Generally, treatment with 6–9 MeV electrons (with surface bolus) provides an adequate depth of treatment. Alternatively, low-energy
x-rays (~100 Kv) may be used.
◊ For certain body surfaces, higher energy photon fields and opposed-field treatment (with bolus) may be required.
Total skin electron beam therapy (TSEBT)
◊ A variety of techniques may be utilized to cover the entire cutaneous surface. Patients are generally treated in the standing position on
a rotating platform or with multiple body positions to ensure total skin coverage.
◊ The dose range is 12–36 Gy, generally 4–6 Gy per week. The advantage of lower total dose includes fewer short-term complications and
better ability to re-treat for relapsed disease.
◊ “Shadowed” areas may need to be supplemented with individual electron fields.
◊ Individual tumors may be boosted with doses of 4–12 Gy.
◊ For patients with recalcitrant sites after generalized skin treatment, additional local treatment may be needed.
• Primary cutaneous ALCL:

RT for curative treatment: 24–36 Gy
Palliative RT: 2 Gy x 2
Doses as low as 6 Gy are used occasionally, but data are limited regarding response and duration.
Treatment Modalities:
• Treatment with photons or electrons may all be appropriate, depending on clinical circumstances.
a See references on PCLYM-A 3 of 3.

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PRINCIPLES OF RADIATION THERAPY

REFERENCES
Akhtari M, Reddy JP, Pinnix CC, et al. Primary cutaneous B-cell lymphoma (non-leg type) has excellent outcomes even after very low dose radiation as single-modality
therapy. Leuk Lymphoma 2016;57:34-38.
Hoppe RT, Harrison C, Tavallaee M, et al. Low-dose total skin electron beam therapy as an effective modality to reduce disease burden in patients with mycosis
fungoides: results of a pooled analysis from 3 phase-II clinical trials. J Am Acad Dermatol 2015;72:286-292.
Million L, Yi EJ, Wu F, et al. Radiation therapy for primary cutaneous anaplastic large cell lymphoma: An International Lymphoma Radiation Oncology Group
Multiinstitutional Experience. Int J Radiat Oncol Biol Phys 2018;95:1454-1459.
Neelis KJ, Schimmel EC, Vermeer MH, et al. Low-dose palliative radiotherapy for cutaneous B- and T-cell lymphomas. Int J Radiat Oncol Biol Phys 2009;74:154-158.
Smith GL, Duvic M, Yehia ZA, et al. Effectiveness of low-dose radiation for primary cutaneous anaplastic large cell lymphoma. Adv Radiat Oncol 2017;2:363-369
Specht L, Dabaja B, Illidge T, et al. Modern radiation therapy for primary cutaneous lymphomas: field and dose guidelines from the International Lymphoma Radiation
Oncology Group. Int J Radiat Oncol Biol Phys 2015;92:32-39.
Thomas TO, Agrawal P, Guitart J, et al. Outcome of patients treated with a single-fraction dose of palliative radiation for cutaneous T-cell lymphoma. Int J Radiat Oncol
Biol Phys 2013;85:747-753.

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PRINCIPLES OF MOLECULAR ANALYSIS IN CUTANEOUS LYMPHOMASa

• Genetic testing, including high-throughput sequencing (HTS), array-based comparative genomic hybridization (CGH), next-generation
sequencing (NGS), karyotype, or FISH to detect somatic mutations or genetic abnormalities are often informative and in some cases essential
for an accurate and precise diagnostic and prognostic assessment of T-cell lymphomas.
T-Cell Antigen Receptor (TCR) Gene Rearrangements
• TCR gene rearrangement testing is recommended to support a diagnosis of T-cell lymphoma.
• Diseases:
PTCLs; MF/SS; primary cutaneous CD30+ T-cell LPDs; T-cell large granular lymphocytic (T-LGL) leukemia; T-cell prolymphocytic leukemia
(T-PLL); extranodal NK/T-cell lymphoma, nasal type; and hepatosplenic gamma-delta T-cell lymphoma
• Description:
TCR gene rearrangement is indicative of T-cell clonal expansion. The test targets the gamma and/or beta TCR genes using polymerase
chain reaction (PCR) methods with capillary or gel electrophoresis detection methods. Alternatively, HTS methods are increasingly utilized.
HTS methods are more sensitive, precise, and capable of providing a unique sequence of the T-cell clone, which allows for comparison and
confirmation of disease evolution and monitoring during remission. Clonal T-cell expansions can also be detected using V beta families in
blood or tissue with flow cytometry methods.
• Diagnostic value:
Clonal TCR gene rearrangements without cytologic histopathologic and immunophenotypic evidence of abnormal T-cell population does
not constitute a diagnosis of T-cell lymphoma since it can be identified in patients with non-malignant conditions. Conversely, a negative
result does not exclude the diagnosis of T-cell lymphoma, which occasionally may fail TCR amplification. Nonetheless, it often provides
essential information and increased precision for many of these complex diagnoses.
• Prognostic value:
Identification of clonal TCR gene rearrangement has no definitive established prognostic value; however, it could be helpful when used to
determine clinical staging or assess relapsed or residual disease.
ALK Gene Rearrangement

• A subset of CD30-positive ALCLs expresses anaplastic lymphoma kinase (ALK) by immunohistochemistry. ALK expression is often
associated with t(2;5)(p23;q35), leading to the fusion of nucleophosmin (NPM1) to ALK and resulting in a chimeric protein.
• Detection:
FISH using probes to ALK (2p23) or mRNA sequencing by HTS technologies
Targeted mRNA sequencing
The current WHO classification of ALCLs includes two entities distinguishing ALK-positive and ALK-negative variants.
Systemic ALK-positive ALCL with t(2,5) and ALK-negative ALCL with DUSP22 rearrangement (to a lesser extent) have been associated with
a favorable prognosis. ALK inhibition can be an effective therapeutic strategy.
a See References on PCLYM-B 3 of 3.

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PRINCIPLES OF MOLECULAR ANALYSIS IN CUTANEOUS LYMPHOMASa

DUSP22-IRF4 Gene Rearrangement
• Testing for DUSP22 rearrangement is considered if CD30-positive ALCL, ALK negative is diagnosed, and considered useful under certain
circumstances for the diagnosis of primary cutaneous CD30+ T-cell LPDs.
• Diseases:
PTCLs, primary cutaneous CD30+ T-cell LPDs
• Description:
DUSP22 (dual-specificity phosphatase 22) is a tyrosine/threonine/serine phosphatase that may function as a tumor suppressor. DUSP22
inactivation contributes to the development of PTCLs.
• Detection:
FISH using probes to DUPS22-IRF4 gene region at 6p25.3
• DUSP22 rearrangements are associated with a newly recognized variant of ALK-negative ALCL and a newly reported subtype of LyP.
ALCL, ALK negative with DUSP22 rearrangement has preliminarily been associated with a favorable prognosis; however, the impact of
this on choice of therapy is not currently known.
TP63 Rearrangement
• TP63 gene rearrangements encoding p63 fusion proteins define a subset of ALK-negative ALCL cases and are associated with aggressive
course in systemic ALCL.
• Detection:
FISH using probes to TP63 (3q28) and TBL1XR1/TP63
Targeted mRNA sequencing
• Disease:
ALK-negative ALCL
To identify ALK-negative ALCL cases associated with aggressive course
a See References on PCLYM-B 3 of 3.

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PRINCIPLES OF MOLECULAR ANALYSIS IN CUTANEOUS LYMPHOMAS

REFERENCES
Chiarle R, Voena C, Ambrogio C, et al. The anaplastic lymphoma kinase in the pathogenesis of cancer. Nat Rev Cancer 2008;8:11-23.
De Schouwer P, Dyer M, Brito-Babapulle V, et al. T-cell prolymphocytic leukemia: antigen receptor gene rearrangement and a novel mode of MTCP1-B1 activation. Br
J Haematol 2000;110:831-838.
Hu Z, Medeiros L, Fang L, et al. Prognostic significance of cytogenetic abnormalities in T-cell prolymphocytic leukemia. Am J Hematol 2017;92:441-447.
Morris SW, Kirstein M, Valentine M, et al. Fusion of a kinase gene, ALK, to a nucleolar protein gene, NPM, in non-Hodgkin’s Lymphoma. Science 1994;263:1281-
1284.
Odejide O, Weigert O, Lane A, et al. A targeted mutational landscape of angioimmunoblastic T-cell lymphoma. Blood 2014;123:1293-1296.
Pedersen M, Hamilton-Dutoit S, Bendix K, et al. DUSP22 and TP63 rearrangements predict outcome of ALK-negative anaplastic large cell lymphoma: a Danish cohort
study. Blood 2017;130:554-557.
Wada D, Law M, Hsi E, et al. Specificity of IRF4 translocations for primary cutaneous anaplastic large cell lymphoma: a multicenter study of 204 skin biopsies. Mod
Pathol 2011;24:596-605.

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SUPPORTIVE CARE FOR PATIENTS WITH CUTANEOUS LYMPHOMAS

For other immunosuppressive situations, see NCCN Guidelines for Prevention and Treatment of Cancer-Related Infections.
Monoclonal Antibody Therapy and Viral Reactivation
• Brentuximab vedotin (anti-CD30 antibody-drug conjugate)
Progressive multifocal leukoencephalopathy (PML):
◊ Caused by reactivation of the JC virus (JCV) and is usually fatal.
◊ Diagnosis made by PCR of cerebrospinal fluid (CSF) and in some cases brain biopsy.
◊ Clinical indications may include changes in behavior such as confusion, dizziness or loss of balance, difficulty talking or walking, and
vision problems.
◊ No known effective treatment.
• Alemtuzumab (anti-CD52 antibody therapy)
Cytomegalovirus (CMV) reactivation:
◊ The current appropriate management is controversial; some NCCN Member Institutions use ganciclovir (PO or IV) preemptively if viremia
is present, others only if viral load is rising.
◊ CMV viremia should be measured by quantitative PCR at least every 2 to 3 weeks.
Antiinfective prophylaxis
◊ Herpes simplex virus (HSV) prophylaxis with acyclovir or equivalent.
◊ PJP prophylaxis with sulfamethoxazole/trimethoprim or equivalent.
◊ Consider antifungal prophylaxis.
◊ Consultation with an infectious disease expert may be necessary. See NCCN Guidelines for Prevention and Treatment of Cancer-Related
Infections.
Adverse events associated with mogamulizumab
• Graft-Versus-Host Disease (GVHD): A retrospective study showed a particularly high risk of developing GVHD in patients proceeding to
allogeneic HCT within 50 days of mogamulizumab (Fuji S, et al. J Clin Oncol 2016;34:3426-3433).
• Drug Eruption: Mogamulizumab has been associated with a drug eruption that can clinically mimic CTCL. Skin biopsy is recommended to
distinguish progression of disease versus drug eruption (Chen L, et al JAMA Dermatology 2019;155:968-971; Hirotsu K, et al JAMA Dermatol
2021;157:700-707).
Pralatrexate-Induced Mucositisa,b,c
• Vitamin B12 (cyanocobalamin) at a dose of 1,000 mcg intramuscular to be started no more than 10 weeks prior to starting therapy with
pralatrexate and then every 8 to 10 weeks.
• Oral folic acid 1 to 1.25 mg daily to be started within 10 days of starting therapy and continuing for 30 days after the last dose of pralatrexate.
• Consider use of oral leucovorin 25 mg three times daily for two consecutive days (total of 6 doses), starting 24 hours after each dose of
pralatrexate.
a Mould DR, Sweeney K, Duffull SB, et al. A population pharmacokinetic and pharmacodynamic evaluation of pralatrexate in patients with relapsed or refractory non-
Hodgkin's or Hodgkin's lymphoma. Clin Pharmacol Ther 2009;86:190-196.
b Shustov AR, Shinohara MM, Dakhil SR, et al. Management of mucositis with the use of leucovorin as adjunct to pralatrexate in treatment of peripheral T-cell lymphomas
(PTCL) – Results from a prospective multicenter phase 2 clinical trial. Blood 2018;132:2910.
c Koch E, Story SK, Geskin LJ. Preemptive leucovorin administration minimizes pralatrexate toxicity without sacrificing efficacy. Leuk Lymphoma 2013;54:2448-2451.

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Classification
WHO-EORTC Classification for Primary Cutaneous Lymphomas (2018)
Cutaneous T-Cell Lymphomas
• Mycosis fungoides
Folliculotropic MF
Pagetoid reticulosis
Granulomatous slack skin
• Sézary syndrome
• Adult T-cell leukemia/lymphoma
• Primary cutaneous CD30+ T-cell lymphoproliferative disorders
Cutaneous anaplastic large cell lymphoma
Lymphomatoid papulosis
• Subcutaneous panniculitis-like T-cell lymphoma
• Extranodal NK/T-cell lymphoma, nasal type
• Chronic active EBV infection
• Primary cutaneous peripheral T-cell lymphoma, rare subtypes
Primary cutaneous gamma-delta T-cell lymphoma
CD8+ AECTCL (primary cutaneous aggressive epidermotropic CD8+ cytotoxic T-cell lymphoma) (provisional)
Primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder (provisional)
Primary cutaneous acral CD8+ T-cell lymphoma (provisional)
• Primary cutaneous peripheral T-cell lymphoma, NOS
Cutaneous B-Cell Lymphomas
• Primary cutaneous marginal zone lymphoma
• Primary cutaneous follicle center lymphoma
• Primary cutaneous DLBCL, leg type
• EBV+ mucocutaneous ulcer (provisional)
• Intravascular large B-cell lymphoma
With permission, Willemze R, Cerroni L, Kempf W, et al. The 2018 update of the WHO-EORTC classification for primary cutaneous lymphomas.
Blood 2019;133:1703-1714.
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NCCN Categories of Evidence and Consensus

Category 1 Based upon high-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2A Based upon lower-level evidence, there is uniform NCCN consensus that the intervention is appropriate.
Category 2B Based upon lower-level evidence, there is NCCN consensus that the intervention is appropriate.
Category 3 Based upon any level of evidence, there is major NCCN disagreement that the intervention is appropriate.
All recommendations are category 2A unless otherwise indicated.
NCCN Categories of Preference

Interventions that are based on superior efficacy, safety, and evidence; and, when appropriate,
Preferred intervention affordability.
Other recommended Other interventions that may be somewhat less efficacious, more toxic, or based on less mature data;
intervention or significantly less affordable for similar outcomes.
Useful in certain
Other interventions that may be used for selected patient populations (defined with recommendation).
circumstances
All recommendations are considered appropriate.
CAT-1
NCCN Guidelines Version 2.2022

Primary Cutaneous Lymphomas
This discussion corresponds to the NCCN Guidelines for Primary Cutaneous Lymphomas. Last updated: June 8, 2022.
Discussion
Table of Contents
Overview .............................................................................................................................................................................................................. MS-2
Primary Cutaneous B-Cell Lymphomas................................................................................................................................................................. MS-2
Mycosis Fungoides and Sézary Syndrome.......................................................................................................................................................... MS-15
Primary Cutaneous CD30+ T-Cell Lymphoproliferative Disorders ........................................................................................................................ MS-48
Version 2.2022 © 2022 National Comprehensive Cancer Network© (NCCN©), All rights reserved. NCCN Guidelines® and this illustration may not be reproduced in any form without the express written permission of NCCN.
MS-1

Overview PCDLBCL, leg type by an activated B-cell (ABC) phenotype.5 Thus, a

Primary cutaneous lymphomas (PCL) are a heterogenous group of germinal (or follicle) center phenotype and large cells in a skin lesion is
extranodal B-cell and T-cell non-Hodgkin lymphomas (NHL) originating in consistent with PCFCL with a diffuse population of large cells
and usually confined to the skin.1,2 In the Surveillance, Epidemiology, and (PCFCL-LC) and not with DLBCL.5 In nodal DLBCL, the GCB phenotype is
End Results (SEER) database population-based analysis of 3884 cases of associated with a better prognosis than the ABC phenotype.
PCL diagnosed in the United States from 2001 to 2005, the incidence of Immunohistochemical and GEP-based algorithms used to classify nodal
cutaneous B-cell lymphomas (CBCL) and cutaneous T-cell lymphomas DLBCL into GCB or non-GCB subtypes based on cell of origin (COO)
(CTCL) accounted for 29% and 71%, respectively.3 have also shown to be useful to distinguish PCFCL from PCDLBCL, leg
type.6-8 However, these algorithms may be of limited utility in the
The World Health Organization-European Organization for Research and differentiation of PC-DLBCL, leg type and PCFCL-LC.8 While all cases of
Treatment of Cancer (WHO-EORTC) classification for cutaneous PCFCL-LC were uniformly classified as GCB phenotype by both
lymphomas was first published in 2005 and was subsequently updated in immunohistochemical and GEP-based algorithms, the classification based
2018.1,2,4 The most common subtypes of PCL that are covered in the on COO was heterogenous in patients with PC-DLBCL, leg type.8
NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) are
listed below: Recent studies suggest that PCMZL can be divided into two subgroups
with different prognosis based on the immunoglobulin (Ig) heavy chain
• Cutaneous B-Cell Lymphomas usage, with the vast majority being CXCR3-negative and Ig class-switched
 Primary cutaneous marginal zone lymphoma (PCMZL); subtype (IgG, IgA, and IgE) and a small subset being CXCR3-positive and
 Primary cutaneous follicle center lymphoma (PCFCL); and IgM-positive.9-12 Emerging data suggest that Ig class-switched subtype
 Primary cutaneous diffuse large B-cell lymphoma, leg type may be categorized as a clonal chronic lymphoproliferative disorder due to
(PCDLBCL, leg type) its indolent disease course.12,13
• Cutaneous T-Cell Lymphomas
PCFCL and PCMZL are generally indolent or slow growing and both are
 Mycosis fungoides (MF) and Sézary syndrome (SS)
associated with excellent prognosis. PCFCL is more prevalent in the
 Primary cutaneous CD30+ T-cell lymphoproliferative disorders
scalp, face, and the forehead, whereas the trunk and extremities are the
(PCTLD)
most common sites for PCMZL.14,15 PCDLBCL, leg type is usually
Primary Cutaneous B-Cell Lymphomas aggressive, associated with a generally poorer prognosis (mainly due to
the higher frequency of extracutaneous relapses), and is found most
Primary cutaneous B-cell lymphomas (PCBCL) account for mainly three
commonly on the leg, although it can arise at other sites.14,15 In
subtypes: PCMZL, PCFCL, and PCDLBCL, leg type.1,4
retrospective series, PCFCL is the most common subtype of the
Gene expression profiling (GEP) studies have shown that PCFCL is cutaneous B-cell lymphomas, diagnosed in 57% of patients followed by
characterized by a germinal center B-cell (GCB) phenotype and PCMZL (24%–31%) and PCDLBCL, leg type (11%–19%).14,15 In a large
MS-2

Italian series of 467 patients with PCBCL, extracutaneous involvement Literature Search Criteria and Guidelines Update Methodology
eventually developed in 6% of patients with PCMZL, 11% with PCFCL, Prior to the update of this version of the NCCN Clinical Practice Guidelines
and 17% with PCDLBCL, leg type.14 The 5-year overall survival (OS) rate (NCCN Guidelines®) Primary Cutaneous Lymphomas, a literature search
was significantly higher for patients with PCMZL and PCFCL than for was performed to obtain key literature on PCBCL published since the
patients with PCDLBCL, leg type (97%, 96%, and 73%, respectively; P < previous Guidelines update, using the following search terms: cutaneous
.0001).14 In patients with PCMZL and PCFCL, the disease-free survival diffuse large B-cell lymphoma, cutaneous follicle center lymphoma, and
(DFS) and OS rates were significantly higher for patients with single cutaneous marginal zone lymphoma. The PubMed database was chosen
lesions compared with those with regional or disseminated lesions (5-year as it remains the most widely used resource for medical literature and
DFS, 62% vs. 44%; 5-year OS, 97% vs. 85%), whereas the difference in indexes peer-reviewed biomedical literature.
outcomes between single and regional or disseminated lesions was not
significant in patients with PCDLBCL, leg type (5-year DFS rate 55% vs. The search results were narrowed by selecting studies in humans
44%; 5-year OS rate 79% vs. 67% for single and regional or disseminated published in English. Results were confined to the following article types:
lesions, respectively).14 In the report from the Dutch Cutaneous Clinical Trial, Phase II; Clinical Trial, Phase III; Clinical Trial, Phase IV;
Lymphoma Registry that included 300 patients with PCBCL, the incidence Guideline; Randomized Controlled Trial; Meta-Analysis; Systematic
of extracutaneous relapse was 47% among patients with PCDLBCL, leg Reviews; and Validation Studies.
type compared to 11% and 9%, respectively, for patients with PCFCL and
PCMZL.15 The 5-year disease-specific survival rates in this series were The data from key PubMed articles deemed as relevant to these
95%, 98%, and 50% for PCFCL, PCMZL, and PCDLBCL, leg type guidelines have been included in this version of the Discussion section.
respectively. Recommendations for which high-level evidence is lacking are based on
the panel’s review of lower-level evidence and expert opinion.
In addition to the aforementioned subtypes, PCDLBCL, not otherwise
specified (PCDLBCL-NOS) with clinicopathologic features intermediate The complete details of the Development and Update of the NCCN
between PCFCL and PCDLBCL, leg type has also been described.16,17 In Guidelines are available at www.NCCN.org.
the 2005 WHO-EORTC classification, the term PCDLBCL-other was
Diagnosis
introduced to include rare cases of CBCL that could not be classified as
either PCDLBCL, leg type or PCFCL.4 The revised 2018 WHO-EORTC While the diagnosis of PCMZL is generally straightforward and
classification does not contain this separate category of PCDLBCL-other reproducible among pathologists, it is more difficult to distinguish between
and rare cases that cannot be classified as either PCDLBCL, leg type or PCFCL and PCDLBCL, leg type, partly because the cell size (large vs.
PCFCL should be given a diagnosis of PCDLBCL-NOS.1 small) is not a defining feature as it is in nodal B-cell lymphomas.
PCMZL are always negative for BCL6 and CD10, but are often
BCL2-positive.18 PCFCL is consistently BCL6-positive, whereas CD10 and
BCL2 are expressed in only a few cases with a follicular growth pattern
MS-3

and the detection of BCL2 rearrangement is generally associated with IgD, IgA, IgG, IgE and FOXP1 expression may also be helpful in
extracutaneous spread.19-21 distinguishing PCDLBCL, leg type from PCFCL.23,24,30 Epstein-Barr virus
(EBV)-positive mucocutaneous ulcer is also included as a new provisional
PCDLBCL, leg type tumors express CD20, IRF4/MUM1, FOXP1, and entity in the updated WHO-EORTC classification and in situ hybridization
BCL2; many cases express BCL6 and lack expression of CD10.5,6,15,22-24 for EBV-encoded nuclear RNA (EBER) may be useful under selected
PCDLBCL, leg type also has a high incidence of MYC rearrangements circumstances.1
and MYC rearrangements are not detected in PCFCL.25 In addition,
PCFCL is usually IRF4/MUM1-negative while PCDLBCL, leg type is A high prevalence of MYD88 L265P mutation has been reported in
usually IRF4/MUM1-positive and shows strong expression of FOXP1.23,24 patients with PCDLBCL, leg type and is associated with inferior clinical
Assessment of FOXP1 expression is helpful to distinguish PCDLBCL, leg outcomes.6,31 In a retrospective analysis of 61 patients (58 patients with
type from PCFCL since all cases of PCFCL are FOXP1-negative.24 interpretable results) diagnosed with PCDLBCL, leg type, MYD88 L265P
GEP-based algorithms and modified Hans immunohistochemical algorithm mutation was detected in 59% of patients.31 It was also associated with
including CD10 and MUM1 have been shown to be useful to distinguish shorter disease-specific survival and was an independent adverse
PCFCL from PCDLBCL, leg type with optimal diagnostic value without the prognostic factor for OS. The 3-year and 5-year disease-specific survival
need for BCL-6.6,7 rates for those with MYD88 L265P mutation were 66% and 60%,
respectively, compared to 85% and 72%, respectively, for patients with the
The diagnosis of PCBCL is established by adequate biopsy of skin wild-type allele. In the aforementioned report that evaluated the
lesions. Incisional, excisional, or punch biopsy is preferred to shave clinicopathologic and molecular characteristics of patients with PCFCL (25
biopsy, as PCBCL have primarily dermal infiltrates, often deep, which are patients) and PCDLBCL, leg type (32 patients), MYD88 L265P mutation
less well-sampled and can be missed by a shave biopsy. Review of the was detected only in patients with PCDLBCL, leg type (n = 22; 69%).6
slides by a pathologist with expertise in the diagnosis of PCBCL is These findings suggest that determination of MYD88 L265P mutation
recommended. Adequate immunophenotyping of the biopsy sample is status could be helpful to further distinguish PCDLBCL, leg type from
essential for the diagnosis of the exact subtype of PCBCL. In addition, PCFCL.
immunophenotyping is also useful to rule out cutaneous lymphoid
hyperplasia (also known as pseudolymphoma or lymphocytoma cutis)26-28 The t(14;18) translocation on FISH analysis has been observed only in a
and in the differential diagnosis of intravascular large B-cell lymphoma, small number of cases with PCFCL and the detection of a t(14;18)
which often manifests in skin and is associated with a poor prognosis.29 translocation suggests the presence of systemic follicular lymphoma
(FL).21,32 Cytogenetics or FISH to detect t(14;18) may be useful if systemic
The initial immunohistochemistry (IHC) panel should include CD20, CD3, FL is suspected. The feasibility of flow cytometric immunophenotyping of
CD5, CD10, BCL2, BCL6, and IRF4/MUM1. Under certain circumstances, skin biopsies for the assessment of B-cell clonality has been reported,
evaluation of additional immunohistochemical markers such as Ki-67, although it has not been widely used.28 If adequate biopsy material is
CD43, CD21, CD23, cyclin D1, and kappa/lambda may be useful to further
establish the lymphoma subtype. Additionally, assessment of surface IgM,
MS-4

available, IGH gene rearrangement studies or flow cytometry could be recommend that bone marrow biopsy be obtained for cutaneous
useful in determining B-cell clonality. lymphomas with intermediate to aggressive behaviors and should be
considered for cutaneous lymphomas with indolent behavior and when
Mantle cell lymphoma (MCL) is not a primary cutaneous lymphoma and there is any evidence of extracutaneous disease, as indicated by other
finding it in the skin requires a careful search for extracutaneous disease. staging assessments (eg, radiographic evidence or serologic clues such
Clinical presentation on the leg and blastoid cytology along with high as elevated monoclonal or polyclonal immunoglobulins).34 Senff et al
proliferative index and expression of BCL2, IRF4/MUM1, and IgM would evaluated 275 patients with histologic features consistent with marginal
often represent MCL with skin involvement.33 The use of cyclin D1 may be zone lymphoma (MZL; n = 82) or follicle center lymphoma (FCL; n = 193)
useful to differentiate PCMZL (negative for CD5 and cyclin D1) from MCL first presenting in the skin.38 Bone marrow involvement was seen in
(positive for CD5 and cyclin D1). approximately 11% of patients in the FCL group compared with 2% in the
MZL group. Among patients with FCL, a positive bone marrow was
Workup
associated with significantly worse prognosis compared with those with
The absence of extracutaneous disease at diagnosis is part of the skin lesions only; the 5-year OS rate was 44% and 84%, respectively.38
definition of primary CBCL. The initial workup is geared toward evaluating The guidelines recommend considering bone marrow biopsy for patients
extent of disease on the skin and seeking extracutaneous disease.34 with unexplained cytopenias or if there is a clinical suspicion of PCDLBCL,
leg type.
The initial workup should include a complete physical examination, a
comprehensive skin examination, complete blood cell (CBC) count with Treatment Options
differential, comprehensive metabolic panel and CT and/or PET/CT of the
Involved-site radiation therapy (ISRT) is very effective when used as
chest, abdomen, and pelvis. Peripheral blood flow cytometry will be useful
initial therapy as well as for cutaneous relapses in most patients with
in selected cases, if CBC demonstrates lymphocytosis. Imaging is
indolent PCBCL.39-43
effective in identifying systemic involvement in patients with indolent
CBCL.35 However, it can be omitted if clinically indicated in patients with In a retrospective study of 34 patients with PCBCL treated with RT,
low-grade indolent CBCL.36 PET/CT may have higher sensitivity in the 5-year relapse-free survival (RFS) rates ranged from 62% to 73% for
detection of both local and distant metastases than CT.37 However, this is PCFCL and PCMZL but were only 33% for patients with PCDLBCL, leg
not validated and the higher rates of false-positive findings can create type.40 The 5-year OS rate was 100% for PCFCL and PCMZL but was
confusion. 67% for PCDLBCL, leg type. Senff et al evaluated the outcome of 153
patients with PCBCL (25 with PCMZL; 101 with PCFCL; and 27 with
Bone marrow biopsy is essential for PCDLBCL, leg type, since this is an
PCDLBCL) who were initially treated with RT with a curative intent.41
aggressive lymphoma that will probably require systemic treatment;
Overall, 45% of patients had single lesions while localized or
however, it appears to have a more limited value in PCFCL and PCMZL,
disseminated lesions were seen in 43% and 12% of patients,
and may be considered only in selected patients.34,36,38 The International
respectively. Complete response (CR) was obtained in 151 of 153
Society for Cutaneous Lymphomas (ISCL) and the EORTC Task Force
MS-5

patients (99%). Relapse rates for PCMZL, PCFCL, and PCDLBCL, leg of initial therapy. In patients with PCDLBCL, leg type, the CR rate and
type were 60%, 29%, and 64%, and the 5-year disease-specific survival 5- and 10-year OS rates were 82%, 73%, and 47%, respectively.
rates were 95%, 97%, and 59%, respectively. The PCFCLs presenting PCDLBCL, leg type was associated with higher relapse rates (55%) and
on the legs also had a higher relapse rate (63%) and a lower 5-year higher incidences of extracutaneous spread (17%) — a higher relapse rate
disease-specific survival (44%) compared with PCFCLs occurring at was confirmed both for patients with single or regional lesions treated with
other sites (25% and 99%, respectively).41 RT and for patients with disseminated cutaneous involvement treated with
chemotherapy.14 In a retrospective analysis of 137 patients with PCMZL,
In another retrospective study of 42 patients with biopsy-proven PCFCL initial treatment with surgical excision, RT, or a combination of both
and PCMZL, RT resulted in CR in all patients.43 The 10-year RFS and resulted in a CR rate of 88% (93% for patients with solitary or localized
OS rates were 71% and 87%, respectively, for the entire cohort, after a disease and 71% for those with multifocal lesions).48 Although there were
median follow-up of 9.5 years. The 5-year RFS rate was higher for no significant differences in the rate of recurrences between the treatment
patients with trunk lesions and single lesions (89% and 84%, modalities, surgery alone was associated with more recurrences at the
respectively) compared to those with extra-trunk lesions and multiple initial site.
lesions (67% and 57%, respectively). Low-dose ISRT (4 Gy in 2 fractions)
is an effective treatment option for palliation of symptoms in patients with Rituximab monotherapy (intravenous50-54 and intralesional55-57) has been
persistent (initial) lesions or recurrent symptomatic disease.44 The results shown to be effective for PCMZL and PCFCL. Intravenous rituximab may
of a more recent retrospective study also showed that RT less than or be more effective for patients with multiple lesions that cannot be
equal to 12 Gy (4 Gy for relapsed disease) was equally effective as RT managed effectively with local therapy.50-54 In a retrospective analysis of
greater than 12 Gy in patients with indolent PCBCL (42 patients; 16 15 patients with indolent PCBCL, rituximab resulted in an overall response
patients had PCFCL).45 rate (ORR) of 87% (60% CR). The ORR was 100% for patients with
PCFCL and 60% for PCMZL. With a median follow-up of 36 months, the
ISRT and excision were also associated with higher response rates median duration of response was 24 months.53 In another series of 16
compared to chemotherapy in patients with indolent histologies, but were patients with PCBCL, 14 patients (88%) achieved a CR with rituximab
generally used for those with more limited disease; therefore, a direct monotherapy; 35% of these patients with CR eventually relapsed between
comparison cannot be made.14,46-49 In a large retrospective analysis by the 6 and 37 months.54 In an observational multicenter study conducted by the
Italian Study Group for Cutaneous Lymphomas involving 467 patients with Spanish Working Group on Cutaneous Lymphoma (17 patients with
PCBCL, the CR rate and the 5- and 10-year OS rates for all patients with PCMZL and 18 patients with PCFCL), intralesional rituximab induced CR
PCFCL and PCMZL who received first-line treatment (RT in 53%, with and partial response (PR) in 71% and 23% of patients, respectively, with a
total dose of 35–45 Gy; chemotherapy in 25%, mainly with CHOP; surgery median DFS of 114 weeks.55 The response rates were similar among
in 23%) were 92% to 95%, 96% to 97%, and 89% to 91%, respectively.14 patients with PCMZL and PCFCL. In a small series that evaluated the
The relapse rate was 44% to 47% and extracutaneous spread was efficacy of intravenous and intralesional rituximab in treatment of patients
observed in 6% to 11% of patients. Relapse rate did not vary by the type with PCMZL and PCFCL, although intralesional rituximab resulted in
MS-6

response rates similar to that of intravenous rituximab, within a 12-month PCMZL and PCFCL; however, the difference was not significant. Among
follow-up period, relapses were more frequent among patients treated with patients with T2/T3 lesions, there was a non-significant trend toward
intralesional rituximab.58 higher rate of recurrence for PCMZL than PCFCL (73% and 38%,
respectively).
Chemotherapy is effective for multifocal skin lesions in patients with
PCFCL or PCMZL.59-61 Additional imaging studies during the course of treatment are not needed
after negative initial staging for systemic involvement and clinical follow-up
Primary Cutaneous Marginal Zone Lymphoma and Primary without routine imaging may be appropriate for patients with PCMZL.35
Cutaneous Follicle Center Cell Lymphoma
PET/CT (preferred) or CT with contrast may be repeated at the end of
Because there are no data from randomized clinical trials, the treatment treatment for assessment of response and can be repeated if there is
recommendations included in the NCCN Guidelines are derived from the clinical suspicion of progressive disease. Extracutaneous disease should
management practices of patients with PCBCL at NCCN Member be managed according to FL as outlined in the NCCN Guidelines for
Institutions based on the limited data from retrospective analyses and B-Cell Lymphomas.
studies involving a small cohort of patients.
While PCMZL and PCFCL respond to initial therapy, disease relapse is
ISRT is the preferred treatment option for patients with solitary/regional common in the majority of patients with regional or generalized disease,
lesions (T1–T2).39-43 Excision or skin-directed therapy may be used in regardless of type of initial treatment. However, relapses are generally
selected cases. Several case reports have shown the effectiveness of confined to the skin in which case survival does not appear to be affected.
skin-directed therapy (steroids, imiquimod, and nitrogen mustard or
bexarotene gel) for patients with multifocal lesions.59,62-65 Interlesional Solitary or Regional Disease (T1–T2)
steroids have also been used in the management of PCFCL or PCMZL,
Initial Treatment
although only limited data are available.46,66,67 Systemic therapy (rituximab
ISRT (24–30 Gy; alone or in combination with excision) or excision alone
monotherapy or combination chemoimmunotherapy) is often more
is recommended as the initial treatment.39-41,45,47,48,69 Local ISRT is the
appropriate for those with generalized disease (skin only; T3).50-54,59-61
preferred initial treatment. Observation is an option when RT or excision is
In a retrospective analysis that assessed the efficacy of various treatment neither desired nor feasible (eg, lesions on the scalp where hair loss is a
modalities (55 patients; majority of patients had indolent PCBCL; 25 major concern). Skin-directed therapy (steroids, imiquimod, or nitrogen
patients with PCMZL and 24 patients with PCFCL), the type of treatment mustard or bexarotene gel) or intralesional steroids may be considered for
modality (skin-directed vs. definitive RT with or without systemic therapy) selected patients.
did not affect the time to first recurrence among patients with T1 and
Observation is recommended for patients with disease responding to initial
T2/T3 lesions.68 The rates of recurrence were higher for T2/T3 lesions
therapy, and those with refractory disease should be managed as
compared to T1 lesions (58% and 31%, respectively). The time to first
described for generalized disease below.
recurrence for T1 lesions was 33% and 29%, respectively, for patients with
MS-7

Treatment for Relapsed or Progressive Disease Primary Cutaneous Diffuse Large B-Cell Lymphoma, Leg Type
Patients with regional relapse should be treated with an alternate initial PCDLBCL, leg type has a poorer prognosis than other types of PCBCL
treatment option and those with generalized disease relapse confined to and is generally treated with more aggressive chemotherapy regimens
the skin should receive treatment options recommended for generalized used for systemic DLBCL as outlined in the NCCN Guidelines for B-Cell
disease at presentation. Low-dose RT (4 Gy) may be adequate for Lymphomas.
relapsed or refractory disease.44,45
RT alone is less often effective in patients with PCDLBCL. While these
Patients with extracutaneous relapse or those with cutaneous relapse that lesions do respond to RT, remissions are often short-lived and higher
is not responding to any of the initial treatment options should be managed rates of dissemination to extracutaneous sites may occur. The potential
according to the FL as outlined in the NCCN Guidelines for B-Cell utility of chemoimmunotherapy for the management of patients with
Lymphomas. PCDLBCL, leg type has been described in retrospective analyses and
case reports.70-75 Multiagent chemoimmunotherapy regimens have been
Generalized Disease (skin only; T3)
associated with excellent outcomes.73-75
Initial Treatment
Observation, skin-directed therapy, local ISRT (24–30 Gy) for palliation of In a retrospective multicenter study from the French Study Group on 60
symptoms, and intralesional steroids or rituximab are included as patients with PCDLBCL, leg type, patients treated with
treatment options. In patients with very extensive or symptomatic disease, anthracycline-containing chemotherapy and rituximab had a more
other combination chemotherapy regimens recommended for FL may be favorable short-term outcome, although no particular therapy (RT or
used.59-61 multiagent chemotherapy with or without rituximab) was significantly
associated with improved survival outcomes.70 Among 12 patients treated
Observation is recommended for patients with disease responding to initial with anthracycline-based chemotherapy with rituximab, the CR rate was
therapy, and those with refractory disease should be treated with an 92% compared to 62% for patients who received other therapies. The
alternate initial treatment option. 2-year OS rate for these two groups was 81% and 59%, respectively.
Treatment for Relapsed or Refractory Disease In a report from the French study group (115 patients), the 3- and 5-year
Patients with relapse localized to skin should be treated with an alternate survival rates were 80% and 74%, respectively, for patients who received
initial treatment option. multiagent chemotherapy with rituximab compared to 48% and 38%,
respectively, for patients who received less-intensive therapies.73 In more
Patients with extracutaneous relapse or those with cutaneous relapse that
recent retrospective analysis involving 28 patients with PCDLBCL, leg type
is not responding to any of the initial treatment options should be managed
treated in a single center, R-CHOP with ISRT resulted in significantly
according to the FL as outlined in the NCCN Guidelines for B-Cell
longer median PFS compared to R-CHOP without ISRT as front-line
Lymphomas.
therapy (58 vs. 14 months; P = .04).75
MS-8

References 9. van Maldegem F, van Dijk R, Wormhoudt TA, et al. The majority of
cutaneous marginal zone B-cell lymphomas expresses class-switched
1. Elder DE, Massi D, Scolyer RA, Willemze R. WHO Classification of Skin immunoglobulins and develops in a T-helper type 2 inflammatory
Tumours. 4th edition. Lyon, France: IARC Press; 2018. environment. Blood 2008;112:3355-3361. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/18687986.
2. Willemze R, Cerroni L, Kempf W, et al. The 2018 update of the
WHO-EORTC classification for primary cutaneous lymphomas. Blood 10. Edinger JT, Kant JA, Swerdlow SH. Cutaneous marginal zone
2019;133:1703-1714. Available at: lymphomas have distinctive features and include 2 subsets. Am J Surg
https://www.ncbi.nlm.nih.gov/pubmed/30635287. Pathol 2010;34:1830-1841. Available at:
3. Bradford PT, Devesa SS, Anderson WF, Toro JR. Cutaneous
lymphoma incidence patterns in the United States: a population-based 11. Kogame T, Takegami T, Sakai TR, et al. Immunohistochemical
study of 3884 cases. Blood 2009;113:5064-5073. Available at: analysis of class-switched subtype of primary cutaneous marginal zone
https://www.ncbi.nlm.nih.gov/pubmed/19279331. lymphoma in terms of inducible skin-associated lymphoid tissue. J Eur
Acad Dermatol Venereol 2019;33:e401-e403. Available at:
4. Willemze R, Jaffe ES, Burg G, et al. WHO-EORTC classification for https://www.ncbi.nlm.nih.gov/pubmed/31124191.
cutaneous lymphomas. Blood 2005;105:3768-3785. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/15692063. 12. Carlsen ED, Swerdlow SH, Cook JR, Gibson SE. Class-switched
Primary Cutaneous Marginal Zone Lymphomas Are Frequently
5. Hoefnagel JJ, Dijkman R, Basso K, et al. Distinct types of primary IgG4-positive and Have Features Distinct From IgM-positive Cases. Am J
cutaneous large B-cell lymphoma identified by gene expression profiling. Surg Pathol 2019;43:1403-1412. Available at:
Blood 2005;105:3671-3678. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31464711.
13. Gibson SE, Swerdlow SH. How I Diagnose Primary Cutaneous
6. Menguy S, Beylot-Barry M, Parrens M, et al. Primary cutaneous large Marginal Zone Lymphoma. Am J Clin Pathol 2020;154:428-449. Available
B-cell lymphomas: relevance of the 2017 World Health Organization at: https://www.ncbi.nlm.nih.gov/pubmed/32808967.
classification: clinicopathological and molecular analyses of 64 cases.
Histopathology 2019;74:1067-1080. Available at: 14. Zinzani PL, Quaglino P, Pimpinelli N, et al. Prognostic factors in
https://www.ncbi.nlm.nih.gov/pubmed/30715765. primary cutaneous B-cell lymphoma: the Italian Study Group for
Cutaneous Lymphomas. J Clin Oncol 2006;24:1376-1382. Available at:
7. Cretella P, Peluso AL, Picariello C, et al. Immunohistochemical https://www.ncbi.nlm.nih.gov/pubmed/16492713.
algorithms and gene expression profiling in primary cutaneous B-cell
lymphoma. Pathol Res Pract 2022;231:153804. Available at: 15. Senff NJ, Hoefnagel JJ, Jansen PM, et al. Reclassification of 300
https://www.ncbi.nlm.nih.gov/pubmed/35183824. primary cutaneous B-Cell lymphomas according to the new WHO-EORTC
classification for cutaneous lymphomas: comparison with previous
8. Schrader AMR, de Groen RAL, Willemze R, et al. Cell-of-origin classifications and identification of prognostic markers. J Clin Oncol
classification using the Hans and Lymph2Cx algorithms in primary 2007;25:1581-1587. Available at:
cutaneous large B-cell lymphomas. Virchows Arch 2022;480:667-675. https://www.ncbi.nlm.nih.gov/pubmed/17353548.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/35028710.
MS-9

16. Lucioni M, Berti E, Arcaini L, et al. Primary cutaneous B-cell lymphoma 23. Hoefnagel JJ, Mulder MM, Dreef E, et al. Expression of B-cell
other than marginal zone: clinicopathologic analysis of 161 cases: transcription factors in primary cutaneous B-cell lymphoma. Mod Pathol
Comparison with current classification and definition of prognostic 2006;19:1270-1276. Available at:
markers. Cancer Med 2016;5:2740-2755. Available at: https://www.ncbi.nlm.nih.gov/pubmed/16778825.
24. Espinet B, Garcia-Herrera A, Gallardo F, et al. FOXP1 molecular
17. Felcht M, Klemke CD, Nicolay JP, et al. Primary cutaneous diffuse cytogenetics and protein expression analyses in primary cutaneous large
large B-cell lymphoma, NOS and leg type: Clinical, morphologic and B cell lymphoma, leg-type. Histol Histopathol 2011;26:213-221. Available
prognostic differences. J Dtsch Dermatol Ges 2019;17:275-285. Available at: https://www.ncbi.nlm.nih.gov/pubmed/21154235.
at: https://www.ncbi.nlm.nih.gov/pubmed/30851152.
25. Schrader AMR, Jansen PM, Vermeer MH, et al. High Incidence and
18. Hoefnagel JJ, Vermeer MH, Jansen PM, et al. Bcl-2, Bcl-6 and CD10 Clinical Significance of MYC Rearrangements in Primary Cutaneous
expression in cutaneous B-cell lymphoma: further support for a follicle Diffuse Large B-Cell Lymphoma, Leg Type. Am J Surg Pathol
centre cell origin and differential diagnostic significance. Br J Dermatol 2018;42:1488-1494. Available at:
2003;149:1183-1191. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30113335.
http://www.ncbi.nlm.nih.gov/pubmed/14674895.
26. Baldassano MF, Bailey EM, Ferry JA, et al. Cutaneous lymphoid
19. de Leval L, Harris NL, Longtine J, et al. Cutaneous b-cell lymphomas hyperplasia and cutaneous marginal zone lymphoma: comparison of
of follicular and marginal zone types: use of Bcl-6, CD10, Bcl-2, and CD21 morphologic and immunophenotypic features. Am J Surg Pathol
in differential diagnosis and classification. Am J Surg Pathol 1999;23:88-96. Available at:
27. Leinweber B, Colli C, Chott A, et al. Differential diagnosis of cutaneous
20. Pham-Ledard A, Cowppli-Bony A, Doussau A, et al. Diagnostic and infiltrates of B lymphocytes with follicular growth pattern. Am J
prognostic value of BCL2 rearrangement in 53 patients with follicular Dermatopathol 2004;26:4-13. Available at:
lymphoma presenting as primary skin lesions. Am J Clin Pathol https://www.ncbi.nlm.nih.gov/pubmed/14726817.
2015;143:362-373. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/25696794. 28. Schafernak KT, Variakojis D, Goolsby CL, et al. Clonality assessment
of cutaneous B-cell lymphoid proliferations: a comparison of flow
21. Servitje O, Climent F, Colomo L, et al. Primary cutaneous vs cytometry immunophenotyping, molecular studies, and
secondary cutaneous follicular lymphomas: A comparative study focused immunohistochemistry/in situ hybridization and review of the literature. Am
on BCL2, CD10, and t(14;18) expression. J Cutan Pathol J Dermatopathol 2014;36:781-795. Available at:
29. Murase T, Yamaguchi M, Suzuki R, et al. Intravascular large B-cell
22. Kodama K, Massone C, Chott A, et al. Primary cutaneous large B-cell lymphoma (IVLBCL): a clinicopathologic study of 96 cases with special
lymphomas: clinicopathologic features, classification, and prognostic reference to the immunophenotypic heterogeneity of CD5. Blood
factors in a large series of patients. Blood 2005;106:2491-2497. Available 2007;109:478-485. Available at:
at: https://www.ncbi.nlm.nih.gov/pubmed/15947086. https://www.ncbi.nlm.nih.gov/pubmed/16985183.
MS-10

30. Koens L, Vermeer MH, Willemze R, Jansen PM. IgM expression on 37. Kumar R, Xiu Y, Zhuang HM, Alavi A.
paraffin sections distinguishes primary cutaneous large B-cell lymphoma, 18F-fluorodeoxyglucose-positron emission tomography in evaluation of
leg type from primary cutaneous follicle center lymphoma. Am J Surg primary cutaneous lymphoma. Br J Dermatol 2006;155:357-363. Available
Pathol 2010;34:1043-1048. Available at: at: https://www.ncbi.nlm.nih.gov/pubmed/16882175.
38. Senff NJ, Kluin-Nelemans HC, Willemze R. Results of bone marrow
31. Pham-Ledard A, Beylot-Barry M, Barbe C, et al. High frequency and examination in 275 patients with histological features that suggest an
clinical prognostic value of MYD88 L265P mutation in primary cutaneous indolent type of cutaneous B-cell lymphoma. Br J Haematol
diffuse large B-cell lymphoma, leg-type. JAMA Dermatol 2008;142:52-56. Available at:
39. Eich HT, Eich D, Micke O, et al. Long-term efficacy, curative potential,
32. Child FJ, Russell-Jones R, Woolford AJ, et al. Absence of the t(14;18) and prognostic factors of radiotherapy in primary cutaneous B-cell
chromosomal translocation in primary cutaneous B-cell lymphoma. Br J lymphoma. Int J Radiat Oncol Biol Phys 2003;55:899-906. Available at:
Dermatol 2001;144:735-744. Available at: https://www.ncbi.nlm.nih.gov/pubmed/12605967.
40. Smith BD, Glusac EJ, McNiff JM, et al. Primary cutaneous B-cell
33. Wehkamp U, Pott C, Unterhalt M, et al. Skin Involvement of Mantle lymphoma treated with radiotherapy: a comparison of the European
Cell Lymphoma May Mimic Primary Cutaneous Diffuse Large B-cell Organization for Research and Treatment of Cancer and the WHO
Lymphoma, Leg Type. Am J Surg Pathol 2015;39:1093-1101. Available at: classification systems. J Clin Oncol 2004;22:634-639. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/26034867. https://www.ncbi.nlm.nih.gov/pubmed/14966086.
34. Kim YH, Willemze R, Pimpinelli N, et al. TNM classification system for 41. Senff NJ, Hoefnagel JJ, Neelis KJ, et al. Results of radiotherapy in 153
primary cutaneous lymphomas other than mycosis fungoides and Sezary primary cutaneous B-Cell lymphomas classified according to the
syndrome: a proposal of the International Society for Cutaneous WHO-EORTC classification. Arch Dermatol 2007;143:1520-1526.
Lymphomas (ISCL) and the Cutaneous Lymphoma Task Force of the Available at: https://www.ncbi.nlm.nih.gov/pubmed/18087001.
European Organization of Research and Treatment of Cancer (EORTC).
Blood 2007;110:479-484. Available at: 42. Pedretti S, Urpis M, Leali C, et al. Primary cutaneous non-Hodgkin
https://www.ncbi.nlm.nih.gov/pubmed/17339420. lymphoma: results of a retrospective analysis in the light of the recent
ILROG guidelines. Tumori 2018;104:394-400. Available at:
35. Kheterpal MK, Dai J, Geller S, et al. Role of imaging in low-grade https://www.ncbi.nlm.nih.gov/pubmed/28218382.
cutaneous B-cell lymphoma presenting in the skin. J Am Acad Dermatol
2019;81:970-976. Available at: 43. De Felice F, Grapulin L, Pieroni A, et al. Radiation therapy in indolent
https://www.ncbi.nlm.nih.gov/pubmed/30703460. primary cutaneous B cell lymphoma: a single institute experience. Ann
Hematol 2018;97:2411-2416. Available at:
36. Vachhani P, Neppalli VT, Cancino CJ, et al. Radiological imaging and https://www.ncbi.nlm.nih.gov/pubmed/30094511.
bone marrow biopsy in staging of cutaneous B-cell lymphoma. Br J
Haematol 2019;184:674-676. Available at: 44. Neelis KJ, Schimmel EC, Vermeer MH, et al. Low-dose palliative
https://www.ncbi.nlm.nih.gov/pubmed/29468663. radiotherapy for cutaneous B- and T-cell lymphomas. Int J Radiat Oncol
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Biol Phys 2009;74:154-158. Available at: 52. Gellrich S, Muche JM, Wilks A, et al. Systemic eight-cycle anti-CD20
https://www.ncbi.nlm.nih.gov/pubmed/18834672. monoclonal antibody (rituximab) therapy in primary cutaneous B-cell
lymphomas--an applicational observation. Br J Dermatol
45. Akhtari M, Reddy JP, Pinnix CC, et al. Primary cutaneous B-cell 2005;153:167-173. Available at:
lymphoma (non-leg type) has excellent outcomes even after very low dose http://www.ncbi.nlm.nih.gov/pubmed/16029344.
radiation as single-modality therapy. Leuk Lymphoma 2016;57:34-38.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/25860237. 53. Morales AV, Advani R, Horwitz SM, et al. Indolent primary cutaneous
B-cell lymphoma: experience using systemic rituximab. J Am Acad
46. Senff NJ, Noordijk EM, Kim YH, et al. European Organization for Dermatol 2008;59:953-957. Available at:
Research and Treatment of Cancer and International Society for http://www.ncbi.nlm.nih.gov/pubmed/18817999.
Cutaneous Lymphoma consensus recommendations for the management
of cutaneous B-cell lymphomas. Blood 2008;112:1600-1609. Available at: 54. Valencak J, Weihsengruber F, Rappersberger K, et al. Rituximab
https://www.ncbi.nlm.nih.gov/pubmed/18567836. monotherapy for primary cutaneous B-cell lymphoma: response and
follow-up in 16 patients. Ann Oncol 2009;20:326-330. Available at:
47. Pashtan I, Mauch PM, Chen YH, et al. Radiotherapy in the https://www.ncbi.nlm.nih.gov/pubmed/18836086.
management of localized primary cutaneous B-cell lymphoma. Leuk
Lymphoma 2013;54:726-730. Available at: 55. Penate Y, Hernandez-Machin B, Perez-Mendez LI, et al. Intralesional
https://www.ncbi.nlm.nih.gov/pubmed/22916994. rituximab in the treatment of indolent primary cutaneous B-cell
lymphomas: an epidemiological observational multicentre study. The
48. Servitje O, Muniesa C, Benavente Y, et al. Primary cutaneous Spanish Working Group on Cutaneous Lymphoma. Br J Dermatol
marginal zone B-cell lymphoma: response to treatment and disease-free 2012;167:174-179. Available at:
survival in a series of 137 patients. J Am Acad Dermatol 2013;69:357-365. https://www.ncbi.nlm.nih.gov/pubmed/22356294.
56. Vakeva L, Ranki A, Malkonen T. Intralesional Rituximab Treatment for
49. Olszewska-Szopa M, Sobas M, Laribi K, et al. Primary cutaneous Primary Cutaneous B-cell Lymphoma: Nine Finnish Cases. Acta Derm
indolent B-cell lymphomas - a retrospective multicenter analysis and a Venereol 2016;96:396-397. Available at:
review of literature. Acta Oncol 2021;60:1361-1368. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26525093.
57. Eberle FC, Holstein J, Scheu A, et al. Intralesional anti-CD20 antibody
50. Heinzerling LM, Urbanek M, Funk JO, et al. Reduction of tumor burden for low-grade primary cutaneous B-cell lymphoma: Adverse reactions
and stabilization of disease by systemic therapy with anti-CD20 antibody correlate with favorable clinical outcome. J Dtsch Dermatol Ges
(rituximab) in patients with primary cutaneous B-cell lymphoma. Cancer 2017;15:319-323. Available at:
58. Kerl K, Prins C, Saurat JH, French LE. Intralesional and intravenous
51. Heinzerling L, Dummer R, Kempf W, et al. Intralesional therapy with treatment of cutaneous B-cell lymphomas with the monoclonal anti-CD20
anti-CD20 monoclonal antibody rituximab in primary cutaneous B-cell antibody rituximab: report and follow-up of eight cases. Br J Dermatol
lymphoma. Arch Dermatol 2000;136:374-378. Available at: 2006;155:1197-1200. Available at:
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59. Bekkenk MW, Vermeer MH, Geerts ML, et al. Treatment of multifocal 66. Perry A, Vincent BJ, Parker SR. Intralesional corticosteroid therapy for
primary cutaneous B-cell lymphoma: a clinical follow-up study of 29 primary cutaneous B-cell lymphoma. Br J Dermatol 2010;163:223-225.
patients. J Clin Oncol 1999;17:2471-2478. Available at: Available at: https://www.ncbi.nlm.nih.gov/pubmed/20394622.
67. Kollipara R, Hans A, Hall J, Lisle A. A case report of primary
60. Rijlaarsdam JU, Toonstra J, Meijer OW, et al. Treatment of primary cutaneous marginal zone lymphoma treated with intralesional steroids.
cutaneous B-cell lymphomas of follicle center cell origin: a clinical Dermatol Online J 2015;21:13030/qt9s15929m. Available at:
follow-up study of 55 patients treated with radiotherapy or https://www.ncbi.nlm.nih.gov/pubmed/26437162.
polychemotherapy. J Clin Oncol 1996;14:549-555. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/8636770. 68. Haverkos B, Tyler K, Gru AA, et al. Primary Cutaneous B-Cell
Lymphoma: Management and Patterns of Recurrence at the Multimodality
61. Brice P, Cazals D, Mounier N, et al. Primary cutaneous large-cell Cutaneous Lymphoma Clinic of The Ohio State University. Oncologist
lymphoma: analysis of 49 patients included in the LNH87 prospective trial 2015;20:1161-1166. Available at:
of polychemotherapy for high-grade lymphomas. Groupe d'Etude des https://www.ncbi.nlm.nih.gov/pubmed/26306900.
Lymphomes de l'Adulte. Leukemia 1998;12:213-219. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/9519784. 69. Specht L, Dabaja B, Illidge T, et al. Modern radiation therapy for
primary cutaneous lymphomas: field and dose guidelines from the
62. Trent JT, Romanelli P, Kerdel FA. Topical targretin and intralesional International Lymphoma Radiation Oncology Group. Int J Radiat Oncol
interferon alfa for cutaneous lymphoma of the scalp. Arch Dermatol Biol Phys 2015;92:32-39. Available at:
70. Grange F, Beylot-Barry M, Courville P, et al. Primary cutaneous diffuse
63. Bachmeyer C, Orlandini V, Aractingi S. Topical mechlorethamine and large B-cell lymphoma, leg type: clinicopathologic features and prognostic
clobetasol in multifocal primary cutaneous marginal zone-B cell analysis in 60 cases. Arch Dermatol 2007;143:1144-1150. Available at:
lymphoma. Br J Dermatol 2006;154:1207-1209. Available at: https://www.ncbi.nlm.nih.gov/pubmed/17875875.
71. Posada Garcia C, Florez A, Pardavila R, et al. Primary cutaneous
64. Coors EA, Schuler G, Von Den Driesch P. Topical imiquimod as large B-cell lymphoma, leg type, successfully treated with rituximab plus
treatment for different kinds of cutaneous lymphoma. Eur J Dermatol chemotherapy. Eur J Dermatol 2009;19:394-395. Available at:
72. Grange F, Maubec E, Bagot M, et al. Treatment of cutaneous B-cell
65. Stavrakoglou A, Brown VL, Coutts I. Successful treatment of primary lymphoma, leg type, with age-adapted combinations of chemotherapies
cutaneous follicle centre lymphoma with topical 5% imiquimod. Br J and rituximab. Arch Dermatol 2009;145:329-330. Available at:
73. Grange F, Joly P, Barbe C, et al. Improvement of survival in patients
with primary cutaneous diffuse large B-cell lymphoma, leg type, in France.
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JAMA Dermatol 2014;150:535-541. Available at:

74. Kim MJ, Hong ME, Maeng CH, et al. Clinical features and treatment
outcomes of primary cutaneous B-cell lymphoma: a single-center analysis
in South Korea. Int J Hematol 2015;101:273-278. Available at:
75. Kraft RM, Ansell SM, Villasboas JC, et al. Outcomes in primary
cutaneous diffuse large B-cell lymphoma, leg type. Hematol Oncol
2021;39:658-663. Available at:
MS-14

Mycosis Fungoides and Sézary Syndrome patients diagnosed with MF and SS be treated at specialized centers
Overview with expertise in the management of this disease.11
Cutaneous T-cell lymphomas (CTCL) are a group of non-Hodgkin Literature Search Criteria and Guidelines Update Methodology
lymphomas (NHL) that primarily present in the skin, and at times
Prior to the update of this version of the NCCN Clinical Practice Guidelines
progress to involve lymph nodes, blood, and visceral organs.1-3 Mycosis
in Oncology (NCCN Guidelines®) Primary Cutaneous Lymphomas, an
fungoides (MF) is the most common subtype and is usually associated
electronic search of the PubMed database was performed to obtain key
with an indolent clinical course with intermittent, stable, or slow
literature on MF and SS published since the previous Guidelines update
progression of the lesions.4 Extracutaneous involvement (lymph nodes,
using the following search terms: cutaneous T-cell lymphomas, mycosis
blood, or less commonly other organs) or large cell transformation (LCT)
fungoides, and Sézary syndrome. The PubMed database was chosen as it
may be seen in advanced-stage disease. Sézary syndrome (SS) is a rare
remains the most widely used resource for medical literature and indexes
erythrodermic, leukemic variant characterized by significant blood
peer-reviewed biomedical literature.12
involvement, erythroderma, and often lymphadenopathy.4-6 MF is caused
by the malignant transformation of skin-resident effector memory T cells The search results were narrowed by selecting studies in humans
while SS is thought to arise from thymic memory T cells, supporting the published in English. Results were confined to the following article types:
contention that SS is a process distinct from MF.5 Cases presenting as an Clinical Trial, Phase II; Clinical Trial, Phase III; Clinical Trial, Phase IV;
overlap of these two conditions also exist. Guideline; Randomized Controlled Trial; Meta-Analysis; Systematic
Reviews; and Validation Studies.
Folliculotropic MF (FMF), granulomatous slack skin, and pagetoid
reticulosis are recognized as distinct clinicopathologic variants of MF in the The data from key PubMed articles deemed as relevant to these
World Health Organization-European Organization for Research and guidelines have been included in this version of the Discussion section.
Treatment of Cancer (WHO-EORTC) classification.2 FMF and LCT are Recommendations for which high-level evidence is lacking are based on
histologic features that can occur irrespective of stage, but the incidence the panel’s review of lower-level evidence and expert opinion.
of LCT is higher in patients with advanced-stage disease.7-9 Expert
dermatopathology and/or hematopathology review is needed to confirm The complete details of the Development and Update of the NCCN
the diagnosis. This is especially true for the less common variants of the Guidelines are available at www.NCCN.org.
disease, which can be difficult to distinguish from other lymphoproliferative
Staging
disorders. Genomic studies have demonstrated further biologic diversity
within MF.4,10 The T (skin), N (node), M (visceral), and B (blood involvement)
classification and clinical staging developed by the International Society
Due to the rarity and diversity of the condition and the need for an for Cutaneous Lymphomas (ISCL) and EORTC13 are outlined on MFSS-3
individualized approach, the NCCN Guidelines Panel recommends that and MFSS-4.
MS-15

The extent of skin involvement is based on the percentage of body surface Prognosis
area (BSA) where the patient’s palm (without digits) is equivalent to 0.5% Age at presentation, overall stage, extent and type of skin involvement (T
BSA and the palm with all five digits is approximately 1% BSA.13 In the classification), presence of extracutaneous disease, extent of peripheral
revised staging system, T1 disease (limited skin involvement) is defined as blood involvement (as defined by flow cytometric measurements of Sézary
patches, papules, and/or plaques covering less than 10% BSA. T2 cell counts), elevated lactate dehydrogenase (LDH), and presence of LCT
(skin-only disease) is defined as patches, papules, and/or plaques have been identified as the most significant factors for disease
covering 10% or greater BSA. Patch diagnosis is noted as T1a or T2a and progression and/or survival in patients with MF.14-20 In a retrospective
plaque diagnosis is noted as T1b or T2b. T3 (tumor-stage disease) is cohort study of 525 patients with MF or SS, patient age, T classification,
defined by the presence of one or more tumors (≥1 cm in diameter with and presence of extracutaneous disease retained independent prognostic
nodular quality). T4 (erythrodermic disease) is defined as confluence of value in a multivariate analysis.15 The risk of disease progression,
erythroderma covering 80% or greater BSA. However, this criterion of 80% development of extracutaneous disease, or death due to MF correlated
is subjective and the BSA can fluctuate in patients with erythrodermic MF with initial T classification. Limited patch or plaque disease has an
or SS. Thus, other features including keratoderma, ectropion, or leg excellent prognosis compared to patients with widespread plaque-type or
edema should also be evaluated in patients with erythrodermic MF or SS. tumor-type skin disease or erythrodermic skin involvement, and
extracutaneous disease is associated with a poor prognosis.17,18
Lymph node biopsy for staging is recommended only for clinically
abnormal nodes (>1.5 cm in longest diameter). Lymphadenopathy can be In the Cutaneous Lymphoma International Consortium (CLIC) study that
clinically reactive or dermatopathic; thus, not all enlarged lymph nodes are evaluated the relevance of prognostic markers on overall survival (OS) in
sampled. The designation “Nx” may be used for abnormal lymph nodes 1275 patients with advanced-stage MF and SS, stage IV disease, aged 60
without histologic evaluation. The designation “Mx” can be used for years, LCT and LDH levels were identified as independent prognostic
presence of abnormal visceral sites without histologic evaluation. Visceral markers that could be used together in a prognostic model to identify three
disease with the involvement of an organ (eg, spleen, liver) other than the risk groups with significantly different survival outcomes.20 The 5-year
skin, nodes, or blood should be documented using imaging studies. survival rates were 68%, 44%, and 28%, respectively, for low-risk,
intermediate-risk, and high-risk groups. A prospective international study
Blood involvement is classified into three groups: B0, B1, and B2 based on
by CLIC (Prospective Cutaneous Lymphoma International Prognostic
the number of immunophenotypically abnormal T cells in the blood
Index [PROCLIPI] international study) is underway to identify any new
(MFSS-3). B1 or B2 is best characterized by both flow cytometry and the
prognostic markers and validate the refined prognostic index model to
presence of clonally related neoplastic T cells as in the skin by T-cell
optimize risk-stratified management in patients with MF or SS.21-23
receptor (TCR) gene rearrangement analysis. A diagnosis of SS requires
B2 level of blood involvement.13 Diagnosis
Biopsy of suspicious skin sites along with immunohistochemistry (IHC) of
biopsy specimen are essential to confirm the diagnosis. Biopsy of
MS-16

enlarged lymph nodes (ie, palpable nodes >1.5 cm in diameter and/or firm, test for malignancy since clonal TCR rearrangements can at times be
irregular, clustered, or fixed nodes) or extracutaneous sites is seen in non-malignant conditions or may not be demonstrated in all
recommended. Excisional or incisional biopsy is preferred over core cases of MF and SS. TCR rearrangement analysis by high throughput
needle biopsy. Fine-needle aspiration (FNA) alone is not sufficient for the sequencing (or next generation sequencing) is a more sensitive and
initial diagnosis. Bone marrow biopsy is not required for disease staging, specific test of clonality that can identify the clones by the genetic
but may be helpful in those with an unexplained hematologic sequence of the TCR.31,32 Demonstration of identical clones in the skin,
abnormality.13 blood, and/or lymph nodes may be helpful both for diagnosis and
differentiating MF and SS from benign inflammatory skin diseases.
MF and SS cells are typically characterized by the following
immunophenotype: CD2+, CD3+, CD5+, CD4+, CD8-, CCR4+, Assessment of peripheral blood involvement optimally by flow cytometry
TCR-beta+, and CD45RO+ and they lack certain T-cell markers, CD7 and is important for staging and is also useful to differentiate CTCL with
CD26.24 However, there are subtypes of MF that are CD8+ (especially the peripheral blood involvement from other forms of leukemic T-cell
hypopigmented variant) or CD4/CD8 dual negative (in those with LCT), lymphomas (eg, T-cell prolymphocytic leukemia, lymphocytic variant of
although rare. The T cells also express cutaneous lymphocyte antigen hypereosinophilic syndrome, adult T-cell leukemia/lymphoma [ATLL]).
(CLA) and TH2 cytokines. They are also associated with a loss of TH1 and Flow cytometry allows for the assessment and quantitation of an
IL-12 cytokines. The IHC panel of skin biopsy should include CD2, CD3, expanded population of CD4+ cells with abnormal immunophenotype
CD4, CD5, CD7, CD8, CD20, and CD30. Additional immunohistochemical (CD4+/CD26- or CD4+/CD7- or other aberrantly expressed phenotype).33
markers such as CD25, CD56, TIA1, granzyme B, TCR beta, and TCR human T-cell lymphotrophic virus (HTLV)-1 status, assessed either by
delta, may be useful in selected circumstances. HTLV-1 serology or other methods, may be useful in at-risk populations to
exclude the diagnosis of ATLL (which is usually HTLV-1positive).
Primary cutaneous follicular helper T-cell (TFH) lymphoma is a recently
described variant of peripheral T-cell lymphoma (PTCL)-not otherwise Workup
specified. This variant usually presents as a sudden onset of multiple The initial workup of patients diagnosed with MF or SS involves a history
plaques and nodules characterized by the expression TFH markers such and complete skin examination (assessment of the extent of disease [ie,
as CXCL13, ICOS, and programmed death-1 (PD-1).25,26 Identification of percent of BSA] and type of skin lesion [eg, patch/plaque, tumor,
these markers along with other clinical and histopathologic features erythroderma]), palpation of peripheral lymph nodes and palpation for
would be useful to distinguish MFSS from CTCL of TFH origin.27,28 organomegaly.13
Molecular analysis to detect clonal TCR gene rearrangements is useful Laboratory studies should include a complete blood count (CBC), Sézary
to support the diagnosis of MF and SS as well as to distinguish MF from flow cytometric study (optional for T1 disease), comprehensive metabolic
inflammatory dermatoses, especially if identical clones are demonstrated panel, and assessment of LDH levels. Analysis of clonal TCR gene
in more than one skin site.29,30 However, results showing clonal TCR
gene rearrangements should not be interpreted as the sole and defining
MS-17

arrangement of peripheral blood lymphocytes is recommended if blood impact of therapy on quality of life, and supportive care for symptom
involvement is suspected. control are a key part of the management of patients with MF and SS.
Most of the treatment options do not result in durable remissions and are
CT with contrast of the chest, abdomen, and pelvis or integrated often given in an ongoing or maintenance fashion to achieve disease
whole-body PET/CT scan is recommended for patients with T3 or T4 control with as little impact on quality of life as possible.
disease and should be considered for patients with T2a (patch disease
with ≥10% BSA), T2b (widespread plaque-type skin disease), FMF or Patients with a clinical benefit and/or those with disease responding to
LCT, palpable adenopathy, or abnormal laboratory studies. In an analysis primary treatment can be considered for maintenance or tapering of
of 375 patients with stage T1/T2 MF enrolled in the PROCLIPI regimens to optimize response duration. Patients with disease that does
international study, the presence of plaques was associated with a not have adequate response to a systemic therapy regimen are generally
significant increase in the identification of radiologically enlarged or treated with an alternative regimen recommended for primary treatment
involved lymph nodes in patients with early-stage MF.22 before moving on to treatment for refractory disease. This supports the
therapeutic principle of initial treatment with less toxic regimens before
A CT scan of the neck may be useful in some circumstances. Integrated moving on to treatment options that carry a higher risk of cumulative
PET/CT was found to be more sensitive for the detection of lymph node toxicity and/or immunosuppression. Disease relapse (with the same
involvement than CT alone and can help direct biopsies.34 PET scan may stage) after discontinuation of therapy often responds well to
also be preferred in patients with extranodal disease that may be re-treatment with previous therapy.
inadequately imaged by CT. Many skin-directed and systemic therapies
are contraindicated or are of unknown safety in pregnancy. Therefore, Selection of Therapy Based on Clinical and Pathologic Features
pregnancy testing is recommended for females of childbearing age. Skin-directed therapies (topical therapy, phototherapy, radiation therapy
Treatment Considerations [RT], or total skin electronic beam therapy [TSEBT]) that can provide
disease control without major cumulative toxicities are recommended for
While MF and SS are treatable, they are not curable with conventional
patients with early-stage disease and limited skin involvement (stage IA or
systemic therapy and the symptoms of the disease have significant
stage IB–IIA). Stage IA MF most often can be treated with skin-directed
impact on the quality of life. Patients with MF, particularly those with
therapies (alone or in combination with other skin-directed therapies).
early-stage disease, can have very good prognosis and may live with the
While stage IB–IIA patch/plaque disease can be effectively treated
disease for decades.17,18
predominantly with skin-directed therapies, systemic therapy can be
The optimal treatment for any patient at any given time should be considered for stage IB–IIA with higher skin disease burden, concerning
individualized based on overall goals of therapy (improve the disease pathologic features (eg, LCT or FMF), predominantly plaque disease,
burden and quality of life, attain adequate response to reduce/control and/or inadequate response to skin-directed therapy.
symptoms, and minimize the risk of progression), route of administration,
and toxicity profile. Discussions regarding cumulative toxicity of therapy,
MS-18

Systemic therapy is recommended for advanced-stage disease (≥ stage generalized skin involvement because these treatments can cause
IIB). However, stage IIB patients with single or few T3 lesions can be substantial irritation.
treated with external beam RT (EBRT) with further delay of systemic
Topical Corticosteroids
therapy and TSEBT may be used for patients with stage IB–IIB disease,
with excellent response expected. In the PROCLIPI study, the use of Topical corticosteroids are effective for early-stage MF (especially for the
systemic therapy was significantly associated with higher clinical stage, treatment of patch-stage MF) resulting in measurable improvement in BSA
presence of plaques, and FMF.23 In multivariate analysis, the presence of involvement and high ORR (94%; 63% complete response [CR]; 13%
plaques and FMF were significantly associated with the use of systemic partial response [PR]) and 82% (25% CR; 57% PR), respectively, in
therapy and skin-directed therapy was superior to systemic therapy even patients with stage T1 and T2 disease).35-37
in patients with these disease characteristics. The overall response rate
Optimal use of topical steroids is often dependent on lesion type and
(ORR) to first-line skin-directed therapy was 73% compared to 57% for
location of disease. This is best done in consultation with a dermatologist
systemic therapy.
or physician with experience in the use of topical steroids. In general,
Systemic therapy can be and often is combined with skin-directed high-potency steroids may be less well-tolerated in intertriginous body
therapy to maximize clinical responses in the skin compartment and also areas or other areas such as the face. Long-term use of a topical steroid
to provide additive efficacy without cumulative toxicities. For those who may lead to skin atrophy or striae formation and the risk becomes greater
require systemic therapy, due to either advanced-stage disease or with increased potency of the steroid. Moreover, high-potency steroids
inadequate disease control on skin-directed therapy, there are many used on large skin surfaces may lead to systemic absorption.
options; however, given the rare nature of this disease, only a few have Topical Mechlorethamine (nitrogen mustard)
been evaluated in randomized studies, as discussed in the section Topical mechlorethamine has been used for the management of MF for
“Systemic Therapies.” Therefore, a clinical trial should be considered many decades resulting in an ORR of 83% (50% CR). Patients with T1
when appropriate and available. disease had a higher ORR (93% vs. 72%), CR rate (65% vs. 34%), longer
median OS (21 vs. 15 months), and higher 5-year OS rate (97% vs. 72%)
Data from clinical trials that have evaluated various treatment strategies
than those with T2 disease.38 The efficacy was similar for aqueous and
(skin-directed therapy, systemic therapy, and combination therapies) are
ointment preparations, although the ointment was associated with reduced
discussed below.
hypersensitivity reactions.
Skin-Directed Therapies
A topical gel formulation of mechlorethamine was approved by the U.S.
Topical therapy with corticosteroids, mechlorethamine (nitrogen mustard),
Food and Drug Administration (FDA) in 2013 based on the results of a
topical retinoids or topical imiquimod, or RT are indicated for patients with
multicenter randomized phase II trial that demonstrated the non-inferiority
localized disease. Phototherapy and TSEBT are indicated for patients with
of topical gel formulation compared to the compounded ointment
widespread skin involvement. Topical retinoids are not recommended for
formulation for the treatment of stage IA or IIA MF in patients (n = 260)
MS-19

who had not been treated with topical mechlorethamine within 2 years of patches/plaques/small tumors that are recalcitrant to treatment or on
study enrollment and had not received prior therapy with topical sun-damaged skin such as forearms, scalp, and face.
mechlorethamine.39 Response rate based on Composite Assessment of
Topical Carmustine
Index Lesion Severity was 59% for the topical gel formulation compared to
48% for the ointment formulation. No study treatment-related serious Topical carmustine is an effective treatment for patch/plaque early-stage
adverse events were reported, and no systemic absorption was detected. MF resulting in high response rates of 92% and 64% in patients with T1
and T2 disease, respectively, at 36 months.48,49 Topical carmustine is
The use of topical gel formulation of mechlorethamine can be complicated included with a category 2B recommendation.
by dermatitis and can result in skin irritation when used on face and
Radiation Therapy
intertriginous body areas. Initiation at less than daily use and slowly
MF is extremely radiosensitive and patients with unilesional or stage IA
increasing the frequency of application as tolerated may improve
MF may be managed effectively with local RT alone (without adjuvant
tolerability. Topical mechlorethamine is prohibited in the genital skin.
therapy), resulting in an ORR of 97% to 100%.50,51 Recent studies have
Topical Retinoids shown that low-dose involved-field RT (IFRT) also results in high response
Bexarotene gel is the only FDA-approved synthetic topical retinoid for the rates without any toxicity in patients with MF.51-53 In a study that included
treatment of MF and SS. In the phase I–II trial of 67 patients with 31 patients with MF, low-dose RT (4 Gy in 2 fractions) resulted in a CR
early-stage MF, the ORR was 63% (21% CR) and the estimated median rate of only 30%, whereas increasing the dose to 8 Gy in two fractions
response duration was 99 weeks.40 Response rates were higher among yielded a CR rate of 92%.52 Patients in whom low-dose RT failed were
the patients who had had no prior therapy compared with those who had re-treated with 20 Gy in eight fractions. In a large series of 58 patients
received prior topical therapies (75% vs. 67%). In the phase III multicenter treated with 8 Gy in a single fraction, the CR rate was 94% for individual
study of 50 patients with early-stage refractory MF, the ORR was 44% (8% lesions after a median follow-up of 41 months.53
CR).41
Optimal management of individual plaque and tumor lesions is with EBRT
Tazarotene 0.1% topical gel/cream was reported to be a well-tolerated and (8–12 Gy, 8 Gy may be given in a single-fraction; 24–30 Gy is
active adjuvant therapy by clinical and histologic assessments in a small recommended for more durable duration of response or for unilesional
series of patients with early patch or plaque MF lesions (stable or presentation).51,53
refractory to therapy).42,43
Total Skin Electron Beam Therapy
Topical Imiquimod TSEBT (conventional dose [30–36 Gy] or low dose [<30 Gy]) either alone
Imiquimod has also demonstrated activity in a small number of patients or in combination with adjuvant therapy has been shown to be effective for
with early-stage MF refractory to other therapies.44-47 Topical imiquimod the treatment of early-stage MF.54-57 TSEBT at a conventional dose of
can be considered (often in consultation with a dermatologist or physician greater than or equal to 30 Gy was associated with a non-significant trend
with experience in its safety and use) for areas with few towards better clinical benefit and was also associated with better
MS-20

outcomes in patients with T2 disease compared to those with T3 complications and better ability to re-treat relapsed disease. It is common
disease.56,57 In a retrospective study that evaluated low-dose TSEBT in practice to follow TSEBT with systemic therapies such as interferon (IFN)
102 patients with T2 to T4 disease (excluding those with extracutaneous or bexarotene to maintain response, for patients with stage IB–IIA disease
disease), TSEBT doses of 10 Gy to less than 20 Gy and 20 Gy to less with higher skin disease burden. Adjuvant systemic therapy can be
than 30 Gy resulted in ORRs of 98% and 97%, respectively, which were considered to improve response rate and PFS in patients with stage IIB
comparable to the ORRs achieved with standard-dose TSEBT (≥30 Gy).55 (tumor stage) disease receiving TSEBT.66,67
The OS and progression-free survival (PFS) rates were not significantly
different by dose groups and were comparable to that of standard-dose TSEBT may not be well tolerated in patients with erythrodermic disease
TSEBT (≥30 Gy). and should be used with caution. In these patients, TSEBT may be used
with lower doses and slower fractionation. Antibiotic therapy should be
Recent studies suggest that lower-dose TSEBT (10–12 Gy over a period considered since patients with erythrodermic disease are at increased risk
of 2–3 weeks) is sufficiently active and may also be associated with fewer of developing secondary infections.
short-term complications and better ability to re-treat progressive disease
Phototherapy
(PD) or cutaneous relapses.58-63 A pooled analysis of three phase II clinical
trials that evaluated low-dose TSEBT (12 Gy; 1 Gy per fraction over 3 Ultraviolet B (UVB including narrowband-UVB)68-72 and psoralen plus
weeks) in 33 patients with MF reported an ORR of 88% (including 9 ultraviolet A1 (PUVA/UVA-1)73-76 are effective treatment options for
patients with a CR).59 The median time to response and median duration patients with early-stage MF. Narrowband UVB is the most common
of clinical benefit were 8 weeks and 71 weeks. In a cohort of 103 patients phototherapy approach and less skin damaging than PUVA/UVA-1. While
with MF treated with low-dose TSEBT (12 Gy in 8 fractions for 2 weeks; some retrospective studies have reported that PUVA results in better
the majority of patients had stage IB or IIB disease), after a median responses and improved disease-free survival (DFS),77-79 others have
follow-up of 21 months, the ORR was 87% (18% CR and 69% PR) and the reported that UVB is as effective as PUVA for the treatment of
median PFS was 13 months.62 The median PFS was significantly longer early-stage MF.80,81 However, these modalities have not been compared
for patients with stage IB disease (27 months) compared to 11 months and in randomized clinical trials.
10 months, respectively, for those with stage IIB or stage III disease.
It may be more beneficial to start with narrowband UVB than PUVA in
Low-dose TSEBT (12 Gy in 6–7 fractions) was also associated with
patients with early patch-stage or thin-plaque disease, since narrowband
favorable outcomes and significantly fewer grade 2 acute toxicities
UVB has less skin toxicity than broadband UVB and PUVA.82 It should be
compared with conventional-dose TSEBT (30 Gy).61,64,65 Further studies
noted that cumulative doses of UV radiation may be associated with
are warranted to confirm these findings and the use of low-dose TSEBT in
increased risk of UV radiation-associated skin malignancies.83-85 Thus, the
combined modality regimens.
risk and benefits of phototherapy should be considered in patients with a
The recommended dose range for TSEBT is 12–36 Gy (generally 4–6 Gy history of squamous or basal cell carcinoma or melanoma. There is limited
per week). Lower total dose is associated with fewer short-term safety data for the use of phototherapy in combination with vorinostat or
romidepsin.
MS-21

Systemic Therapies extracorporeally with 8-methoxypsoralen and UVA, and then returned to
The selection of systemic therapy regimens is dependent on clinical (eg, the patient.109-111 ECP may be a more appropriate systemic therapy for
extent of patch/plaques; disease burden profile in the skin, lymph nodes, patients with some level of blood involvement (B1 or B2).
and blood; prior therapies; and comorbidities) and pathologic features (eg,
Gemcitabine112-115 and pegylated liposomal doxorubicin116-118 also have
LCT or FMF) and IHC data (eg, CD30 positivity). In general, systemic
substantial activity in patients with advanced MF and SS. Multiagent
therapy regimens that can be tolerated for longer durations of therapy with
chemotherapy regimens used for the treatment of systemic PTCLs have
lower rates of cumulative toxicity, less immunosuppression, and/or higher
activity but are associated with greater toxicity and a potentially higher risk
efficacy are used in earlier lines of therapy. Regimens with lower
of death when used in earlier lines of treatment.119,120 Therefore,
side-effect profiles and an absence of cumulative toxicity are often given in
multiagent chemotherapy regimens are generally reserved only for
an ongoing or maintenance fashion to improve and maintain disease
refractory disease to multiple prior therapies or bulky lymph node or solid
control and quality of life. In patients requiring chemotherapy, single
organ disease, and/or as a bridge to allogeneic hematopoietic cell
agents are preferred over combination chemotherapy, due to the higher
transplant (HCT).
toxicity profiles associated with multi-agent regimens and the short-lived
responses seen with time-limited combination chemotherapy. Data supporting the use of some of these agents in patients with MF and
SS are discussed below. The data for systemic therapy agents particularly
Brentuximab vedotin, bexarotene, histone deacetylase (HDAC) inhibitors
those studied in larger prospective phase II and III studies are also
(vorinostat and romidepsin), methotrexate, pralatrexate, mogamulizumab,
summarized in Table 1.
alemtuzumab, and pembrolizumab are effective systemic therapy options
for patients with advanced MF and SS. Bexarotene, brentuximab vedotin, Systemic Retinoids
mogamulizumab, vorinostat, and romidepsin are approved by the FDA for Bexarotene, an oral retinoid, can have prolonged disease control without
the treatment of MF and SS. The efficacy of brentuximab vedotin and cumulative toxicity and is often considered for patients with higher skin
mogamulizumab compared to standard therapy has been demonstrated in burden with plaque disease.88,89 In phase II–III studies, oral bexarotene
phase III randomized trials (ALCANZA and MAVORIC, respectively).86,87 (≥300 mg/m2) was well tolerated, resulting in an ORR of 45% to 67% in
Bexarotene,88,89 vorinostat,90-92 romidepsin,93-95 and other systemic patients with early stage and advanced stage disease.88,89 Given the
therapies such as pralatrexate,96-98 alemtuzumab,99-104 and favorable tolerability profile without significant cumulative toxicity, we
pembrolizumab105 have been evaluated only in phase II studies. IFNs (alfa consider bexarotene for patients with early stage MF who have insufficient
and gamma) and methotrexate also offer clinical benefit but have not been disease control with skin-directed therapy. Bexarotene is also used in
studied in phase II studies in the era of modern staging of MF and combination with phototherapy or ECP for early stage disease with
SS.106-108 inadequate response to single agent therapy and in patients with
advanced stage disease.121-124 It is important to note that bexarotene is
Extracorporeal photopheresis (ECP) is an immunomodulatory therapy in
associated with hypertriglyceridemia and central hypothyroidism, which
which patient’s leukocytes are removed by leukapheresis, treated
MS-22

necessitates laboratory monitoring for triglycerides, and free thyroxine CD30min expression) were significantly higher for brentuximab vedotin
(T4), often requiring additional management. compared to vorinostat across all CD30 expression levels.
Retinoic-acid receptor (RAR) agonists such as all-trans retinoic acid In other phase II studies, clinical responses with brentuximab vedotin were
(ATRA), acitretin, and isotretinoin (13-cis-retinoic acid) have also been observed across all CD30 expression levels (including negligible CD30
shown to be effective for the treatment of early-stage MF.125-128 In a expression) and in patients with high blood Sézary cell count.131,132
retrospective comparison study, ATRA induced similar outcomes with Lesions with less than 5% CD30 expression had a lower likelihood of
modest single-agent activity compared to bexarotene in the treatment of global response than those with greater than or equal to 5% CD30
patients with relapsed MF and SS.125 In a small cohort of 35 patients with expression (P < .005), but responses are still seen in those with CD30
early-stage MF, acitretin and isotretinoin resulted in ORRs of 64% and positivity of greater than or equal to 1%.131,132 While responses were
80%, respectively (although the CR rates were low at 4% and 8%, observed in patients with very low or absent CD30 expression, the
respectively).127 likelihood and/or depth of response may be lower in these situations and
further studies are needed to define the activity of brentuximab in this
Brentuximab Vedotin
setting. Brentuximab vedotin is a more effective treatment option than
In the ALCANZA trial, brentuximab vedotin, an anti-CD30 antibody drug methotrexate or bexarotene for patients with CD30-positive MF but carries
conjugate, was more effective than methotrexate or bexarotene in patients greater risk, particularly a cumulative risk of peripheral neuropathy.133
with previously treated MF (≥ stage IB).86 The final analysis confirmed that
brentuximab vedotin resulted in significantly improved ORR lasting for at Patients with SS were excluded from ALCANZA trial and the efficacy of
least 4 months (ORR4; 55% vs.13%), median PFS (17 vs. 4 months) and brentuximab vedotin in patients with SS in the setting of refractory disease
patient-reported symptom burden compared to methotrexate or or low CD30 skin expression has only been demonstrated in a small case
bexarotene in patients with CD30-positive MF.129 Peripheral neuropathy series of 13 patients.134
was the most common adverse event reported in 44 (69%) patients. At the
median follow-up of 46 months, 86% (38 of 44) of patients had complete Mogamulizumab
resolution or improvement to grades 1 and 2. In the MAVORIC trial, mogamulizumab, a humanized anti CCR4
monoclonal antibody, was more effective than vorinostat in patients with
In ALCANZA trial, CD30 positivity was defined as CD30 expression in previously treated MF (≥ stage IB) and SS. Mogamulizumab resulted in
≥10% of total lymphoid cells in at least 1 skin sample (43% of patients had significantly higher ORR (28% vs. 5%) and median PFS (8 vs. 3 months)
at least 1 sample with CD30 <10%).86 The results of an exploratory compared with vorinostat and the ORR was higher in patients with SS
analysis showed that brentuximab vedotin resulted in higher ORR4 and than those with MF (37% vs. 21%).87 Patients with LCT were excluded
improved PFS in patients with ≥10% CD30 expression, regardless of LCT from this trial. In a post hoc analysis, the number of prior therapies did
status.130 The ORR4 (41% vs. 10% for <10% CD30min expression; 57% vs. not impact the ORR, PFS, and duration of response observed with
10% for ≥10% CD30min expression) and median PFS (17 months vs. 2 mogamulizumab.135 Among the 186 patients randomly assigned to
months for <10% CD30min expression; 16 months vs. 4 months for ≥10% vorinostat, 136 patients (109 patients with disease progression and 27
MS-23

patients after intolerable toxicity) crossed over to mogamulizumab. The Mogamulizumab is associated with a drug-induced skin eruption that has
ORR was 31% for the 133 patients who crossed over from vorinostat to variable clinical and pathologic features and can mimic CTCL and this
mogamulizumab and subsequently received mogamulizumab. The most was the most frequent adverse event leading to treatment
common adverse events associated with mogamulizumab were mostly discontinuation in the MAVORIC trial.87,138-141
grade 1–2 and manageable (infusion-related reactions [37%], skin Mogamulizumab-associated skin rash has also been identified as a
eruptions [25%], and diarrhea [14%]). Pyrexia (4%) and cellulitis (3%) potential marker for tumor response.142 Skin biopsy (with adequate
were the most common grade 3 adverse events in the mogamulizumab immunohistochemical stains and clonality assessment) is recommended
group. Patients with the greatest symptom burden and functional to rule out disease progression in patients experiencing
impairment derived the most benefit from mogamulizumab in terms of mogamulizumab-associated drug eruptions or skin rash.140,143
quality of life.136
Histone Deacetylase Inhibitors
The clinical benefit with mogamulizumab was higher in patients with stage Vorinostat was the first HDAC inhibitor to be approved for the treatment of
III or stage IV disease and also for patients with B1 and B2 blood MF and SS. In the initial phase IIB registration study, vorinostat resulted in
involvement.87,137 In the post-hoc subgroup analysis by clinical stage, the an ORR of 30%.91 A post-hoc subset analysis of patients who experienced
ORRs for mogamulizumab were 23% and 36%, respectively for patients clinical benefit with greater than or equal to 2 years of vorinostat therapy in
with stage III or stage IV disease compared to 19% and 16%, respectively the phase IIB study provided some evidence for the long-term safety and
for patients with stage IB/IIA disease or stage IIB disease.87 efficacy of vorinostat in patients with heavily pretreated MF and SS,
Mogamulizumab also resulted in higher ORR than vorinostat across all regardless of previous treatment failures.92 While cumulative toxicities
disease compartments. The compartment-specific ORRs for were rare with vorinostat, patients need to be monitored for
mogamulizumab were 42%, 68%, and 17%, respectively, for skin, blood gastrointestinal toxicity, including nausea, diarrhea, and resultant
involvement, and lymph nodes. The corresponding ORRs for vorinostat dehydration, which could be more detrimental for elderly patients.
were 16%, 19%, and 4%, respectively. This trial, however, was not
powered to detect OS differences between the two groups within the Romidepsin has demonstrated clinical activity across all disease
defined follow-up period. In another post-hoc analysis that evaluated the compartments.93-95 The median duration of response is 13 to 15 months
efficacy of mogamulizumab based on blood tumor burden, the ORRs for for patients with disease responding to romidepsin.93,94 Importantly,
mogamulizumab were 26% and 37%, respectively for patients with B1 romidepsin was associated with a high rate of reduction in pruritus score
and B2 blood involvement compared to 16% for those with B0 blood irrespective of clinical objective response.35 The compartment specific
involvement.137 Mogamulizumab also was associated with sustained ORRs were 40%, 35%, 32%, and 27%, respectively, for skin involvement,
reductions seen in CD4+ CD26- cell counts and CD4:CD8 ratios in erythroderma, blood involvement, and lymphadenopathy.95 It is important
patients for all B classes of blood involvement. to initially monitor for QTc prolongation when administering romidepsin,
particularly with the concomitant use of antiemetics that also prolong QTc.
Romidepsin is included as a preferred regimen for patients with SS with
high Sézary cell burden.
MS-24

Alemtuzumab Gemcitabine
Alemtuzumab (a humanized anti-CD52 monoclonal antibody) has Gemcitabine monotherapy is an effective treatment option resulting in an
significant clinical activity in patients with previously treated advanced MF ORR of 48% to 71% in patients with heavily pretreated advanced-stage
and SS.99,100,102-104 The ORR with alemtuzumab (30 mg IV) was higher in MF and SS.112-115 In a retrospective observational study of 25 patients with
patients with erythroderma or SS than those with advanced MF; however, advanced MF and SS, after a long-term follow-up of 15 years, the
it was associated with myelotoxicities and infectious complications.100,104 estimated OS, PFS, and DFS rates were 47%, 9%, and 40%,
Reduced-dose subcutaneous alemtuzumab (3–15 mg per administration) respectively.115 Gemcitabine monotherapy also has demonstrated activity
given for a shorter duration was equally effective with lower incidence of as front-line therapy in patients with untreated MF and SS.144
infectious complications in patients with SS.101 While alemtuzumab is no
Liposomal Doxorubicin
longer commercially available, it may be obtained for compassionate use
for patients with CTCL and other hematologic malignancies. Pegylated liposomal doxorubicin has shown single-agent activity in
patients with pretreated, advanced, or refractory MF and SS.116-118 In a
Pembrolizumab phase II EORTC multicenter trial of 49 patients with relapsed/refractory
In a phase II trial, pembrolizumab (an immune checkpoint inhibitor) advanced MF (stage IIB, IVA, IVB) after at least two prior systemic
resulted in durable responses in both MF and SS with an ORR of 38% and therapies, liposomal doxorubicin resulted in an ORR of 41% (6% CR).118
median duration of response not reached at a median follow up of 58 The median time to progression (TTP) was 7 months, and the median
weeks.105 Pembrolizumab was associated with a skin flare reaction, duration of response was 6 months. Pegylated liposomal doxorubicin was
occurring exclusively in patients with SS; the flare reaction correlated with well tolerated with no grade 3 or 4 hematologic toxicities; the most
high PD-1 expression on Sezary cells and it should be distinguished from common grade 3 or 4 toxicities included dermatologic toxicity other than
disease progression. hand and foot reaction (6%), constitutional symptoms (4%),
gastrointestinal toxicities (4%), and infection (4%).118
Pralatrexate
Pralatrexate is a folate analog with demonstrated activity in patients with Extracorporeal Photopheresis
heavily pretreated MF and SS.96-98 In a multicenter dose-finding study that ECP has been demonstrated as an effective treatment option in many
evaluated pralatrexate (10–30 mg/m2 given weekly for 2 of 3 weeks or 3 of retrospective studies, resulting in an ORR of 42% to 74%.110,145-152 In a
4 weeks) in 54 patients with relapsed or refractory MF and SS, the ORR meta-analysis involving more than 400 patients with MF and SS, ECP as
for all evaluable patients was 41% (6% CR).96 Among the 29 patients who monotherapy resulted in a 56% ORR with a 15% CR.146 The
received the recommended dose (15 mg/m2 weekly for 3 weeks of a corresponding response rates were 58% (15% CR) for erythrodermic
4-week cycle), the ORR was 45% (3% CR).96 In the subgroup of patients disease (T4) and 43% (10% CR) for SS. In one retrospective study of 39
with relapsed/refractory LCT of MF treated on the PROPEL trial, patients with MF and SS (31 patients with T4 disease and 8 patients with
pralatrexate (30 mg/m2) resulted in an ORR of 58% (25% by independent T2 disease), ECP resulted in a skin ORR of 74% (33% of patients
review).97 The median PFS and OS were 5 months and 13 months, achieved ≥50% partial skin response and 41% of patients achieved ≥90%
respectively. improvement).149 After a median follow-up of 72 months, the median OS
MS-25

was 9 years from diagnosis and 7 years from the initiation of treatment combination arm, although the differences were not significant.121 This trial
with ECP. A more recent retrospective study of 50 patients with MF was closed prematurely due to low patient accrual.
reported an ORR of 42% and an OS of 72 months with no statistically
significant differences in OS among patients with early-stage and A small prospective study evaluated the combination of low-dose
late-stage disease (77 months and 69 months, respectively; P = .077).151 bexarotene in combination with PUVA maintenance in 21 patients with MF
and SS (stages IB–IV) resistant or intolerant to previous therapies.158 The
The degree of blood involvement, CD4/CD8 ratio, and amount of ORR was 86% after induction therapy with bexarotene (93% for
circulating CD3+CD8+ cells or CD4(+)CD7(-) lymphocytes have been early-stage disease and 66.6% for advanced disease). At the end of
identified as predictors of clinical response.109,110,153 ECP is generally given maintenance, the ORR was 76% (33% CR) and the median event-free
for at least 6 months and may be more appropriate as systemic therapy for survival (EFS) for the whole group was 31 months.
patients with or at risk of blood involvement (B1 or B2; erythrodermic stage
III disease or IVA with SS).146,152 In a retrospective analysis of 128 patients with MF (118 patients had early
stage disease; stage ≤IIA), acitretin (either as monotherapy or in
Combination Therapies combination with phototherapy or topical steroids) resulted in an ORR of
Skin-Directed + Systemic Therapies 77% (44% CR and 33% PR) with a trend towards better response rate in
Phototherapy is most commonly used in combination with either IFN154-157 the combination arm compared to monotherapy.128 The median duration of
or systemic retinoid.121,128,158-160 response was 24 months.
In a prospective randomized study that evaluated IFN combined with ECP used in combination with TSEBT or phototherapy (narrowband UVB
PUVA versus IFN combined with retinoids in patients with stage I or II or PUVA) has also resulted in high durable clinical response in patients
CTCL (n = 82 evaluable), the combination of IFN with PUVA resulted in with erythrodermic MF and SS.161,162 In a retrospective study of 44 patients
significantly higher CR rates in this patient population (70% vs. 38%).154 In with erythrodermic MF, the combination of TSEBT with ECP (concurrent or
another prospective phase II trial in patients with early-stage MF (stages sequential following TSEBT) significantly improved PFS compared with
IA–IIA; n = 89), the combination of low-dose IFN alfa with PUVA resulted TSEBT alone.161 The 2-year PFS and OS rates were 36% and 63%,
in an ORR of 98% (84% CR).156 respectively, for patients treated with TSEBT alone compared with 66%
and 88% for those treated with TSEBT + ECP.
In a phase III randomized study from the EORTC that evaluated the
combination of bexarotene with PUVA compared with PUVA alone in There is limited efficacy and safety data for the use of TSEBT in
patients with early-stage MF (stage IB and IIA; n = 93), the ORR for the combination with systemic retinoids, HDAC inhibitors (vorinostat or
combination of bexarotene with PUVA was 77% (31% CR) compared to romidepsin), or mogamulizumab.
71% (22% CR) for PUVA alone; the median duration of response was 6
months and 10 months, respectively.121 A trend towards fewer PUVA
sessions and lower UVA doses to achieve CR was observed with the
MS-26

Systemic Combination Therapies patients with early-stage disease were 62 months and 145 months,
The combination of ECP with IFN124,163-165 or systemic retinoids122-124 has respectively. The corresponding endpoints for patients with
been shown to improve response rates in patients with early-stage advanced-stage disease were 7 months and 36 months, respectively. The
disease with inadequate response to single-agent therapy or for those with 5-year estimated OS rate was 94% for patients with early-stage and 35%
advanced-stage CTCL. for advanced-stage MF. Disease stage was the only independent
prognostic factor for survival based on multivariate analysis.
In a retrospective study of 47 patients with advanced CTCL, the
combination of ECP with IFN and/or systemic retinoids resulted in In a phase II study of 22 patients with CTCL, oral bexarotene in
improved response rates (84% vs. 75%) and median OS (74 vs. 66 combination with IFN alfa (added in cases of <CR after 8 weeks of
months) compared with ECP alone despite poor prognostic features bexarotene alone) resulted in an ORR of 39% (6% CR). Although the
among patients treated with combined modality therapy; however, these regimen was well tolerated, response rates were not improved relative to
differences in outcomes were not statistically significant.164 The median the ORR expected with bexarotene alone.123
OS in the subgroup of patients with stage III or IV disease with blood
involvement was 55 months. In a retrospective cohort study of patients In another phase II study that evaluated pegylated liposomal doxorubicin
with SS (n = 98) who received at least 3 months of ECP combined with followed sequentially by oral bexarotene in 37 patients with
one or more biologic agents (ie, IFN alfa, systemic retinoid, IFN gamma, advanced-stage or refractory MF and SS, treatment with 8 doses (16
granulocyte-macrophage colony-stimulating factor [GM-CSF]), the ORR weeks) of liposomal doxorubicin resulted in an ORR of 41% including
was 75% (30% CR) and the 5-year OS rate from time of diagnosis was clinical CR in two patients with a median PFS of 5 months.166 The
55%.165 A higher monocyte percentage at baseline was significantly maximum response was observed after 16 weeks of treatment with
associated with CR rates. Most patients in this study received ECP in liposomal doxorubicin; sequential bexarotene did not improve the
combination with IFN alfa (89%) and/or systemic retinoids (86%); 30% of response rate or duration.
these patients were treated with ECP combined with both IFN alfa and
Additional Therapy Based on Response to Primary Treatment
systemic retinoids. The 5-year OS rates for the subgroups of patients with
stage IIIB, IVA1, IVA2, and IVB were 80%, 80%, 76%, and 0%, Historically, the response criteria for MF and SS were poorly defined and
respectively. validated response assessments were lacking. Response criteria for MF
and SS have not been demonstrated to correlate with prognosis, and
In a study of 95 patients with MF (stages IA–IIA, n = 50; stages IIB–IVB, n responses can vary between the different disease compartments (ie, skin,
= 45), the combination of oral isotretinoin and IFN alfa (followed by TSEBT blood, lymph nodes).
and long-term maintenance therapy with topical mechlorethamine and IFN
alfa) resulted in an ORR of 85% (60% CR).122 The CR rate was 76% More recent studies have incorporated consensus response assessments
among patients with early-stage MF (remission duration >5 years in 24% and newer FDA-approved agents have undergone central review for
of responders) and 40% among those with advanced-stage disease efficacy outcomes. A proposal for the standardization of definition of
(remission duration >5 years in 17%). The median DFS and OS rates for response in skin, nodes, blood, and viscera has been published.167 The
MS-27

decisions to continue with or switch treatment regimens are often made associated with significantly higher disease-specific survival compared to
based on clinical parameters. Imaging with the same modalities used in advanced-stage cutaneous disease.172-174
workup is indicated when there is suspicion of disease progression or
extracutaneous disease. In a report from the Dutch Cutaneous Lymphoma Group that evaluated
the treatment outcomes in patients with FMF (203 patients; 84 patients
All patients (stage IA–IV) with a clinical benefit and/or those with disease with early-stage FMF, 102 patients with advanced-stage FMF, and 17
responding to primary treatment should be considered for maintenance or patients with extracutaneous FMF), treatment with topical steroids and
tapering of regimens to optimize response duration. Disease relapse (with phototherapy with UVB or PUVA were more effective in patients with
the same stage) after discontinuation of therapy often responds well to early-stage FMF resulting in an ORR of 83% (28% CR), 83%, and 88%,
re-treatment with previous therapy. Patients with persistent disease respectively.175 Local RT, TSEBT, and PUVA combined with RT were
following completion of primary treatment should be treated with the other more effective in patients with advanced-stage FMF resulting in an ORR
primary treatment options not received before to improve response before of 100% (63% CR), 100% (59% CR), and 75% (5% CR), respectively.
moving onto treatment for refractory disease.
Patients with early-stage FMF may benefit from standard skin-directed
Currently there is no definitive treatment for refractory disease that can therapies used for the treatment of early-stage MF, and those with
produce reliable durable remissions or curative results. Participation in a generalized indolent/plaque FMF (without evidence of LCT) should initially
clinical trial is recommended for all patients with refractory disease. be considered for single agent systemic therapy regimens before receiving
Multiagent chemotherapy regimens recommended for PTCL are multiagent chemotherapy regimens.
appropriate for the management of refractory disease to multiple prior
Large-Cell Transformed Mycosis Fungoides
therapies.
LCT is diagnosed when large cells are present in greater than 25% of
Special Considerations for Clinical Situations with Specific lymphoid/tumor cell infiltrates in a skin lesion biopsy, and the incidence
Pathologic Features of LCT is strongly dependent on the disease stage at diagnosis (1% for
Folliculotropic Mycosis Fungoides early-stage disease, compared with 27% for stage IIB disease and 56%–
FMF is characterized by the infiltration of hair follicles by atypical T 67% for stage IV disease).7-9 LCT is often, but not always, aggressive.
lymphocytes and resultant alopecia. Disease typically presents as plaques CD30 expression is associated with LCT in MF or SS in 30% to 50% of
and tumors mainly on the head/neck and the risk profile varies with stage cases, and this finding may have potential implications for CD30-directed
of the disease.20,168-171 Recent studies have reported that FMF presents therapies.7-9,176 However, it should be noted that CD30 expression is
with two distinct patterns of clinicopathologic features with different variable in MF and SS, with the leukemic Sézary cells typically being
prognostic implications (early stage and advanced stage); in a subgroup of CD30-negative.
patients with early skin-limited disease, FMF has an indolent disease
Systemic therapy (brentuximab vedotin, gemcitabine, liposomal
course and a favorable prognosis, with early-stage cutaneous disease
doxorubicin, pralatrexate, romidepsin or pembrolizumab) with
MS-28

skin-directed therapies is the initial treatment for generalized cutaneous an updated analysis, advanced stage disease (refractory or progressive
or extracutaneous lesions with LCT. In addition, concurrent management disease after ≥3 lines of systemic therapy prior to transplant), a short
of coexisting disease based on clinical stage is recommended. Selected interval between diagnosis and transplant (<18 months) were independent
patients with localized LCT (ie, restricted to one or few T3 lesions or adverse prognostic factors for PFS; advanced-stage disease and the use
stage IA–IIA plaque disease) could be treated with EBRT alone, with of unrelated donors were independent adverse prognostic factors for
continuation of other treatment modalities used prior to transformation. OS.182
Depending on the goals of treatment, multiagent chemotherapy regimens
recommended for PTCL may be appropriate for the management of LCT In a case series of 47 patients with advanced-stage MF and SS who
that is refractory to multiple prior therapies or when significant underwent allogeneic HCT after failure of standard therapy, the estimated
extracutaneous disease is present. 4-year OS and PFS rates were 51% and 26%, respectively.180 While there
was no statistical difference in the OS in patients who had MF without
Role of Allogeneic Hematopoietic Cell Transplant in MFSS LCT, SS, MF with LCT, or SS with LCT, the 4-year PFS rate was superior
Allogeneic HCT has a role in a subset of patients with advanced-stage in patients who had SS versus those who did not (52% vs.10%; P =
MF and SS who have received multiple lines of therapy as shown in .02). Recent systematic review and meta-analysis have reported pooled
retrospective studies and small prospective series of patients with PFS and OS rates of 36% and 59%, respectively.183,184 Autologous HCT
advanced MF and SS.177-182 is not recommended for patients with CTCL, due to short duration of
response despite its toxicity, thus limiting its utility.185
In a multicenter retrospective analysis of 37 patients with advanced-stage
primary CTCL treated with allogeneic HCT (24 patients [65%] had stage IV While the majority of the deaths among patients undergoing autologous
MFSS or disseminated nodal or visceral involvement), after a median HCT may be attributable to PD, deaths associated with allogeneic HCT
follow-up of 29 months, the incidence of relapse was 56% and the may be more due to NRM (the incidence of 1-year NRM in published
estimated 2-year OS and PFS rates were 57% and 31%, respectively.177 reports with allogeneic HCT is approximately 11% to 25%).177-181
In a retrospective analysis of patients with advanced-stage MF and SS in The use of TSEBT with non-myeloablative allogeneic HCT has also been
the European Group for Blood and Marrow Transplantation (EBMT) evaluated in patients with advanced MF and SS.186-189 In a study of 19
database (n = 60) treated with allogeneic HCT, the 5-year PFS and OS patients with advanced CTCL, the use of TSEBT prior to allogeneic HCT
rates were 32% and 46%, respectively. The corresponding 7-year survival provided improved disease control with an ORR of 68% (58% CR) with
rates were 44% and 30%, respectively.178 The non-relapse mortality median OS not reached at the time of the report; the treatment related
(NRM) rate at 7 years was 22%. Outcomes were not significantly different mortality (TRM) rate was 21%.186 The most recent data comes from a
between histology types. However, patients with advanced-stage disease prospective clinical study that evaluated a non-myeloablative conditioning
had an increased risk of relapse or progression as well as lower PFS, and regimen consisting of TSEBT, total lymphoid irradiation (TLI) +
myeloablative conditioning was associated with poorer NRM and OS. In anti-thymocyte globulin (ATG) in 35 patients with advanced stage disease
(13 patients with MF and 22 patients with SS).187 This regimen was
MS-29

associated with 1-year and 2-year NRM of 3% and 14%, respectively. The Supportive Care
2-year incidence of moderate/severe chronic graft-versus-host disease Management of Pruritus
(GVHD) was 32%. With a median posttransplant follow-up of 5 years, the Symptoms of pruritus can be present in a large majority (nearly 90%) of
2-year, 3-year, and 5-year OS rates were 68%, 62%, and 56%, patients with CTCL, and may be associated with decreased quality of life
respectively. The 5-year PFS rate was 41%. Patients older than 65 years for patients.191-193 Patients should be evaluated for pruritus at each visit.
at the time of transplant had similar clinical outcomes compared with Other potential causes of pruritus (eg, contact dermatitis, atopic dermatitis,
younger patients. This study also evaluated the utilization of psoriasis, other inflammatory skin conditions) should be ruled out. The
high-throughput sequencing (HTS) to monitor minimal residual disease extent of pruritus (localized vs. generalized) and potential correlation
(MRD) and molecular remission after allogeneic HCT (achieved in 43% of between disease site and localization of pruritus should be noted.
patients) was associated with a lower incidence of progressive disease or
relapse. The treatment of pruritus requires optimizing skin-directed and systemic
treatments. Daily use of moisturizers and emollients are helpful in
Allogeneic HCT may be considered for appropriate patients with stage maintaining and protecting the skin barrier. Topical steroids (with or
IIB–IV disease that is refractory to multiple primary treatment options. without occlusion) can be effective in managing the disease and
Based on the limited evidence, patients with erythrodermic MF and SS accompanying pruritus in early-stage disease.193,194 First-line options
appear to receive the most benefit from allogeneic HCT, despite high include H1 antihistamines (single-agent or combination of antihistamines
post-transplant relapse rate. Allogeneic HCT is generally reserved for from different classes) or the anticonvulsant gabapentin.191,195,196
patients with systemic disease and/or extensive skin involvement that is Neurokinin-1 (NK-1) receptor antagonist aprepitant,197-199 the tetracyclic
refractory to or progressive after multiple lines of systemic therapy options. antidepressant mirtazapine, or selective serotonin reuptake inhibitors
When appropriate, TSEBT may be considered as cytoreductive therapy (SSRIs) may be considered in the second-line setting.200,201 Treatment with
before transplant.186,187 Novel conditioning regimens are being explored to the oral opioid receptor antagonist naltrexone may be considered if
provide improved disease control while limiting transplant-related symptoms of pruritus do not resolve with the above agents.202
complications.
Prevention and Treatment of Infections
The ideal timing for allogeneic HCT is when the disease is well controlled Infectious complications are frequent among patients with MF and SS,
with induction therapy and before the disease has progressed to a state particularly cutaneous bacterial infections and cutaneous herpes viral
where the chance of response or survival with allogeneic HCT is low.190 A infections (eg, herpes simplex virus [HSV] or herpes zoster virus [HZV]
transplant decision requires careful counseling to weigh the significant infections).203 Bacteremia/sepsis and bacterial pneumonia were reported
risks of this procedure versus the likelihood of long-term benefits and as the major cause of death due to infections in a retrospective cohort
availability of alternate treatments. study of patients with MF and SS.203 Several preventive measures such as
maintaining/protecting the skin barrier (routine use of skin moisturizers
and/or emollients), bleach baths or soaks (for limited areas only),
MS-30

avoidance of central lines (particularly for erythrodermic patients), and

prophylactic use of mupirocin in cases of Staphylococcus aureus
colonization can be incorporated to minimize infectious complications.
HSV prophylaxis with acyclovir or equivalent should be considered for
patients with frequent recurrence of HSV infection. Patients undergoing
treatment with alemtuzumab-containing regimens should be closely
monitored for cytomegalovirus (CMV) reactivation and preemptively
treated with antivirals to avoid overt CMV disease.
Cultures from skin swab and nares (nostrils) should be taken to evaluate
for S. aureus colonization/infection in patients with erythroderma and an
active or suspected infection. Antimicrobial treatments may include
intranasal mupirocin and/or oral dicloxacillin or cephalexin. Bleach baths
or soaks may be helpful if the affected area is limited. Doxycycline or
trimethoprim/sulfamethoxazole (TMP/SMX) should be considered for
patients with suspected methicillin-resistant S. aureus (MRSA) infection. If
no improvements in infection status are observed with the above agents,
or if bacteremia is suspected, vancomycin should be initiated.
Infection with Gram-negative rods is common in necrotic tumors, and may

lead to serious complications such as bacteremia/sepsis. For active or
suspected infections in patients with ulcerated and necrotic tumors, blood
cultures should be obtained and empiric therapy with antibacterials should
be considered even in the absence of a fever. An antimicrobial agent with
broad-spectrum coverage (including coverage for both Gram-negative
rods and Gram-positive cocci) should be chosen initially. The role of
skin/wound culture is not clear in this setting.
Further information on empiric therapy in cancer patients at risk for

infections is included in the NCCN Guidelines® for the Prevention and
Treatment of Cancer-Related Infections (available at www.NCCN.org).
MS-31
Table 1. Systemic Therapy for MF and SS
Disease stage and

Trial Regimen/Dose ORR Median PFS
No. of patients (n)
Brentuximab vedotin Stage IA–IVB MF
ALCANZA trial 55% (17% CR) 17 months
(1·8 mg/kg every 3 weeks; up to 16 3-week cycles) (n = 48)
(Phase III RCT)a,129
Oral methotrexate (5–50 mg once per week) for up to 48 weeks or Stage IA–IVB MF
13% (2% CR) 4 months
Oral bexarotene (300 mg/m² once per day) for up to 48 weeks (n = 49)
Mogamulizumab (1 mg/kg intravenously [IV] on a weekly basis for the Stage IB–IVA 28% 8 months
MAVORIC trial first 28-day cycle, then on days 1 and 15 of subsequent cycles) (n = 186) (23% by IR) (7 months by IR)
(Phase III RCT)b,87
Stage IB–IVA 5% 3 months
Vorinostat (400 mg daily)
(n = 186) (4% by IR) (4 months by IR)
Stage IA–IIA
300 mg/m2/day 54%
Phase II and III88 Bexarotene (n = 28)
Stage IA–IIA
>300 mg/m2/day 67%
(n = 15)
Stage IIB–IVB
300 mg/m2/day 45%
Phase II and III89 (n = 56)
Bexarotene
Stage IIB–IVB
>300 mg/m2/day 55% (13% CR)
(n = 38)
Stage IB–IVA
Phase IIB91 Vorinostat (400 mg daily) 30%
(n = 74)
Phase II94 Romidepsin (14 mg/m2 as a 4-hour IV infusion on days 1, 8, and 15 of Stage IB–IVA
34% (6% CR)
each 28-day cycle for up to 6 cycles) (n = 96)
PDX-010 Stage IB–IVA 45%
Pralatrexate (15 mg/m2, weekly for 3 out of 4 weeks) Not reached
(Dose-escalation study)96 (n = 29)
Stage III or IV 55% (32% CR)
Phase II100 Alemtuzumab (IV 30 mg)
(n = 22)
86% (21% CR) Median survival
Alemtuzumab (SC 10 mg maximum per administration)c,101 SS (n = 14)
(35 months)
Phase II Stage IIB-IVB 38% 65%
Pembrolizumab (2 mg/kg IV, every 3 weeks)
(CITN-10)105 (n = 24) (1-year PFS rate)
CR, complete response; IR, independent review; MF, mycosis fungoides; ORR, overall response rate; PFS, progression-free survival; a. Median follow-up 46 months; b. Median follow-up 17 months; c.
Subcutaneous alemtuzumab at lower doses given for shorter duration based on Sezary cell levels was associated with a more favorable toxicity profile
MS-32

References 8. Vergier B, de Muret A, Beylot-Barry M, et al. Transformation of mycosis

fungoides: clinicopathological and prognostic features of 45 cases. French
1. Bradford PT, Devesa SS, Anderson WF, Toro JR. Cutaneous Study Group of Cutaneious Lymphomas. Blood 2000;95:2212-2218.
lymphoma incidence patterns in the United States: a population-based Available at: https://www.ncbi.nlm.nih.gov/pubmed/10733487.
study of 3884 cases. Blood 2009;113:5064-5073. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/19279331. 9. Arulogun SO, Prince HM, Ng J, et al. Long-term outcomes of patients
with advanced-stage cutaneous T-cell lymphoma and large cell
2. Willemze R, Cerroni L, Kempf W, et al. The 2018 update of the transformation. Blood 2008;112:3082-3087. Available at:
WHO-EORTC classification for primary cutaneous lymphomas. Blood https://www.ncbi.nlm.nih.gov/pubmed/18647960.
2019;133:1703-1714. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/30635287. 10. Choi J, Goh G, Walradt T, et al. Genomic landscape of cutaneous T
cell lymphoma. Nat Genet 2015;47:1011-1019. Available at:
3. Teras LR, DeSantis CE, Cerhan JR, et al. 2016 US lymphoid https://www.ncbi.nlm.nih.gov/pubmed/26192916.
malignancy statistics by World Health Organization subtypes. CA Cancer J
Clin 2016;66:443-459. Available at: 11. Kann BH, Park HS, Yeboa DN, et al. Annual Facility Treatment
https://www.ncbi.nlm.nih.gov/pubmed/27618563. Volume and Patient Survival for Mycosis Fungoides and Sezary
Syndrome. Clin Lymphoma Myeloma Leuk 2017;17:520-526.e522.
4. Dummer R, Vermeer MH, Scarisbrick JJ, et al. Cutaneous T cell Available at: https://www.ncbi.nlm.nih.gov/pubmed/28655598.
lymphoma. Nat Rev Dis Primers 2021;7:61. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/34446710. 12. PubMed Overview. Available at:
https://pubmed.ncbi.nlm.nih.gov/about/. Accessed June 8, 2022.
5. Campbell JJ, Clark RA, Watanabe R, Kupper TS. Sezary syndrome and
mycosis fungoides arise from distinct T-cell subsets: a biologic rationale 13. Olsen E, Vonderheid E, Pimpinelli N, et al. Revisions to the staging
for their distinct clinical behaviors. Blood 2010;116:767-771. Available at: and classification of mycosis fungoides and Sezary syndrome: a proposal
https://www.ncbi.nlm.nih.gov/pubmed/20484084. of the International Society for Cutaneous Lymphomas (ISCL) and the
cutaneous lymphoma task force of the European Organization of
6. Olsen EA, Rook AH, Zic J, et al. Sezary syndrome: Research and Treatment of Cancer (EORTC). Blood 2007;110:1713-1722.
immunopathogenesis, literature review of therapeutic options, and Available at: https://www.ncbi.nlm.nih.gov/pubmed/17540844.
recommendations for therapy by the United States Cutaneous Lymphoma
Consortium (USCLC). J Am Acad Dermatol 2011;64:352-404. Available at: 14. de Coninck EC, Kim YH, Varghese A, Hoppe RT. Clinical
https://www.ncbi.nlm.nih.gov/pubmed/21145619. characteristics and outcome of patients with extracutaneous mycosis
fungoides. J Clin Oncol 2001;19:779-784. Available at:
7. Diamandidou E, Colome-Grimmer M, Fayad L, et al. Transformation of https://www.ncbi.nlm.nih.gov/pubmed/11157031.
mycosis fungoides/Sezary syndrome: clinical characteristics and
prognosis. Blood 1998;92:1150-1159. Available at: 15. Kim YH, Liu HL, Mraz-Gernhard S, et al. Long-term outcome of 525
https://www.ncbi.nlm.nih.gov/pubmed/9694702. patients with mycosis fungoides and Sezary syndrome: clinical prognostic
factors and risk for disease progression. Arch Dermatol
2003;139:857-866. Available at:
MS-33

16. Vidulich KA, Talpur R, Bassett RL, Duvic M. Overall survival in from the PROspective Cutaneous Lymphoma International Prognostic
erythrodermic cutaneous T-cell lymphoma: an analysis of prognostic Index (PROCLIPI) international study. Br J Dermatol 2021;184:524-531.
factors in a cohort of patients with erythrodermic cutaneous T-cell Available at: https://www.ncbi.nlm.nih.gov/pubmed/32574377.
lymphoma. Int J Dermatol 2009;48:243-252. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/19261011. 23. Quaglino P, Prince HM, Cowan R, et al. Treatment of early-stage
mycosis fungoides: results from the PROspective Cutaneous Lymphoma
17. Agar NS, Wedgeworth E, Crichton S, et al. Survival outcomes and International Prognostic Index (PROCLIPI) study. Br J Dermatol
prognostic factors in mycosis fungoides/Sezary syndrome: validation of 2021;184:722-730. Available at:
the revised International Society for Cutaneous Lymphomas/European https://www.ncbi.nlm.nih.gov/pubmed/32479678.
Organisation for Research and Treatment of Cancer staging proposal. J
Clin Oncol 2010;28:4730-4739. Available at: 24. Kim EJ, Hess S, Richardson SK, et al. Immunopathogenesis and
https://www.ncbi.nlm.nih.gov/pubmed/20855822. therapy of cutaneous T cell lymphoma. J Clin Invest 2005;115:798-812.
18. Talpur R, Singh L, Daulat S, et al. Long-term outcomes of 1,263
patients with mycosis fungoides and Sezary syndrome from 1982 to 2009. 25. Battistella M, Beylot-Barry M, Bachelez H, et al. Primary cutaneous
Clin Cancer Res 2012;18:5051-5060. Available at: follicular helper T-cell lymphoma: a new subtype of cutaneous T-cell
https://www.ncbi.nlm.nih.gov/pubmed/22850569. lymphoma reported in a series of 5 cases. Arch Dermatol
2012;148:832-839. Available at:
19. Alberti-Violetti S, Talpur R, Schlichte M, et al. Advanced-stage mycosis https://www.ncbi.nlm.nih.gov/pubmed/22508770.
fungoides and Sezary syndrome: survival and response to treatment. Clin
Lymphoma Myeloma Leuk 2015;15:e105-112. Available at: 26. Wang JY, Nguyen GH, Ruan J, Magro CM. Primary Cutaneous
https://www.ncbi.nlm.nih.gov/pubmed/25817937. Follicular Helper T-Cell Lymphoma: A Case Series and Review of the
Literature. Am J Dermatopathol 2017;39:374-383. Available at:
20. Scarisbrick JJ, Prince HM, Vermeer MH, et al. Cutaneous Lymphoma https://www.ncbi.nlm.nih.gov/pubmed/28375859.
International Consortium Study of Outcome in Advanced Stages of
Mycosis Fungoides and Sezary Syndrome: Effect of Specific Prognostic 27. Bosisio FM, Cerroni L. Expression of T-follicular helper markers in
Markers on Survival and Development of a Prognostic Model. J Clin Oncol sequential biopsies of progressive mycosis fungoides and other primary
2015;33:3766-3773. Available at: cutaneous T-cell lymphomas. Am J Dermatopathol 2015;37:115-121.
https://www.ncbi.nlm.nih.gov/pubmed/26438120. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25406852.
21. Scarisbrick JJ, Quaglino P, Prince HM, et al. The PROCLIPI 28. Park JH, Han JH, Kang HY, et al. Expression of follicular helper T-cell
international registry of early-stage mycosis fungoides identifies markers in primary cutaneous T-cell lymphoma. Am J Dermatopathol
substantial diagnostic delay in most patients. Br J Dermatol 2014;36:465-470. Available at:
29. Thurber SE, Zhang B, Kim YH, et al. T-cell clonality analysis in biopsy
22. Hodak E, Sherman S, Papadavid E, et al. Should we be imaging specimens from two different skin sites shows high specificity in the
lymph nodes at initial diagnosis of early-stage mycosis fungoides? Results diagnosis of patients with suggested mycosis fungoides. J Am Acad
MS-34

Dermatol 2007;57:782-790. Available at: 37. Kartan S, Shalabi D, O'Donnell M, et al. Response to topical
https://www.ncbi.nlm.nih.gov/pubmed/17646032. corticosteroid monotherapy in mycosis fungoides. J Am Acad Dermatol
2021;84:615-623. Available at:
30. Zhang B, Beck AH, Taube JM, et al. Combined use of PCR-based https://www.ncbi.nlm.nih.gov/pubmed/32428610.
TCRG and TCRB clonality tests on paraffin-embedded skin tissue in the
differential diagnosis of mycosis fungoides and inflammatory dermatoses. 38. Kim YH, Martinez G, Varghese A, Hoppe RT. Topical nitrogen mustard
J Mol Diagn 2010;12:320-327. Available at: in the management of mycosis fungoides: update of the Stanford
https://www.ncbi.nlm.nih.gov/pubmed/20203005. experience. Arch Dermatol 2003;139:165-173. Available at:
31. Kirsch IR, Watanabe R, O'Malley JT, et al. TCR sequencing facilitates
diagnosis and identifies mature T cells as the cell of origin in CTCL. Sci 39. Lessin SR, Duvic M, Guitart J, et al. Topical chemotherapy in
Transl Med 2015;7:308ra158. Available at: cutaneous T-cell lymphoma: positive results of a randomized, controlled,
https://www.ncbi.nlm.nih.gov/pubmed/26446955. multicenter trial testing the efficacy and safety of a novel
mechlorethamine, 0.02%, gel in mycosis fungoides. JAMA Dermatol
32. de Masson A, O'Malley JT, Elco CP, et al. High-throughput 2013;149:25-32. Available at:
sequencing of the T cell receptor beta gene identifies aggressive https://www.ncbi.nlm.nih.gov/pubmed/23069814.
early-stage mycosis fungoides. Sci Transl Med 2018;10:eaar5894.
Available at: https://www.ncbi.nlm.nih.gov/pubmed/29743350. 40. Breneman D, Duvic M, Kuzel T, et al. Phase 1 and 2 trial of
bexarotene gel for skin-directed treatment of patients with cutaneous
33. Horna P, Wang SA, Wolniak KL, et al. Flow cytometric evaluation of T-cell lymphoma. Arch Dermatol 2002;138:325-332. Available at:
peripheral blood for suspected Sezary syndrome or mycosis fungoides: https://www.ncbi.nlm.nih.gov/pubmed/11902983.
International guidelines for assay characteristics. Cytometry B Clin Cytom
2021;100:142-155. Available at: 41. Heald P, Mehlmauer M, Martin AG, et al. Topical bexarotene therapy
https://www.ncbi.nlm.nih.gov/pubmed/32319723. for patients with refractory or persistent early-stage cutaneous T-cell
lymphoma: results of the phase III clinical trial. J Am Acad Dermatol
34. Tsai EY, Taur A, Espinosa L, et al. Staging accuracy in mycosis 2003;49:801-815. Available at:
fungoides and sezary syndrome using integrated positron emission https://www.ncbi.nlm.nih.gov/pubmed/14576658.
tomography and computed tomography. Arch Dermatol
2006;142:577-584. Available at: 42. Apisarnthanarax N, Talpur R, Ward S, et al. Tazarotene 0.1% gel for
https://www.ncbi.nlm.nih.gov/pubmed/16702495. refractory mycosis fungoides lesions: an open-label pilot study. J Am Acad
Dermatol 2004;50:600-607. Available at:
35. Zackheim HS, Kashani-Sabet M, Amin S. Topical corticosteroids for https://www.ncbi.nlm.nih.gov/pubmed/15034511.
mycosis fungoides. Experience in 79 patients. Arch Dermatol
1998;134:949-954. Available at: 43. Besner Morin C, Roberge D, Turchin I, et al. Tazarotene 0.1% Cream
https://www.ncbi.nlm.nih.gov/pubmed/9722724. as Monotherapy for Early-Stage Cutaneous T-Cell Lymphoma. J Cutan
Med Surg 2016;20:244-248. Available at:
36. Zackheim HS. Treatment of patch-stage mycosis fungoides with https://www.ncbi.nlm.nih.gov/pubmed/26742957.
topical corticosteroids. Dermatol Ther 2003;16:283-287. Available at:
MS-35

44. Deeths MJ, Chapman JT, Dellavalle RP, et al. Treatment of patch and 52. Neelis KJ, Schimmel EC, Vermeer MH, et al. Low-dose palliative
plaque stage mycosis fungoides with imiquimod 5% cream. J Am Acad radiotherapy for cutaneous B- and T-cell lymphomas. Int J Radiat Oncol
Dermatol 2005;52:275-280. Available at: Biol Phys 2009;74:154-158. Available at:
45. Coors EA, Schuler G, Von Den Driesch P. Topical imiquimod as 53. Thomas TO, Agrawal P, Guitart J, et al. Outcome of patients treated
treatment for different kinds of cutaneous lymphoma. Eur J Dermatol with a single-fraction dose of palliative radiation for cutaneous T-cell
2006;16:391-393. Available at: lymphoma. Int J Radiat Oncol Biol Phys 2013;85:747-753. Available at:
46. Martinez-Gonzalez MC, Verea-Hernando MM, Yebra-Pimentel MT, et 54. Ysebaert L, Truc G, Dalac S, et al. Ultimate results of radiation therapy
al. Imiquimod in mycosis fungoides. Eur J Dermatol 2008;18:148-152. for T1-T2 mycosis fungoides (including reirradiation). Int J Radiat Oncol
Available at: https://www.ncbi.nlm.nih.gov/pubmed/18424373. Biol Phys 2004;58:1128-1134. Available at:
47. Lewis DJ, Byekova YA, Emge DA, Duvic M. Complete resolution of
mycosis fungoides tumors with imiquimod 5% cream: a case series. J 55. Harrison C, Young J, Navi D, et al. Revisiting low-dose total skin
Dermatolog Treat 2017;28:567-569. Available at: electron beam therapy in mycosis fungoides. Int J Radiat Oncol Biol Phys
https://www.ncbi.nlm.nih.gov/pubmed/28635518. 2011;81:e651-657. Available at:
48. Zackheim HS. Topical carmustine (BCNU) for patch/plaque mycosis
fungoides. Semin Dermatol 1994;13:202-206. Available at: 56. Navi D, Riaz N, Levin YS, et al. The Stanford University experience
https://www.ncbi.nlm.nih.gov/pubmed/7986689. with conventional-dose, total skin electron-beam therapy in the treatment
of generalized patch or plaque (T2) and tumor (T3) mycosis fungoides.
49. Zackheim HS. Topical carmustine (BCNU) in the treatment of mycosis Arch Dermatol 2011;147:561-567. Available at:
fungoides. Dermatol Ther 2003;16:299-302. Available at: https://www.ncbi.nlm.nih.gov/pubmed/21576575.
57. Elsayad K, Kriz J, Moustakis C, et al. Total Skin Electron Beam for
50. Piccinno R, Caccialanza M, Cuka E, Recalcati S. Localized Primary Cutaneous T-cell Lymphoma. Int J Radiat Oncol Biol Phys
conventional radiotherapy in the treatment of Mycosis Fungoides: our 2015;93:1077-1086. Available at:
experience in 100 patients. J Eur Acad Dermatol Venereol https://www.ncbi.nlm.nih.gov/pubmed/26581145.
2014;28:1040-1044. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/23998331. 58. Kamstrup MR, Lindahl LM, Gniadecki R, et al. Low-dose total skin
electron beam therapy as a debulking agent for cutaneous T-cell
51. Specht L, Dabaja B, Illidge T, et al. Modern radiation therapy for lymphoma: an open-label prospective phase II study. Br J Dermatol
primary cutaneous lymphomas: field and dose guidelines from the 2012;166:399-404. Available at:
International Lymphoma Radiation Oncology Group. Int J Radiat Oncol https://www.ncbi.nlm.nih.gov/pubmed/21967035.
Biol Phys 2015;92:32-39. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/25863751. 59. Hoppe RT, Harrison C, Tavallaee M, et al. Low-dose total skin electron
beam therapy as an effective modality to reduce disease burden in
MS-36

patients with mycosis fungoides: results of a pooled analysis from 3 66. Kudelka MR, Switchenko JM, Lechowicz MJ, et al. Maintenance
phase-II clinical trials. J Am Acad Dermatol 2015;72:286-292. Available at: Therapy for Cutaneous T-cell Lymphoma After Total Skin Electron
https://www.ncbi.nlm.nih.gov/pubmed/25476993. Irradiation: Evidence for Improved Overall Survival With Ultraviolet
Therapy. Clin Lymphoma Myeloma Leuk 2020;20:757-767 e753. Available
60. Kamstrup MR, Gniadecki R, Iversen L, et al. Low-dose (10-Gy) total at: https://www.ncbi.nlm.nih.gov/pubmed/32703750.
skin electron beam therapy for cutaneous T-cell lymphoma: an open
clinical study and pooled data analysis. Int J Radiat Oncol Biol Phys 67. Elsayad K, Rolf D, Sunderkotter C, et al. Low-dose total skin electron
2015;92:138-143. Available at: beam therapy plus oral bexarotene maintenance therapy for cutaneous
https://www.ncbi.nlm.nih.gov/pubmed/25863761. T-cell lymphoma. J Dtsch Dermatol Ges 2022;20:279-285. Available at:
61. Kroeger K, Elsayad K, Moustakis C, et al. Low-dose total skin electron
beam therapy for cutaneous lymphoma : Minimal risk of acute toxicities. 68. Gathers RC, Scherschun L, Malick F, et al. Narrowband UVB
Strahlenther Onkol 2017;193:1024-1030. Available at: phototherapy for early-stage mycosis fungoides. J Am Acad Dermatol
https://www.ncbi.nlm.nih.gov/pubmed/28785772. 2002;47:191-197. Available at:
62. Morris S, Scarisbrick J, Frew J, et al. The Results of Low-Dose Total
Skin Electron Beam Radiation Therapy (TSEB) in Patients With Mycosis 69. Dereure O, Picot E, Comte C, et al. Treatment of early stages of
Fungoides From the UK Cutaneous Lymphoma Group. Int J Radiat Oncol mycosis fungoides with narrowband ultraviolet B. A clinical, histological
Biol Phys 2017;99:627-633. Available at: and molecular evaluation of results. Dermatology 2009;218:1-6. Available
https://www.ncbi.nlm.nih.gov/pubmed/28843374. at: https://www.ncbi.nlm.nih.gov/pubmed/18832806.
63. Georgakopoulos I, Papadavid E, Platoni K, et al. Low dose total skin 70. Gokdemir G, Barutcuoglu B, Sakiz D, Koslu A. Narrowband UVB
electron beam therapy for the management of T cell cutaneous phototherapy for early-stage mycosis fungoides: evaluation of clinical and
lymphomas. Dermatol Ther 2020;33:e13478. Available at: histopathological changes. J Eur Acad Dermatol Venereol
64. Song A, Gochoco A, Zhan T, et al. A prospective cohort study of
condensed low-dose total skin electron beam therapy for mycosis 71. Drucker AM, Baibergenova A, Rosen CF, Shear NH. Narrowband UVB
fungoides: Reduction of disease burden and improvement in quality of life. as an effective substitute for psoralen plus UVA: lessons from a psoralen
J Am Acad Dermatol 2020;83:78-85. Available at: shortage. Photodermatol Photoimmunol Photomed 2012;28:267-268.
65. Elsayad K, Kroeger K, Greve B, et al. Low-dose total skin electron 72. Elcin G, Duman N, Karahan S, et al. Long-term follow-up of early
beam therapy: Quality of life improvement and clinical impact of mycosis fungoides patients treated with narrowband ultraviolet B
maintenance and adjuvant treatment in patients with mycosis fungoides or phototherapy. J Dermatolog Treat 2014;25:268-273. Available at:
Sezary syndrome. Strahlenther Onkol 2020;196:77-84. Available at: https://www.ncbi.nlm.nih.gov/pubmed/23030414.
73. Querfeld C, Rosen ST, Kuzel TM, et al. Long-term follow-up of patients
with early-stage cutaneous T-cell lymphoma who achieved complete
MS-37

remission with psoralen plus UV-A monotherapy. Arch Dermatol 80. Ahmad K, Rogers S, McNicholas PD, Collins P. Narrowband UVB and
2005;141:305-311. Available at: PUVA in the treatment of mycosis fungoides: a retrospective study. Acta
https://www.ncbi.nlm.nih.gov/pubmed/15781671. Derm Venereol 2007;87:413-417. Available at:
74. Pavlotsky F, Hodak E, Ben Amitay D, Barzilai A. Role of bath psoralen
plus ultraviolet A in early-stage mycosis fungoides. J Am Acad Dermatol 81. Ponte P, Serrao V, Apetato M. Efficacy of narrowband UVB vs. PUVA
2014;71:536-541. Available at: in patients with early-stage mycosis fungoides. J Eur Acad Dermatol
https://www.ncbi.nlm.nih.gov/pubmed/24836546. Venereol 2010;24:716-721. Available at:
75. Amitay-Laish I, Prag-Naveh H, Dalal A, et al. Treatment of Early
Folliculotropic Mycosis Fungoides with Special Focus on Psoralen plus 82. Diederen PV, van Weelden H, Sanders CJ, et al. Narrowband UVB
Ultraviolet A. Acta Derm Venereol 2018;98:951-955. Available at: and psoralen-UVA in the treatment of early-stage mycosis fungoides: a
https://www.ncbi.nlm.nih.gov/pubmed/30085321. retrospective study. J Am Acad Dermatol 2003;48:215-219. Available at:
76. Vieyra-Garcia P, Fink-Puches R, Porkert S, et al. Evaluation of
Low-Dose, Low-Frequency Oral Psoralen-UV-A Treatment With or Without 83. Hearn RM, Kerr AC, Rahim KF, et al. Incidence of skin cancers in
Maintenance on Early-Stage Mycosis Fungoides: A Randomized Clinical 3867 patients treated with narrow-band ultraviolet B phototherapy. Br J
Trial. JAMA Dermatol 2019;155:538-547. Available at: Dermatol 2008;159:931-935. Available at:
77. Almohideb M, Walsh S, Walsh S, et al. Bath Psoralen-ultraviolet A and 84. Olsen EA, Hodak E, Anderson T, et al. Guidelines for phototherapy of
Narrowband Ultraviolet B Phototherapy as Initial Therapy for Early-stage mycosis fungoides and Sezary syndrome: A consensus statement of the
Mycosis Fungoides: A Retrospective Cohort of 267 Cases at the United States Cutaneous Lymphoma Consortium. J Am Acad Dermatol
University of Toronto. Clin Lymphoma Myeloma Leuk 2017;17:604-612. 2016;74:27-58. Available at:
Available at: https://www.ncbi.nlm.nih.gov/pubmed/28711574. https://www.ncbi.nlm.nih.gov/pubmed/26547257.
78. Nikolaou V, Sachlas A, Papadavid E, et al. Phototherapy as a first-line 85. Ahad T, Wang EY, Liu YA, et al. Incidence of skin cancers in patients
treatment for early-stage mycosis fungoides: The results of a large with eczema treated with ultraviolet phototherapy. J Am Acad Dermatol
retrospective analysis. Photodermatol Photoimmunol Photomed 2021. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34864113.
2018;34:307-313. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/29533478. 86. Prince HM, Kim YH, Horwitz SM, et al. Brentuximab vedotin or
physician's choice in CD30-positive cutaneous T-cell lymphoma
79. Phan K, Ramachandran V, Fassihi H, Sebaratnam DF. Comparison of (ALCANZA): an international, open-label, randomised, phase 3,
Narrowband UV-B With Psoralen-UV-A Phototherapy for Patients With multicentre trial. Lancet 2017;390:555-566. Available at:
Early-Stage Mycosis Fungoides: A Systematic Review and Meta-analysis. https://www.ncbi.nlm.nih.gov/pubmed/28600132.
JAMA Dermatol 2019;155:335-341. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/30698622. 87. Kim YH, Bagot M, Pinter-Brown L, et al. Mogamulizumab versus
vorinostat in previously treated cutaneous T-cell lymphoma (MAVORIC):
an international, open-label, randomised, controlled phase 3 trial. Lancet
MS-38

Oncol 2018;19:1192-1204. Available at: 95. Kim EJ, Kim YH, Rook AH, et al. Clinically significant responses
https://www.ncbi.nlm.nih.gov/pubmed/30100375. achieved with romidepsin across disease compartments in patients with
cutaneous T-cell lymphoma. Leuk Lymphoma 2015;56:2847-2854.
88. Duvic M, Martin AG, Kim Y, et al. Phase 2 and 3 clinical trial of oral Available at: https://www.ncbi.nlm.nih.gov/pubmed/25791237.
bexarotene (Targretin capsules) for the treatment of refractory or
persistent early-stage cutaneous T-cell lymphoma. Arch Dermatol 96. Horwitz SM, Kim YH, Foss F, et al. Identification of an active,
2001;137:581-593. Available at: well-tolerated dose of pralatrexate in patients with relapsed or refractory
https://www.ncbi.nlm.nih.gov/pubmed/11346336. cutaneous T-cell lymphoma. Blood 2012;119:4115-4122. Available at:
89. Duvic M, Hymes K, Heald P, et al. Bexarotene is effective and safe for
treatment of refractory advanced-stage cutaneous T-cell lymphoma: 97. Foss F, Horwitz SM, Coiffier B, et al. Pralatrexate is an effective
multinational phase II-III trial results. J Clin Oncol 2001;19:2456-2471. treatment for relapsed or refractory transformed mycosis fungoides: a
Available at: https://www.ncbi.nlm.nih.gov/pubmed/11331325. subgroup efficacy analysis from the PROPEL study. Clin Lymphoma
Myeloma Leuk 2012;12:238-243. Available at:
90. Duvic M, Talpur R, Ni X, et al. Phase 2 trial of oral vorinostat https://www.ncbi.nlm.nih.gov/pubmed/22542448.
(suberoylanilide hydroxamic acid, SAHA) for refractory cutaneous T-cell
lymphoma (CTCL). Blood 2007;109:31-39. Available at: 98. Talpur R, Thompson A, Gangar P, Duvic M. Pralatrexate alone or in
https://www.ncbi.nlm.nih.gov/pubmed/16960145. combination with bexarotene: long-term tolerability in relapsed/refractory
mycosis fungoides. Clin Lymphoma Myeloma Leuk 2014;14:297-304.
91. Olsen EA, Kim YH, Kuzel TM, et al. Phase IIb multicenter trial of Available at: https://www.ncbi.nlm.nih.gov/pubmed/24589156.
vorinostat in patients with persistent, progressive, or treatment refractory
cutaneous T-cell lymphoma. J Clin Oncol 2007;25:3109-3115. Available 99. Kennedy GA, Seymour JF, Wolf M, et al. Treatment of patients with
at: https://www.ncbi.nlm.nih.gov/pubmed/17577020. advanced mycosis fungoides and Sezary syndrome with alemtuzumab.
Eur J Haematol 2003;71:250-256. Available at:
92. Duvic M, Olsen EA, Breneman D, et al. Evaluation of the long-term https://www.ncbi.nlm.nih.gov/pubmed/12950233.
tolerability and clinical benefit of vorinostat in patients with advanced
cutaneous T-cell lymphoma. Clin Lymphoma Myeloma 2009;9:412-416. 100. Lundin J, Hagberg H, Repp R, et al. Phase 2 study of alemtuzumab
Available at: https://www.ncbi.nlm.nih.gov/pubmed/19951879. (anti-CD52 monoclonal antibody) in patients with advanced mycosis
fungoides/Sezary syndrome. Blood 2003;101:4267-4272. Available at:
93. Piekarz RL, Frye R, Turner M, et al. Phase II multi-institutional trial of https://www.ncbi.nlm.nih.gov/pubmed/12543862.
the histone deacetylase inhibitor romidepsin as monotherapy for patients
with cutaneous T-cell lymphoma. J Clin Oncol 2009;27:5410-5417. 101. Bernengo MG, Quaglino P, Comessatti A, et al. Low-dose intermittent
Available at: http://www.ncbi.nlm.nih.gov/pubmed/19826128. alemtuzumab in the treatment of Sezary syndrome: clinical and
immunologic findings in 14 patients. Haematologica 2007;92:784-794.
94. Whittaker SJ, Demierre MF, Kim EJ, et al. Final results from a Available at: https://www.ncbi.nlm.nih.gov/pubmed/17550851.
multicenter, international, pivotal study of romidepsin in refractory
cutaneous T-cell lymphoma. J Clin Oncol 2010;28:4485-4491. Available 102. Alinari L, Geskin L, Grady T, et al. Subcutaneous alemtuzumab for
at: https://www.ncbi.nlm.nih.gov/pubmed/20697094. Sezary Syndrome in the very elderly. Leuk Res 2008;32:1299-1303.
Available at: http://www.ncbi.nlm.nih.gov/pubmed/18096224.
MS-39

103. Querfeld C, Mehta N, Rosen ST, et al. Alemtuzumab for relapsed and data and a brief overview of the literature. Int J Dermatol
refractory erythrodermic cutaneous T-cell lymphoma: a single institution 2013;52:1308-1318. Available at:
experience from the Robert H. Lurie Comprehensive Cancer Center. Leuk https://www.ncbi.nlm.nih.gov/pubmed/23786842.
Lymphoma 2009;50:1969-1976. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/19860617. 111. Knobler R, Arenberger P, Arun A, et al. European dermatology
forum - updated guidelines on the use of extracorporeal photopheresis
104. de Masson A, Guitera P, Brice P, et al. Long-term efficacy and safety 2020 - part 1. J Eur Acad Dermatol Venereol 2020;34:2693-2716.
of alemtuzumab in advanced primary cutaneous T-cell lymphomas. Br J Available at: https://www.ncbi.nlm.nih.gov/pubmed/33025659.
Dermatol 2014;170:720-724. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/24438061. 112. Zinzani PL, Baliva G, Magagnoli M, et al. Gemcitabine treatment in
pretreated cutaneous T-cell lymphoma: experience in 44 patients. J Clin
105. Khodadoust MS, Rook AH, Porcu P, et al. Pembrolizumab in Oncol 2000;18:2603-2606. Available at:
Relapsed and Refractory Mycosis Fungoides and Sezary Syndrome: A https://www.ncbi.nlm.nih.gov/pubmed/10893292.
Multicenter Phase II Study. J Clin Oncol 2020;38:20-28. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/31532724. 113. Duvic M, Talpur R, Wen S, et al. Phase II evaluation of gemcitabine
monotherapy for cutaneous T-cell lymphoma. Clin Lymphoma Myeloma
106. Olsen EA. Interferon in the treatment of cutaneous T-cell lymphoma. 2006;7:51-58. Available at:
Dermatol Ther 2003;16:311-321. Available at: https://www.ncbi.nlm.nih.gov/pubmed/16879770.
114. Jidar K, Ingen-Housz-Oro S, Beylot-Barry M, et al. Gemcitabine
107. Kaplan EH, Rosen ST, Norris DB, et al. Phase II study of treatment in cutaneous T-cell lymphoma: a multicentre study of 23 cases.
recombinant human interferon gamma for treatment of cutaneous T-cell Br J Dermatol 2009;161:660-663. Available at:
lymphoma. J Natl Cancer Inst 1990;82:208-212. Available at: https://www.ncbi.nlm.nih.gov/pubmed/19438862.
115. Pellegrini C, Stefoni V, Casadei B, et al. Long-term outcome of
108. Zackheim HS, Kashani-Sabet M, McMillan A. Low-dose methotrexate patients with advanced-stage cutaneous T cell lymphoma treated with
to treat mycosis fungoides: a retrospective study in 69 patients. J Am Acad gemcitabine. Ann Hematol 2014;93:1853-1857. Available at:
116. Pulini S, Rupoli S, Goteri G, et al. Pegylated liposomal doxorubicin in
109. McGirt LY, Thoburn C, Hess A, Vonderheid EC. Predictors of the treatment of primary cutaneous T-cell lymphomas. Haematologica
response to extracorporeal photopheresis in advanced mycosis fungoides 2007;92:686-689. Available at:
and Sezary syndrome. Photodermatol Photoimmunol Photomed https://www.ncbi.nlm.nih.gov/pubmed/17488695.
2010;26:182-191. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/20626820. 117. Quereux G, Marques S, Nguyen JM, et al. Prospective multicenter
study of pegylated liposomal doxorubicin treatment in patients with
110. Quaglino P, Knobler R, Fierro MT, et al. Extracorporeal advanced or refractory mycosis fungoides or Sezary syndrome. Arch
photopheresis for the treatment of erythrodermic cutaneous T-cell Dermatol 2008;144:727-733. Available at:
lymphoma: a single center clinical experience with long-term follow-up https://www.ncbi.nlm.nih.gov/pubmed/18559761.
MS-40

118. Dummer R, Quaglino P, Becker JC, et al. Prospective international The Hellenic experience. Transfus Apher Sci 2012;46:189-193. Available
multicenter phase II trial of intravenous pegylated liposomal doxorubicin at: https://www.ncbi.nlm.nih.gov/pubmed/22178592.
monochemotherapy in patients with stage IIB, IVA, or IVB advanced
mycosis fungoides: final results from EORTC 21012. J Clin Oncol 125. Querfeld C, Rosen ST, Guitart J, et al. Comparison of selective
2012;30:4091-4097. Available at: retinoic acid receptor- and retinoic X receptor-mediated efficacy, tolerance,
https://www.ncbi.nlm.nih.gov/pubmed/23045580. and survival in cutaneous t-cell lymphoma. J Am Acad Dermatol
2004;51:25-32. Available at:
119. Hughes CF, Khot A, McCormack C, et al. Lack of durable disease https://www.ncbi.nlm.nih.gov/pubmed/15243520.
control with chemotherapy for mycosis fungoides and Sezary syndrome: a
comparative study of systemic therapy. Blood 2015;125:71-81. Available 126. Cheeley J, Sahn RE, DeLong LK, Parker SR. Acitretin for the
at: https://www.ncbi.nlm.nih.gov/pubmed/25336628. treatment of cutaneous T-cell lymphoma. J Am Acad Dermatol
2013;68:247-254. Available at:
120. Quaglino P, Maule M, Prince HM, et al. Global patterns of care in https://www.ncbi.nlm.nih.gov/pubmed/22917895.
advanced stage mycosis fungoides/Sezary syndrome: a multicenter
retrospective follow-up study from the Cutaneous Lymphoma International 127. Amitay-Laish I, Reiter O, Prag-Naveh H, et al. Retinoic acid receptor
Consortium. Ann Oncol 2017;28:2517-2525. Available at: agonist as monotherapy for early-stage mycosis fungoides: does it work?
https://www.ncbi.nlm.nih.gov/pubmed/28961843. J Dermatolog Treat 2019;30:258-263. Available at:
121. Whittaker S, Ortiz P, Dummer R, et al. Efficacy and safety of
bexarotene combined with psoralen-ultraviolet A (PUVA) compared with 128. Nikolaou V, Patsatsi A, Sidiropoulou P, et al. Monotherapy and
PUVA treatment alone in stage IB-IIA mycosis fungoides: final results from combination therapy with acitretin for mycosis fungoides: results of a
the EORTC Cutaneous Lymphoma Task Force phase III randomized retrospective, multicentre study. J Eur Acad Dermatol Venereol
clinical trial (NCT00056056). Br J Dermatol 2012;167:678-687. Available 2020;34:2534-2540. Available at:
at: https://www.ncbi.nlm.nih.gov/pubmed/22924950. https://www.ncbi.nlm.nih.gov/pubmed/32364303.
122. Duvic M, Apisarnthanarax N, Cohen DS, et al. Analysis of long-term 129. Horwitz SM, Scarisbrick JJ, Dummer R, et al. Randomized phase 3
outcomes of combined modality therapy for cutaneous T-cell lymphoma. J ALCANZA study of brentuximab vedotin vs physician's choice in
Am Acad Dermatol 2003;49:35-49. Available at: cutaneous T-cell lymphoma: final data. Blood Adv 2021;5:5098-5106.
123. Straus DJ, Duvic M, Kuzel T, et al. Results of a phase II trial of oral 130. Kim YH, Prince HM, Whittaker S, et al. Response to brentuximab
bexarotene (Targretin) combined with interferon alfa-2b (Intron-A) for vedotin versus physician's choice by CD30 expression and large cell
patients with cutaneous T-cell lymphoma. Cancer 2007;109:1799-1803. transformation status in patients with mycosis fungoides: An ALCANZA
Available at: https://www.ncbi.nlm.nih.gov/pubmed/17366595. sub-analysis. Eur J Cancer 2021;148:411-421. Available at:
124. Siakantaris MP, Tsirigotis P, Stavroyianni N, et al. Management of
cutaneous T-Cell lymphoma patients with extracorporeal photopheresis. 131. Duvic M, Tetzlaff MT, Gangar P, et al. Results of a Phase II Trial of
Brentuximab Vedotin for CD30+ Cutaneous T-Cell Lymphoma and
MS-41

Lymphomatoid Papulosis. J Clin Oncol 2015;33:3759-3765. Available at: 138. Hirotsu KE, Neal TM, Khodadoust MS, et al. Clinical Characterization
https://www.ncbi.nlm.nih.gov/pubmed/26261247. of Mogamulizumab-Associated Rash During Treatment of Mycosis
Fungoides or Sezary Syndrome. JAMA Dermatol 2021;157:700-707.
132. Kim YH, Tavallaee M, Sundram U, et al. Phase II Available at: https://www.ncbi.nlm.nih.gov/pubmed/33881447.
Investigator-Initiated Study of Brentuximab Vedotin in Mycosis Fungoides
and Sezary Syndrome With Variable CD30 Expression Level: A 139. Trum NA, Zain J, Martinez XU, et al. Mogamulizumab efficacy is
Multi-Institution Collaborative Project. J Clin Oncol 2015;33:3750-3758. underscored by its associated rash that mimics cutaneous T-cell
Available at: https://www.ncbi.nlm.nih.gov/pubmed/26195720. lymphoma: a retrospective single-centre case series. Br J Dermatol
2022;186:153-166. Available at:
133. Dummer R, Prince HM, Whittaker S, et al. Patient-reported quality of https://www.ncbi.nlm.nih.gov/pubmed/34427917.
life in patients with relapsed/refractory cutaneous T-cell lymphoma:
Results from the randomised phase III ALCANZA study. Eur J Cancer 140. Wang JY, Hirotsu KE, Neal TM, et al. Histopathologic
2020;133:120-130. Available at: Characterization of Mogamulizumab-associated Rash. Am J Surg Pathol
134. Lewis DJ, Haun PL, Samimi SS, et al. Brentuximab Vedotin for
Relapsed or Refractory Sezary Syndrome. JAMA Dermatol 141. Wang J, de Masson A, Ram-Wolff C, et al. Granulomatous rash
2021;157:317-321. Available at: associated with mogamulizumab mimicking mycosis fungoides: a case
https://www.ncbi.nlm.nih.gov/pubmed/33377934. series. Eur J Cancer 2021;156 Suppl 1:S49. Available at:
135. Horwitz S, Zinzani PL, Bagot M, et al. Lack of impact of type and 142. Chen L, Carson KR, Staser KW, et al. Mogamulizumab-Associated
extent of prior therapy on outcomes of mogamulizumab therapy in patients Cutaneous Granulomatous Drug Eruption Mimicking Mycosis Fungoides
with cutaneous T cell lymphoma in the MAVORIC trial. Leuk Lymphoma but Possibly Indicating Durable Clinical Response. JAMA Dermatol
2021;62:3109-3118. Available at: 2019;155:968-971. Available at:
143. Musiek ACM, Rieger KE, Bagot M, et al. Dermatologic Events
136. Porcu P, Hudgens S, Horwitz S, et al. Quality of Life Effect of the Associated with the Anti-CCR4 Antibody Mogamulizumab:
Anti-CCR4 Monoclonal Antibody Mogamulizumab Versus Vorinostat in Characterization and Management. Dermatol Ther (Heidelb)
Patients With Cutaneous T-cell Lymphoma. Clin Lymphoma Myeloma 2022;12:29-40. Available at:
Leuk 2021;21:97-105. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34816383.
144. Marchi E, Alinari L, Tani M, et al. Gemcitabine as frontline treatment
137. Cowan RA, Scarisbrick JJ, Zinzani PL, et al. Efficacy and safety of for cutaneous T-cell lymphoma: phase II study of 32 patients. Cancer
mogamulizumab by patient baseline blood tumour burden: a post hoc 2005;104:2437-2441. Available at:
analysis of the MAVORIC trial. J Eur Acad Dermatol Venereol https://www.ncbi.nlm.nih.gov/pubmed/16216001.
2021;35:2225-2238. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/34273208. 145. Bisaccia E, Gonzalez J, Palangio M, et al. Extracorporeal
photochemotherapy alone or with adjuvant therapy in the treatment of
cutaneous T-cell lymphoma: a 9-year retrospective study at a single
MS-42

institution. J Am Acad Dermatol 2000;43:263-271. Available at: outcome in the treatment of Sezary syndrome and erythrodermic mycosis
https://www.ncbi.nlm.nih.gov/pubmed/10906649. fungoides with extracorporeal photopheresis. Arch Dermatol
2002;138:1347-1350. Available at:
146. Zic JA. The treatment of cutaneous T-cell lymphoma with https://www.ncbi.nlm.nih.gov/pubmed/12374541.
photopheresis. Dermatol Ther 2003;16:337-346. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/14686977. 154. Stadler R, Otte HG, Luger T, et al. Prospective randomized
multicenter clinical trial on the use of interferon -2a plus acitretin versus
147. Arulogun S, Prince HM, Gambell P, et al. Extracorporeal interferon -2a plus PUVA in patients with cutaneous T-cell lymphoma
photopheresis for the treatment of Sezary syndrome using a novel stages I and II. Blood 1998;92:3578-3581. Available at:
treatment protocol. J Am Acad Dermatol 2008;59:589-595. Available at: http://www.ncbi.nlm.nih.gov/pubmed/9808550.
155. Chiarion-Sileni V, Bononi A, Fornasa CV, et al. Phase II trial of
148. Talpur R, Demierre MF, Geskin L, et al. Multicenter photopheresis interferon-alpha-2a plus psolaren with ultraviolet light A in patients with
intervention trial in early-stage mycosis fungoides. Clin Lymphoma cutaneous T-cell lymphoma. Cancer 2002;95:569-575. Available at:
Myeloma Leuk 2011;11:219-227. Available at: https://www.ncbi.nlm.nih.gov/pubmed/12209749.
156. Rupoli S, Goteri G, Pulini S, et al. Long-term experience with
149. Knobler R, Duvic M, Querfeld C, et al. Long-term follow-up and low-dose interferon-alpha and PUVA in the management of early mycosis
survival of cutaneous T-cell lymphoma patients treated with extracorporeal fungoides. Eur J Haematol 2005;75:136-145. Available at:
photopheresis. Photodermatol Photoimmunol Photomed 2012;28:250-257. https://www.ncbi.nlm.nih.gov/pubmed/16000130.
157. Olisova OY, Megna M, Grekova EV, et al. PUVA and interferon
150. Knobler R, Berlin G, Calzavara-Pinton P, et al. Guidelines on the use alpha2b combined therapy for patients with mycosis fungoides at different
of extracorporeal photopheresis. J Eur Acad Dermatol Venereol 2014;28 stages of the disease: a seven-year retrospective study in Russia. J Eur
Suppl 1:1-37. Available at: Acad Dermatol Venereol 2019;33:e72-e74. Available at:
151. Atilla E, Atilla PA, Bozdag SC, et al. Extracorporeal 158. Rupoli S, Canafoglia L, Goteri G, et al. Results of a prospective
photochemotherapy in mycosis fungoides. Transfus Clin Biol phase II trial with oral low-dose bexarotene plus photochemotherapy
2017;24:454-457. Available at: (PUVA) in refractory and/or relapsed patients with mycosis fungoides. Eur
https://www.ncbi.nlm.nih.gov/pubmed/28578935. J Dermatol 2016;26:13-20. Available at:
152. Gao C, McCormack C, van der Weyden C, et al. Prolonged survival
with the early use of a novel extracorporeal photopheresis regimen in 159. Fujimura T, Sato Y, Tanita K, et al. Case series of cutaneous T-cell
patients with Sezary syndrome. Blood 2019;134:1346-1350. Available at: lymphomas treated with bexarotene-based therapy. J Dermatol
153. Stevens SR, Baron ED, Masten S, Cooper KD. Circulating
CD4+CD7- lymphocyte burden and rapidity of response: predictors of
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160. Morita A, Tateishi C, Muramatsu S, et al. Efficacy and safety of 167. Olsen EA, Whittaker S, Kim YH, et al. Clinical end points and
bexarotene combined with photo(chemo)therapy for cutaneous T-cell response criteria in mycosis fungoides and Sezary syndrome: a
lymphoma. J Dermatol 2020;47:443-451. Available at: consensus statement of the International Society for Cutaneous
https://www.ncbi.nlm.nih.gov/pubmed/32189402. Lymphomas, the United States Cutaneous Lymphoma Consortium, and
the Cutaneous Lymphoma Task Force of the European Organisation for
161. Wilson LD, Jones GW, Kim D, et al. Experience with total skin Research and Treatment of Cancer. J Clin Oncol 2011;29:2598-2607.
electron beam therapy in combination with extracorporeal photopheresis in Available at: https://www.ncbi.nlm.nih.gov/pubmed/21576639.
the management of patients with erythrodermic (T4) mycosis fungoides. J
Am Acad Dermatol 2000;43:54-60. Available at: 168. van Doorn R, Scheffer E, Willemze R. Follicular mycosis fungoides, a
https://www.ncbi.nlm.nih.gov/pubmed/10863224. distinct disease entity with or without associated follicular mucinosis: a
clinicopathologic and follow-up study of 51 patients. Arch Dermatol
162. Atzmony L, Amitay-Laish I, Gurion R, et al. Erythrodermic mycosis 2002;138:191-198. Available at:
fungoides and Sezary syndrome treated with extracorporeal photopheresis https://www.ncbi.nlm.nih.gov/pubmed/11843638.
as part of a multimodality regimen: A single-centre experience. J Eur Acad
Dermatol Venereol 2015;29:2382-2389. Available at: 169. Gerami P, Rosen S, Kuzel T, et al. Folliculotropic mycosis fungoides:
https://www.ncbi.nlm.nih.gov/pubmed/26299651. an aggressive variant of cutaneous T-cell lymphoma. Arch Dermatol
2008;144:738-746. Available at:
163. Wollina U, Looks A, Meyer J, et al. Treatment of stage II cutaneous https://www.ncbi.nlm.nih.gov/pubmed/18559762.
T-cell lymphoma with interferon alfa-2a and extracorporeal
photochemotherapy: a prospective controlled trial. J Am Acad Dermatol 170. Lehman JS, Cook-Norris RH, Weed BR, et al. Folliculotropic mycosis
2001;44:253-260. Available at: fungoides: single-center study and systematic review. Arch Dermatol
164. Suchin KR, Cucchiara AJ, Gottleib SL, et al. Treatment of cutaneous
T-cell lymphoma with combined immunomodulatory therapy: a 14-year 171. Wieser I, Wang C, Alberti-Violetti S, et al. Clinical characteristics, risk
experience at a single institution. Arch Dermatol 2002;138:1054-1060. factors and long-term outcome of 114 patients with folliculotropic mycosis
Available at: https://www.ncbi.nlm.nih.gov/pubmed/12164743. fungoides. Arch Dermatol Res 2017;309:453-459. Available at:
165. Raphael BA, Shin DB, Suchin KR, et al. High clinical response rate of
Sezary syndrome to immunomodulatory therapies: prognostic markers of 172. Hodak E, Amitay-Laish I, Atzmony L, et al. New insights into
response. Arch Dermatol 2011;147:1410-1415. Available at: folliculotropic mycosis fungoides (FMF): A single-center experience. J Am
https://www.ncbi.nlm.nih.gov/pubmed/21844430. Acad Dermatol 2016;75:347-355. Available at:
166. Straus DJ, Duvic M, Horwitz SM, et al. Final results of phase II trial of
doxorubicin HCl liposome injection followed by bexarotene in advanced 173. van Santen S, Roach RE, van Doorn R, et al. Clinical Staging and
cutaneous T-cell lymphoma. Ann Oncol 2014;25:206-210. Available at: Prognostic Factors in Folliculotropic Mycosis Fungoides. JAMA Dermatol
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174. Charli-Joseph Y, Kashani-Sabet M, McCalmont TH, et al. Association a single institution. Ann Oncol 2015;26:2490-2495. Available at:
of a Proposed New Staging System for Folliculotropic Mycosis Fungoides https://www.ncbi.nlm.nih.gov/pubmed/26416896.
With Prognostic Variables in a US Cohort. JAMA Dermatol
2021;157:157-165. Available at: 181. Shiratori S, Fujimoto K, Nishimura M, et al. Allogeneic hematopoietic
https://www.ncbi.nlm.nih.gov/pubmed/33295938. stem cell transplantation following reduced-intensity conditioning for
mycosis fungoides and Sezary syndrome. Hematol Oncol 2016;34:9-16.
175. van Santen S, van Doorn R, Neelis KJ, et al. Recommendations for Available at: https://www.ncbi.nlm.nih.gov/pubmed/25312300.
treatment in folliculotropic mycosis fungoides: report of the Dutch
Cutaneous Lymphoma Group. Br J Dermatol 2017;177:223-228. Available 182. Domingo-Domenech E, Duarte RF, Boumedil A, et al. Allogeneic
at: https://www.ncbi.nlm.nih.gov/pubmed/28132406. hematopoietic stem cell transplantation for advanced mycosis fungoides
and Sezary syndrome. An updated experience of the Lymphoma Working
176. Lansigan F, Horwitz SM, Pinter-Brown LC, et al. Outcomes of Party of the European Society for Blood and Marrow Transplantation.
Patients with Transformed Mycosis Fungoides: Analysis from a Bone Marrow Transplant 2021;56:1391-1401. Available at:
Prospective Multicenter US Cohort Study. Clin Lymphoma Myeloma Leuk https://www.ncbi.nlm.nih.gov/pubmed/33420392.
2020;20:744-748. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/32532611. 183. Johnson WT, Mukherji R, Kartan S, et al. Allogeneic hematopoietic
stem cell transplantation in advanced stage mycosis fungoides and Sezary
177. de Masson A, Beylot-Barry M, Bouaziz JD, et al. Allogeneic stem cell syndrome: a concise review. Chin Clin Oncol 2019;8:12. Available at:
transplantation for advanced cutaneous T-cell lymphomas: a study from https://www.ncbi.nlm.nih.gov/pubmed/30525754.
the French Society of Bone Marrow Transplantation and French Study
Group on Cutaneous Lymphomas. Haematologica 2014;99:527-534. 184. Iqbal M, Reljic T, Ayala E, et al. Efficacy of Allogeneic Hematopoietic
Available at: https://www.ncbi.nlm.nih.gov/pubmed/24213148. Cell Transplantation in Cutaneous T Cell Lymphoma: Results of a
Systematic Review and Meta-Analysis. Biol Blood Marrow Transplant
178. Duarte RF, Boumendil A, Onida F, et al. Long-term outcome of 2020;26:76-82. Available at:
allogeneic hematopoietic cell transplantation for patients with mycosis https://www.ncbi.nlm.nih.gov/pubmed/31494227.
fungoides and Sezary syndrome: a European society for blood and
marrow transplantation lymphoma working party extended analysis. J Clin 185. Duarte RF, Schmitz N, Servitje O, Sureda A. Haematopoietic stem
Oncol 2014;32:3347-3348. Available at: cell transplantation for patients with primary cutaneous T-cell lymphoma.
https://www.ncbi.nlm.nih.gov/pubmed/25154828. Bone Marrow Transplant 2008;41:597-604. Available at:
179. Lechowicz MJ, Lazarus HM, Carreras J, et al. Allogeneic
hematopoietic cell transplantation for mycosis fungoides and Sezary 186. Duvic M, Donato M, Dabaja B, et al. Total skin electron beam and
syndrome. Bone Marrow Transplant 2014;49:1360-1365. Available at: non-myeloablative allogeneic hematopoietic stem-cell transplantation in
https://www.ncbi.nlm.nih.gov/pubmed/25068422. advanced mycosis fungoides and Sezary syndrome. J Clin Oncol
2010;28:2365-2372. Available at:
180. Hosing C, Bassett R, Dabaja B, et al. Allogeneic stem-cell https://www.ncbi.nlm.nih.gov/pubmed/20351328.
transplantation in patients with cutaneous lymphoma: updated results from
187. Weng WK, Arai S, Rezvani A, et al. Nonmyeloablative allogeneic
transplantation achieves clinical and molecular remission in cutaneous
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T-cell lymphoma. Blood Adv 2020;4:4474-4482. Available at: 195. Eschler DC, Klein PA. An evidence-based review of the efficacy of
https://www.ncbi.nlm.nih.gov/pubmed/32941647. topical antihistamines in the relief of pruritus. J Drugs Dermatol
2010;9:992-997. Available at:
188. Isufi I, Seropian S, Gowda L, et al. Outcomes for allogeneic stem cell https://www.ncbi.nlm.nih.gov/pubmed/20684150.
transplantation in refractory mycosis fungoides and primary cutaneous
gamma Delta T cell lymphomas. Leuk Lymphoma 2020;61:2955-2961. 196. Matsuda KM, Sharma D, Schonfeld AR, Kwatra SG. Gabapentin and
Available at: https://www.ncbi.nlm.nih.gov/pubmed/32643494. pregabalin for the treatment of chronic pruritus. J Am Acad Dermatol
2016;75:619-625.e616. Available at:
189. Thompson LL, Pan CX, Chang MS, et al. Alemtuzumab, total skin https://www.ncbi.nlm.nih.gov/pubmed/27206757.
electron beam, and non-myeloablative allogeneic haematopoietic
stem-cell transplantation in advanced sezary syndrome: a retrospective 197. Duval A, Dubertret L. Aprepitant as an antipruritic agent? N Engl J
cohort study. J Eur Acad Dermatol Venereol 2021;35:e373-e375. Med 2009;361:1415-1416. Available at:
Available at: https://www.ncbi.nlm.nih.gov/pubmed/33545747. https://www.ncbi.nlm.nih.gov/pubmed/19797294.
190. Mori T, Shiratori S, Suzumiya J, et al. Outcome of allogeneic 198. Booken N, Heck M, Nicolay JP, et al. Oral aprepitant in the therapy of
hematopoietic stem cell transplantation for mycosis fungoides and Sezary refractory pruritus in erythrodermic cutaneous T-cell lymphoma. Br J
syndrome. Hematol Oncol 2020;38:266-271. Available at: Dermatol 2011;164:665-667. Available at:
191. Demierre MF, Gan S, Jones J, Miller DR. Significant impact of 199. Jimenez Gallo D, Albarran Planelles C, Linares Barrios M, et al.
cutaneous T-cell lymphoma on patients' quality of life: results of a 2005 Treatment of pruritus in early-stage hypopigmented mycosis fungoides
National Cutaneous Lymphoma Foundation Survey. Cancer with aprepitant. Dermatol Ther 2014;27:178-182. Available at:
200. Demierre MF, Taverna J. Mirtazapine and gabapentin for reducing
192. Sampogna F, Frontani M, Baliva G, et al. Quality of life and pruritus in cutaneous T-cell lymphoma. J Am Acad Dermatol
psychological distress in patients with cutaneous lymphoma. Br J 2006;55:543-544. Available at:
201. Stander S, Bockenholt B, Schurmeyer-Horst F, et al. Treatment of
193. Meyer N, Paul C, Misery L. Pruritus in cutaneous T-cell lymphomas: chronic pruritus with the selective serotonin re-uptake inhibitors paroxetine
frequent, often severe and difficult to treat. Acta Derm Venereol and fluvoxamine: results of an open-labelled, two-arm proof-of-concept
2010;90:12-17. Available at: study. Acta Derm Venereol 2009;89:45-51. Available at:
194. Trautinger F, Knobler R, Willemze R, et al. EORTC consensus 202. Bigliardi PL, Stammer H, Jost G, et al. Treatment of pruritus with
recommendations for the treatment of mycosis fungoides/Sezary topically applied opiate receptor antagonist. J Am Acad Dermatol
syndrome. Eur J Cancer 2006;42:1014-1030. Available at: 2007;56:979-988. Available at:
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203. Axelrod PI, Lorber B, Vonderheid EC. Infections complicating

mycosis fungoides and Sezary syndrome. JAMA 1992;267:1354-1358.
MS-47

Primary Cutaneous CD30+ T-Cell Lymphoproliferative lymphomas such as MF, PC-ALCL, systemic ALCL, or Hodgkin
Disorders lymphoma.12-17 Older age, positive TCR gene rearrangement, or diagnosis
Primary cutaneous CD30+ T-cell lymphoproliferative disorders (PCTLD) of mixed-type LyP have been reported as prognostic indicators of disease
represent a spectrum that includes primary cutaneous anaplastic large-cell progression to lymphoma.13,15
lymphoma (PC-ALCL), lymphomatoid papulosis (LyP), and “borderline”
Literature Search Criteria and Guidelines Update Methodology
cases with overlapping clinical and histopathologic features.1,2 Primary
cutaneous disease, spontaneous regression, and absence of Prior to the update of this version of the NCCN Guidelines for Primary
extracutaneous spread are associated with a better prognosis.3,4 Cutaneous Lymphomas, an electronic search of the PubMed database
was performed to obtain key literature on PCTLD published since the
PC-ALCL represents approximately 8% of all CTCL and is histologically previous Guidelines update using the following search terms: primary
characterized by diffuse, cohesive sheets of large CD30-positive (in cutaneous anaplastic large cell lymphoma and lymphomatoid papulosis.
>75%) cells with anaplastic, pleomorphic, or immunoblastic appearance.5 The PubMed database was chosen as it remains the most widely used
Patches and plaques may also be present, and some degree of resource for medical literature and indexes peer-reviewed biomedical
spontaneous remittance in lesions may also be seen. PC-ALCL typically literature.18
follows an indolent course with an excellent prognosis, although
cutaneous relapses are more common.6-8 Clinical features typically include The search results were narrowed by selecting studies in humans
solitary or localized nodules or tumors (often ulcerated); multifocal lesions published in English. Results were confined to the following article types:
occur in approximately 20% of cases. Extracutaneous disease occurs in Clinical Trial, Phase II; Clinical Trial, Phase III; Clinical Trial, Phase IV;
approximately 10% of cases, usually involving regional lymph nodes.7 The Guideline; Randomized Controlled Trial; Meta-Analysis; Systematic
presence of multiple cutaneous lesions at presentation, extensive skin Reviews; and Validation Studies.
lesions on the leg, disease progression to extracutaneous disease, early
The data from key PubMed articles deemed as relevant to these
cutaneous relapse, and nodal progression are associated with poorer
guidelines have been included in this version of the Discussion section.
outcomes.9-11
Recommendations for which high-level evidence is lacking are based on
LyP is histologically heterogenous with large atypical anaplastic, the panel’s review of lower-level evidence and expert opinion.
immunoblastic, or Hodgkin-like cells in a marked inflammatory
The complete details of the Development and Update of the NCCN
background.2 Several histologic subtypes have been defined based on the
Guidelines are available at www.NCCN.org.
evolution of skin lesions. Clinical features include chronic, recurrent,
spontaneously regressing papulonodular (grouped or generalized) skin Diagnosis
lesions. LyP is not considered a malignant disorder and has an excellent
As described earlier, PCTLD is a spectrum of clinical presentation
prognosis with an OS rate of 92% at 5 and 10 years.8 However, LyP has
including LyP (mostly papular and always regressing), PC-ALCL (mostly
also been reported to be associated with an increased risk of secondary
MS-48

nodular and persistent), and also “borderline” presentations where lesions of GATA3 while the CD30+ PCTLD showed variable/moderate expression
regress but take longer or are larger and not papular as in LyP.5 Clinical of GATA3.21
and pathologic correlation is essential for distinguishing within the
spectrum of PCTLD as well as distinguishing PCTLD from other PCTLD are characterized by the following immunophenotype: CD30+
cutaneous CD30+ disorders (ie, systemic ALCL, adult T-cell (>75% cells), CD4+, variable loss of CD2/CD5/CD3, and CD8+ (<5%)
leukemia/lymphoma [ATLL], PTCL, mycosis fungoides (MF; especially cytotoxic granule-associated proteins positive. IHC panel may include
with large cell transformation (LCT) and benign disorders such as CD3, CD4, CD8, CD20, CD30, CD56, and anaplastic lymphoma kinase
lymphomatoid drug reactions, arthropod bites, viral infections, and others. (ALK). ALK-positive PC-ALCL is extremely uncommon and t(2;5)
MF and PCTLD can coexist in the same patient. Lymphomatoid drug translocation is typically absent in CD30+ PCTLD.22,23 ALK positivity and
reactions have been linked with certain drugs (eg, amlodipine, differential expression of t(2;5) can help to distinguish between CD30+
carbamazepine, cefuroxime) and may be associated with CD30+ atypical PCTLD and ALCL of nodal origin.
large cells in histology. Classical Hodgkin lymphoma (CHL) is less often
Additional markers such as CD2, CD5, CD7, CD25, TIA1, granzyme B,
associated with MF and PCTLD than previously thought; however,
perforin, TCR beta, and TCR delta, IRF4/MUM1, and epithelial membrane
coexpression of CD30 and CD15 in these T-cell lymphomas may lead to a
antigen (EMA) may be useful in selected circumstances. Abnormal T-cell
mistaken diagnosis of CHL.19 It is therefore important not to diagnose
phenotype and perforin expression are significantly more frequent in
CD30+ T-cell lymphomas in lymph nodes as Hodgkin lymphoma.
PC-ALCL than in transformed MF and may be useful for the differential
Complete skin examination (for evidence of MF), adequate biopsy (punch, diagnosis between PC-ALCL and CD30-expressing transformed MF.24
incisional, or excisional) of suspicious skin lesions, and IHC of skin biopsy
MUM1 expression is valuable for the distinction between LyP and
specimen are essential to confirm the diagnosis. Molecular analysis to
PC-ALCL, since the majority of cases of LyP (87%) are positive for MUM1
detect clonal TCR gene rearrangements, excisional or incisional biopsy of
staining compared to only 20% of cases with PC-ALCL.25 DUSP22-IRF4
suspicious lymph nodes, and assessment of HTLV-1 serology to identify
(6p25.3) gene rearrangement has been described in patients with
CD30+ ATLL would be helpful in selected circumstances. However, TCR
PC-ALCL and LyP but is not associated with prognostic significance.26-28 In
gene rearrangement may not be demonstrated in all cases of PCTLD and
a large multicenter study that investigated the clinical utility of detecting
TCR rearrangements can also be seen in patients with non-malignant
IRF4 translocations in skin biopsies of T-cell lymphoproliferative disorders,
conditions. Demonstration of identical clones in skin, blood, and/or lymph
fluorescence in situ hybridization (FISH) for IRF4 had a specificity and
nodes may be helpful in selected cases.20 Identification of clonal TCR
positive predictive value of 99% and 90%, respectively, for cutaneous
gene rearrangement has no definitive established prognostic value;
ALCL.26 FISH to detect ALK and DUSP22-IRF4 rearrangements would be
however, it could be helpful to determine clinical staging or assess
useful in selected circumstances. HTLV-1 status, assessed either by
relapsed or residual disease. Immunohistochemical expression of GATA3
HTLV-1 serology or other methods, may be useful in at risk populations to
has been proposed to be useful to differentiate between MF-LCT and
CD30+ PCTLD (MF-LCT was associated with a strong/diffuse expression
MS-49

exclude the diagnosis of CD30-positive ATLL (which is usually HTLV-1 Primary Cutaneous ALCL
positive). Radiation Therapy
Involved-site RT (ISRT) alone or surgical excision (with or without ISRT)
Workup
are recommended for patients with solitary or grouped lesions.6-8,30-33
The initial workup involves a history and complete physical examination
including entire skin, palpation of peripheral lymph node regions, and liver In a report from the Dutch Cutaneous Lymphoma Group that evaluated the
or spleen. Laboratory studies should include CBC with differential, a long-term outcome of patients with PCTLD (118 patients with LyP, 79
comprehensive metabolic panel, and assessment of LDH levels. Many patients with PC-ALCL, and 11 patients with PC-ALCL with regional node
skin-directed and systemic therapies are contraindicated or are of involvement), RT or surgical excision as initial therapy (given for 48% and
unknown safety in pregnancy. Therefore, pregnancy testing is 19% of patients, respectively) resulted in a CR rate of 100% in patients
recommended for females of childbearing age. with PC-ALCL.7 After a median follow-up of 61 months, subsequent
skin-only relapse and extracutaneous disease were reported in 41% and
Biopsy of enlarged lymph nodes or extracutaneous sites is recommended 10% of patients, respectively.
if biopsy of skin is non-diagnostic. FNA alone is not sufficient for the initial
diagnosis. Excisional or incisional biopsy is preferred over core needle A multicenter retrospective analysis restricted to patients with PC-ALCL (n
biopsy. In certain circumstances, when a lymph node is not easily = 56) eligible to receive RT (primary therapy or after surgical excision)
accessible for excisional or incisional biopsy, a combination of core needle reported a clinical complete response (cCR) rate of 95% and a local
biopsy and FNA in conjunction with appropriate ancillary techniques may control rate of 98% after a median follow-up of 4 years.34 Although the
be sufficient for diagnosis. Bone marrow evaluation has limited value in median RT dose was 35 Gy (range, 6–45 Gy), CRs were seen with doses
the staging of patients with PC-ALCL and is not required for disease as low as 6 Gy and the achievement of cCR was independent of the RT
staging.29 Bone marrow aspiration and biopsy may be considered for dose, suggesting that lower RT dose of <30 Gy may be appropriate for the
solitary PC-ALCL or PC-ALCL without extracutaneous involvement on management of localized lesions. The efficacy of low-dose RT (≤20 Gy)
imaging. for the treatment of solitary or localized PC-ALCL was also confirmed in
other recent reports.35-37
Contrast-enhanced CT scan of the chest, abdomen, and pelvis or
integrated whole-body PET/CT is recommended for PC-ALCL. PET scan Systemic Therapy
may be preferred for patients with extranodal disease, which is Systemic therapy is indicated only for multifocal lesions (± skin-directed
inadequately imaged by CT. In LyP, imaging studies and bone marrow therapy) and for those with regional node involvement (± ISRT).
evaluation are done only if there is suspicion of systemic involvement by Observation (if asymptomatic) is appropriate for patients with multifocal
an associated lymphoma. lesions, and ISRT alone is an appropriate option in selected patients with
regional lymph node involvement ± primary skin lesions.
MS-50

Brentuximab vedotin is the preferred systemic treatment option based on experienced skin relapses during follow-up. After a median follow-up of 58
the results of the ALCANZA study.38 In this study that included 31 patients months, disease-related 5-year survival rate was 91%.
with previously treated PC-ALCL, ORR lasting for 4 months or more was
significantly higher for brentuximab vedotin compared to the physician’s In November 2018, the FDA approved brentuximab vedotin in combination
choice of treatment with methotrexate or bexarotene (75% vs. 20%), and with cyclophosphamide, doxorubicin, and prednisone (CHP) for the
the proportion of patients achieving CR was also higher with brentuximab treatment of previously untreated systemic ALCL or other CD30‐positive
vedotin than with physician’s choice (31% vs. 7%).38 PTCL based on the results of the ECHELON‐2 trial, which showed that
brentuximab vedotin + CHP was superior to CHOP for patients with
In a multicenter study that evaluated the efficacy of treatment options in CD30-positive PTCL as shown by a significant improvement in PFS and
patients with multifocal lesions included in the Dutch Registry for OS.51 This trial, however, excluded patients with PC-ALCL. However,
Cutaneous Lymphomas prior to the FDA approval of brentuximab vedotin since CHOP is included as an option for primary treatment (other
(24 patients with initial presentation and 17 patients with relapsed recommended regimens) for cutaneous ALCL with regional nodes, the
disease), RT (n = 21), systemic chemotherapy (n = 9), and low-dose panel acknowledged that brentuximab vedotin + CHP would also be an
methotrexate (n = 7) were the most common treatment options resulting appropriate option for these patients. Brentuximab vedotin + CHP is
in ORRs of 100% (100% CR), 100% (78% CR), and 57% (43% CR), included as an option under other recommended regimens for the primary
respectively.39 The presence of greater than 5 skin lesions was associated treatment for patients with cutaneous ALCL with regional nodes.
with a higher risk of extracutaneous relapse (56% vs. 20% for the
presence of 2–5 skin lesions). Low-dose methotrexate (50 mg weekly),40,41 Lymphomatoid Papulosis
pralatrexate,42 systemic retinoids (bexarotene for multifocal lesions),43-46 When managing patients with LyP, it is important to be reminded that this
and IFN (multifocal lesions)43,47-49 are included as options for other is not a malignant disorder but a recurrent, benign, self-regressing
recommended regimens based on the limited available data. lymphoid proliferation.
Multiagent chemotherapy (CHOP [cyclophosphamide, doxorubicin, Observation is preferred for patients with asymptomatic disease. Topical
vincristine and prednisone] or CHOEP [cyclophosphamide, doxorubicin, steroids or phototherapy are appropriate initial treatment options for
vincristine, etoposide and prednisone]) with or without ISRT has also been limited lesions (in symptomatic patients) or extensive lesions.7,44,52-54 In
studied in patients with PC-ALCL and is included as an option for selected patients receiving phototherapy, narrow band-UVB is generally preferred
patients with regional lymph node involvement.7,50 In the aforementioned over PUVA. In the aforementioned report from the Dutch Cutaneous
report from the Dutch Cutaneous Lymphoma Group that evaluated the Lymphoma Group that included118 patients with LyP, topical steroids and
long-term outcome of 219 patients with PCTLD, 9 of 11 patients (82%) phototherapy were the most common skin-directed therapies used as
with PC-ALCL and regional node involvement received CHOP-like initial treatment in 56% and 35% of patients, respectively.7 Although CR or
multiagent chemotherapy as initial therapy (82%), resulting in a CR in PR were common, none of these therapies resulted in sustained CR. In a
eight patients (88%).7 However, five out of these eight patients retrospective multicenter study of 252 patients with LyP, topical steroids
MS-51

and phototherapy were the most common first-line treatments (prescribed to the same treatment. In patients with PC-ALCL, refractory disease to
in 35% and 14% of the patients, respectively) resulting in a CR rate of multiple prior therapies should be managed with systemic therapy options
48%.55 The overall estimated median DFS was 11 months, but the DFS recommended for LCT of MF.
was longer for patients treated with phototherapy (23 months; P < .03).
The presence of type A LyP and the use of first-line treatment other than Brentuximab vedotin is included as an option for LyP that is refractory to
phototherapy were significantly associated with increased risk of early multiple primary treatment options.63,64 In a phase II study of 12 patients
cutaneous relapse. with refractory LyP, brentuximab vedotin resulted in an ORR of 100% and
a CR rate of 58%.64 The median duration of response was 20 weeks.
Systemic therapy is indicated only for patients with extensive lesions. Grade 1 or 2 peripheral neuropathy was the most common adverse event
Methotrexate is widely used for the treatment of LyP.40,55-62 In a reported in 10 patients (83%). Further studies are needed to optimize the
retrospective study of 45 patients with LyP and other CD30+ PCTLD, dosing to minimize the incidences of peripheral neuropathy.
low-dose methotrexate (≤25 mg) resulted in satisfactory disease control in
87% of patients, and the median total duration of treatment was greater Regular follow-up (including complete skin examination) is essential during
than 39 months for all patients.58 After discontinuation, 25% of patients observation since these patients can develop associated hematologic
remained free of disease relapse during the follow-up period of 24 to 227 malignancies (particularly MF or ALCL) over time.55,65 Life-long follow-up
months. Another study that evaluated the efficacy of low-dose (including thorough skin examination) is warranted for patients with LyP
methotrexate in a cohort of 28 patients with LyP reported that satisfactory (even for patients responding to initial treatment) due to high risks for
disease control could be achieved at 7.5-mg to 10-mg weekly doses of second lymphoid malignancies.
methotrexate.40 Systemic retinoids (bexarotene) are included as an option
based on limited available data mainly from case reports.43-46
Although multiagent chemotherapy often leads to reduction or clearance of

lesions, rapid recurrence shortly after or even during treatment is a
consistent finding in patients with LyP.
Follow-Up and Treatment for Relapsed/Refractory Disease

Patients with a clinical benefit and/or those with disease responding to
initial treatment can be considered for maintenance or tapering of
regimens to optimize response duration. Patients with disease that does
not have adequate response to initial treatment are generally treated with
an alternative regimen recommended for initial treatment before moving
on to treatment for refractory disease. Disease relapse often responds well
MS-52

References patients. Cancer 1993;71:2097-2104. Available at:

1. Kim YH, Willemze R, Pimpinelli N, et al. TNM classification system for
primary cutaneous lymphomas other than mycosis fungoides and Sezary 7. Bekkenk MW, Geelen FA, van Voorst Vader PC, et al. Primary and
syndrome: a proposal of the International Society for Cutaneous secondary cutaneous CD30(+) lymphoproliferative disorders: a report from
Lymphomas (ISCL) and the Cutaneous Lymphoma Task Force of the the Dutch Cutaneous Lymphoma Group on the long-term follow-up data of
European Organization of Research and Treatment of Cancer (EORTC). 219 patients and guidelines for diagnosis and treatment. Blood
Blood 2007;110:479-484. Available at: 2000;95:3653-3661. Available at:
2. Kempf W, Pfaltz K, Vermeer MH, et al. EORTC, ISCL, and USCLC 8. Liu HL, Hoppe RT, Kohler S, et al. CD30+ cutaneous
consensus recommendations for the treatment of primary cutaneous lymphoproliferative disorders: the Stanford experience in lymphomatoid
CD30-positive lymphoproliferative disorders: lymphomatoid papulosis and papulosis and primary cutaneous anaplastic large cell lymphoma. J Am
primary cutaneous anaplastic large-cell lymphoma. Blood Acad Dermatol 2003;49:1049-1058. Available at:
9. Woo DK, Jones CR, Vanoli-Storz MN, et al. Prognostic factors in
3. Paulli M, Berti E, Rosso R, et al. CD30/Ki-1-positive lymphoproliferative primary cutaneous anaplastic large cell lymphoma: characterization of
disorders of the skin--clinicopathologic correlation and statistical analysis clinical subset with worse outcome. Arch Dermatol 2009;145:667-674.
of 86 cases: a multicentric study from the European Organization for Available at: https://www.ncbi.nlm.nih.gov/pubmed/19528422.
Research and Treatment of Cancer Cutaneous Lymphoma Project Group.
J Clin Oncol 1995;13:1343-1354. Available at: 10. Benner MF, Willemze R. Applicability and prognostic value of the new
https://www.ncbi.nlm.nih.gov/pubmed/7751878. TNM classification system in 135 patients with primary cutaneous
anaplastic large cell lymphoma. Arch Dermatol 2009;145:1399-1404.
4. Vergier B, Beylot-Barry M, Pulford K, et al. Statistical evaluation of Available at: https://www.ncbi.nlm.nih.gov/pubmed/20026848.
diagnostic and prognostic features of CD30+ cutaneous
lymphoproliferative disorders: a clinicopathologic study of 65 cases. Am J 11. Fernandez-de-Misa R, Hernandez-Machin B, Combalia A, et al.
Surg Pathol 1998;22:1192-1202. Available at: Prognostic factors in patients with primary cutaneous anaplastic large cell
https://www.ncbi.nlm.nih.gov/pubmed/9777981. lymphoma: a multicentric, retrospective analysis of the Spanish Group of
Cutaneous Lymphoma. J Eur Acad Dermatol Venereol 2020;34:762-768.
5. Willemze R, Cerroni L, Kempf W, et al. The 2018 update of the Available at: https://www.ncbi.nlm.nih.gov/pubmed/31591786.
WHO-EORTC classification for primary cutaneous lymphomas. Blood
2019;133:1703-1714. Available at: 12. Wang HH, Myers T, Lach LJ, et al. Increased risk of lymphoid and
https://www.ncbi.nlm.nih.gov/pubmed/30635287. nonlymphoid malignancies in patients with lymphomatoid papulosis.
Cancer 1999;86:1240-1245. Available at:
6. Beljaards RC, Kaudewitz P, Berti E, et al. Primary cutaneous https://www.ncbi.nlm.nih.gov/pubmed/10506709.
CD30-positive large cell lymphoma: definition of a new type of cutaneous
lymphoma with a favorable prognosis. A European Multicenter Study of 47 13. de Souza A, el-Azhary RA, Camilleri MJ, et al. In search of prognostic
indicators for lymphomatoid papulosis: a retrospective study of 123
MS-53

patients. J Am Acad Dermatol 2012;66:928-937. Available at: 21. Collins K, Gu J, Aung PP, et al. Is immunohistochemical expression of
https://www.ncbi.nlm.nih.gov/pubmed/21982062. GATA3 helpful in the differential diagnosis of transformed mycosis
fungoides and primary cutaneous CD30-positive T cell lymphoproliferative
14. Nikolaou V, Papadavid E, Ekonomidi A, et al. Association of disorders? Virchows Arch 2021;479:377-383. Available at:
clinicopathological characteristics with secondary neoplastic https://www.ncbi.nlm.nih.gov/pubmed/33604757.
lymphoproliferative disorders in patients with lymphomatoid papulosis.
Leuk Lymphoma 2015;56:1303-1307. Available at: 22. DeCoteau JF, Butmarc JR, Kinney MC, Kadin ME. The t(2;5)
https://www.ncbi.nlm.nih.gov/pubmed/25242096. chromosomal translocation is not a common feature of primary cutaneous
CD30+ lymphoproliferative disorders: comparison with anaplastic
15. Cordel N, Tressieres B, D'Incan M, et al. Frequency and Risk Factors large-cell lymphoma of nodal origin. Blood 1996;87:3437-3441. Available
for Associated Lymphomas in Patients With Lymphomatoid Papulosis. at: https://www.ncbi.nlm.nih.gov/pubmed/8605362.
Oncologist 2016;21:76-83. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/26668250. 23. Melchers RC, Willemze R, van de Loo M, et al. Clinical, Histologic, and
Molecular Characteristics of Anaplastic Lymphoma Kinase-positive
16. Wieser I, Oh CW, Talpur R, Duvic M. Lymphomatoid papulosis: Primary Cutaneous Anaplastic Large Cell Lymphoma. Am J Surg Pathol
Treatment response and associated lymphomas in a study of 180 patients. 2020;44:776-781. Available at:
J Am Acad Dermatol 2016;74:59-67. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32412717.
24. Fauconneau A, Pham-Ledard A, Cappellen D, et al. Assessment of
17. AbuHilal M, Walsh S, Shear N. Associated Hematolymphoid diagnostic criteria between primary cutaneous anaplastic large-cell
Malignancies in Patients With Lymphomatoid Papulosis: A Canadian lymphoma and CD30-rich transformed mycosis fungoides; a study of 66
Retrospective Study. J Cutan Med Surg 2017;21:507-512. Available at: cases. Br J Dermatol 2015;172:1547-1554. Available at:
18. PubMed Overview. Available at: 25. Kempf W, Kutzner H, Cozzio A, et al. MUM1 expression in cutaneous
https://pubmed.ncbi.nlm.nih.gov/about/. Accessed June 8, 2022. CD30+ lymphoproliferative disorders: a valuable tool for the distinction
between lymphomatoid papulosis and primary cutaneous anaplastic
19. Eberle FC, Song JY, Xi L, et al. Nodal involvement by cutaneous large-cell lymphoma. Br J Dermatol 2008;158:1280-1287. Available at:
CD30-positive T-cell lymphoma mimicking classical Hodgkin lymphoma. https://www.ncbi.nlm.nih.gov/pubmed/18410414.
Am J Surg Pathol 2012;36:716-725. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/22367293. 26. Wada DA, Law ME, Hsi ED, et al. Specificity of IRF4 translocations for
primary cutaneous anaplastic large cell lymphoma: a multicenter study of
20. Thurber SE, Zhang B, Kim YH, et al. T-cell clonality analysis in biopsy 204 skin biopsies. Mod Pathol 2011;24:596-605. Available at:
specimens from two different skin sites shows high specificity in the https://www.ncbi.nlm.nih.gov/pubmed/21169992.
diagnosis of patients with suggested mycosis fungoides. J Am Acad
Dermatol 2007;57:782-790. Available at: 27. Karai LJ, Kadin ME, Hsi ED, et al. Chromosomal rearrangements of
https://www.ncbi.nlm.nih.gov/pubmed/17646032. 6p25.3 define a new subtype of lymphomatoid papulosis. Am J Surg
MS-54

Pathol 2013;37:1173-1181. Available at: Phys 2016;95:1454-1459. Available at:

28. Onaindia A, Montes-Moreno S, Rodriguez-Pinilla SM, et al. Primary 35. Melchers RC, Willemze R, Daniels LA, et al. Recommendations for the
cutaneous anaplastic large cell lymphomas with 6p25.3 rearrangement Optimal Radiation Dose in Patients With Primary Cutaneous Anaplastic
exhibit particular histological features. Histopathology 2015;66:846-855. Large Cell Lymphoma: A Report of the Dutch Cutaneous Lymphoma
Available at: https://www.ncbi.nlm.nih.gov/pubmed/25131361. Group. Int J Radiat Oncol Biol Phys 2017;99:1279-1285. Available at:
29. Benner MF, Willemze R. Bone marrow examination has limited value
in the staging of patients with an anaplastic large cell lymphoma first 36. Smith GL, Duvic M, Yehia ZA, et al. Effectiveness of low-dose
presenting in the skin. Retrospective analysis of 107 patients. Br J radiation for primary cutaneous anaplastic large cell lymphoma. Adv
Dermatol 2008;159:1148-1151. Available at: Radiat Oncol 2017;2:363-369. Available at:
30. Yu JB, McNiff JM, Lund MW, Wilson LD. Treatment of primary 37. Piccinno R, Damiani G, Rossi LC, Berti E. Radiotherapy of primary
cutaneous CD30+ anaplastic large-cell lymphoma with radiation therapy. cutaneous anaplastic large cell lymphoma: our experience in 30 cases. Int
Int J Radiat Oncol Biol Phys 2008;70:1542-1545. Available at: J Dermatol 2020;59:469-473. Available at:
31. Booken N, Goerdt S, Klemke CD. Clinical spectrum of primary 38. Prince HM, Kim YH, Horwitz SM, et al. Brentuximab vedotin or
cutaneous CD30-positive anaplastic large cell lymphoma: an analysis of physician's choice in CD30-positive cutaneous T-cell lymphoma
the Mannheim Cutaneous Lymphoma Registry. J Dtsch Dermatol Ges (ALCANZA): an international, open-label, randomised, phase 3,
2012;10:331-339. Available at: multicentre trial. Lancet 2017;390:555-566. Available at:
32. Huang BS, Chen WY, Wang CW, et al. Relapse Pattern and 39. Melchers RC, Willemze R, Bekkenk MW, et al. Evaluation of treatment
Treatment Outcome of Curative Radiotherapy for Primary Cutaneous results in multifocal primary cutaneous anaplastic large cell lymphoma:
CD30+ Anaplastic Large-cell Lymphoma: A Retrospective Cohort Study. report of the Dutch Cutaneous Lymphoma Group. Br J Dermatol
Acta Derm Venereol 2016;96:394-395. Available at: 2018;179:724-731. Available at:
33. Hapgood G, Pickles T, Sehn LH, et al. Outcome of primary cutaneous 40. Bruijn MS, Horvath B, van Voorst Vader PC, et al. Recommendations
anaplastic large cell lymphoma: a 20-year British Columbia Cancer for treatment of lymphomatoid papulosis with methotrexate: a report from
Agency experience. Br J Haematol 2017;176:234-240. Available at: the Dutch Cutaneous Lymphoma Group. Br J Dermatol
34. Million L, Yi EJ, Wu F, et al. Radiation Therapy for Primary Cutaneous
Anaplastic Large Cell Lymphoma: An International Lymphoma Radiation 41. Park JB, Yang MH, Kwon DI, et al. Low-dose Methotrexate Treatment
Oncology Group Multi-institutional Experience. Int J Radiat Oncol Biol for Solitary or Localized Primary Cutaneous Anaplastic Large Cell
MS-55

Lymphoma: A Long-term Follow-up Study. Acta Derm Venereol 49. Schmuth M, Topar G, Illersperger B, et al. Therapeutic use of
2020;100:adv00069. Available at: interferon-alpha for lymphomatoid papulosis. Cancer 2000;89:1603-1610.
42. Horwitz SM, Kim YH, Foss F, et al. Identification of an active, 50. Brice P, Cazals D, Mounier N, et al. Primary cutaneous large-cell
well-tolerated dose of pralatrexate in patients with relapsed or refractory lymphoma: analysis of 49 patients included in the LNH87 prospective trial
cutaneous T-cell lymphoma. Blood 2012;119:4115-4122. Available at: of polychemotherapy for high-grade lymphomas. Groupe d'Etude des
https://www.ncbi.nlm.nih.gov/pubmed/22394596. Lymphomes de l'Adulte. Leukemia 1998;12:213-219. Available at:
43. Wyss M, Dummer R, Dommann SN, et al. Lymphomatoid
papulosis--treatment with recombinant interferon alfa-2a and etretinate. 51. Horwitz S, O'Connor OA, Pro B, et al. Brentuximab vedotin with
Dermatology 1995;190:288-291. Available at: chemotherapy for CD30-positive peripheral T-cell lymphoma
https://www.ncbi.nlm.nih.gov/pubmed/7655107. (ECHELON-2): a global, double-blind, randomised, phase 3 trial. Lancet
2019;393:229-240. Available at:
44. Krathen RA, Ward S, Duvic M. Bexarotene is a new treatment option https://www.ncbi.nlm.nih.gov/pubmed/30522922.
for lymphomatoid papulosis. Dermatology 2003;206:142-147. Available at:
https://www.ncbi.nlm.nih.gov/pubmed/12592082. 52. Zackheim HS, Epstein EH, Jr., Crain WR. Topical carmustine therapy
for lymphomatoid papulosis. Arch Dermatol 1985;121:1410-1414.
45. Sheehy O, Catherwood M, Pettengell R, Morris TC. Sustained Available at: https://www.ncbi.nlm.nih.gov/pubmed/4051529.
response of primary cutaneous CD30 positive anaplastic large cell
lymphoma to bexarotene and photopheresis. Leuk Lymphoma 53. Thomsen K, Wantzin GL. Lymphomatoid papulosis. A follow-up study
2009;50:1389-1391. Available at: of 30 patients. J Am Acad Dermatol 1987;17:632-636. Available at:
46. Fujimura T, Furudate S, Tanita K, et al. Successful control of 54. Calzavara-Pinton P, Venturini M, Sala R. Medium-dose UVA1 therapy
phototherapy-resistant lymphomatoid papulosis with oral bexarotene. J of lymphomatoid papulosis. J Am Acad Dermatol 2005;52:530-532.
Dermatol 2018;45:e37-e38. Available at: Available at: https://www.ncbi.nlm.nih.gov/pubmed/15761440.
55. Fernandez-de-Misa R, Hernandez-Machin B, Servitje O, et al.
47. Proctor SJ, Jackson GH, Lennard AL, Marks J. Lymphomatoid First-line treatment in lymphomatoid papulosis: a retrospective multicentre
papulosis: response to treatment with recombinant interferon alfa-2b. J study. Clin Exp Dermatol 2018;43:137-143. Available at:
Clin Oncol 1992;10:170. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28994134.
56. Everett MA. Treatment of lymphomatoid papulosis with methotrexate.
48. Yagi H, Tokura Y, Furukawa F, Takigawa M. Th2 cytokine mRNA Br J Dermatol 1984;111:631. Available at:
expression in primary cutaneous CD30-positive lymphoproliferative https://www.ncbi.nlm.nih.gov/pubmed/6498098.
disorders: successful treatment with recombinant interferon-gamma. J
Invest Dermatol 1996;107:827-832. Available at: 57. Christensen HK, Thomsen K, Vejlsgaard GL. Lymphomatoid
https://www.ncbi.nlm.nih.gov/pubmed/8941669. papulosis: a follow-up study of 41 patients. Semin Dermatol
MS-56

1994;13:197-201. Available at: 65. Melchers RC, Willemze R, Bekkenk MW, et al. Frequency and
https://www.ncbi.nlm.nih.gov/pubmed/7986688. prognosis of associated malignancies in 504 patients with lymphomatoid
papulosis. J Eur Acad Dermatol Venereol 2020;34:260-266. Available at:
58. Vonderheid EC, Sajjadian A, Kadin ME. Methotrexate is effective https://www.ncbi.nlm.nih.gov/pubmed/31715046.
therapy for lymphomatoid papulosis and other primary cutaneous
CD30-positive lymphoproliferative disorders. J Am Acad Dermatol
1996;34:470-481. Available at:
59. Yazawa N, Kondo S, Kagaya M, et al. Successful treatment of a

patient with lymphomatoid papulosis by methotrexate. J Dermatol
2001;28:373-378. Available at:
60. Fujita H, Nagatani T, Miyazawa M, et al. Primary cutaneous anaplastic

large cell lymphoma successfully treated with low-dose oral methotrexate.
Eur J Dermatol 2008;18:360-361. Available at:
61. Cornejo CM, Novoa RA, Krisch RE, Kim EJ. Low-dose radiotherapy for
primary cutaneous anaplastic large-cell lymphoma while on low-dose
methotrexate. Cutis 2016;98:253-256. Available at:
62. Newland KM, McCormack CJ, Twigger R, et al. The efficacy of

methotrexate for lymphomatoid papulosis. J Am Acad Dermatol
2015;72:1088-1090. Available at:
63. Duvic M, Tetzlaff MT, Gangar P, et al. Results of a Phase II Trial of

Brentuximab Vedotin for CD30+ Cutaneous T-Cell Lymphoma and
Lymphomatoid Papulosis. J Clin Oncol 2015;33:3759-3765. Available at:
64. Lewis DJ, Talpur R, Huen AO, et al. Brentuximab Vedotin for Patients
With Refractory Lymphomatoid Papulosis: An Analysis of Phase 2
Results. JAMA Dermatol 2017;153:1302-1306. Available at:
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NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®)

NCCN Guidelines Version 2.2022 NCCN Guidelines Index

*Steven M. Horwitz, MD/Chair † Þ Ahmad Halwani, MD ‡ Saurabh A. Rajguru, MD † ‡

NCCN Guidelines Version 2.2022 NCCN Guidelines Index

NCCN Primary Cutaneous Lymphomas Panel Members

NCCN Guidelines Version 2.2022 NCCN Guidelines Index

NCCN Guidelines Version 2.2022 NCCN Guidelines Index

NCCN Guidelines Version 2.2022 NCCN Guidelines Index

PRINCIPLES FOR PRIMARY CUTANEOUS B-CELL LYMPHOMAS (PCBCL)

Note: All recommendations are category 2A unless otherwise indicated. Continued

NCCN Guidelines Version 2.2022 NCCN Guidelines Index

PRINCIPLES FOR PRIMARY CUTANEOUS B-CELL LYMPHOMAS (PCBCL)

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Version 2.2022 NCCN Guidelines Index

Note: All recommendations are category 2A unless otherwise indicated.

NCCN Guidelines Version 2.2022 NCCN Guidelines Index