Prepared by Kurt Schaberg

Salivary Gland Tumors

Normal Salivary Gland
Normal components:
1) Ducts: Interlobar, to intercalated, and striated.
Cuboidal to columnar epithelium. Surrounded by
myoepithelial cells. 3 2
2) Acini: Serous (esp. in parotid, with zymogen
granules) to mucous (esp. sublingual), surrounded by
myoepithelial cells. Looks like grapes on cytology. 1
3) Fat (esp. in parotid)
Also: lymph nodes (esp. in parotid, where salivary
gland can be within benign lymph nodes).
If have symmetric enlargement of salivary glands with
no discrete mass, consider sialadenosis.

Oncocytic Pink cells, often because they contain abundant mitochondria. Often big,
polygonal, with well-defined borders, granular cytoplasm, with large round
nuclei with prominent nucleoli.

Oncocytic hyperplasia
Oncocytic metaplasia: Non-mass forming transformation of glandular epithelium to oncocytes
Oncocytic hyperplasia (aka Oncocytosis): Non-neoplastic, mass-forming proliferation of oncocytes, which
can be focal or diffuse. Unencapsulated. Often multifocal, admixed with normal salivary tissue.

Oncocytoma Oncocytic Carcinoma

Benign
Malignant
Circumscribed to encapsulated
Oncocytic lesion with
proliferation of oncocytes.
pleomorphism, mitoses,
and/or invasion.
Actually Biphasic
1. Inner oncocytes,
May or may not be
2. Outer myoepithelial cells
encapsulated.
Usually in parotid
No significant: pleomorphism,
mitotic activity, or invasive
growth
 Warthin Tumor
Old name: Papillary cystadenoma lyphomatosum
Benign
Key elements:
1) Mature lymphoid tissue, surrounding
2) Bilayerd oncocytic epithelium, with
3) Cystic to papillary growth
Strongly linked to smoking, can be bilateral
Likely develops from transformation of salivary gland
tissue entrapped in a lymph node.
Almost exclusively in parotid, usually at angle of jaw.
Aspirated fluid often thick, dark “motor oil.”

Secretory Carcinoma
Formerly: “Mammary Analogue Secretory Carcinoma”
Eosinophilic, granular to vacuolated cytoplasm
Tubular, papillary and cystic growth.
Sometimes has distinctive eosinophilic secretions in
lumina.
No zymogens present.
ETV6-NTRK3 gene fusions.
Stains: Positive for S100 and mammaglobin.
Malignant, but relatively indolent.

Intraductal Carcinoma
Non-invasive carcinoma with retained myoepithelial
cells. Think of as like DCIS of the breast.
Can highlight myoepithelial cells with p63.
If totally non-invasive→ Excellent prognosis!

Usually in Parotid.

Intercalated duct type Apocrine type

Always low-grade Variable grade
S100+, mammaglobin+ AR+, GCDFP15+, S100 –, mammaglobin –
Most have RET fusion (with NCOA4 or TRIM27) Salivary duct carcinoma-like genetics
Only rarely associated with invasion Often associated with invasion
 Basaloid Looks very cellular and blue at low-power

Basal Cell Adenoma / Basal Cell Adenocarcinoma

Monomorphic Adenoma Malignant
Benign, well-circumscribed, Usually Parotid Like a basal cell adenoma, but with invasion,
Solid, trabecular, or tubular growth necrosis, and numerous mitotic figures
Perpendicular basal cells on outside of nests
Epithelial cells on inside of nests
No significant stroma, aside from possibly a
“membrane” surrounding a nest
(Think of pleomorphic adenoma without the stroma
– hence the name monomorphic adenoma)

Polymorphous Carcinoma
Cytologically uniform cells (monophasic)
Bland, round to spindled cells with moderate amounts of
cytoplasm. Oval nuclei with vesicular chromatin.
Strong, diffuse staining with S100. p63+ but p40 -
Varied architecture (hence the “polymorphous”)
Concentric layering, “whorled,” Tubules to single file
Infiltrative with significant PNI
PRKD fusions/mutations

Always in MINOR salivary glands, often palate

Formerly called “Polymorphous Low-Grade Adenocarcinoma” → “PLGA”

Canalicular Adenoma
Almost always upper lip
Encapsulated
Monophasic
Characteristic “canalicular” pattern of cords and
ribbons of basaloid tumor cells with occasional
interconnecting.

Cords separated by loose fibrillar stroma

Benign
 Acinic Cell Carcinoma
Composed of acinar cells with variable cytoplasm
(vacuolated, clear, oncocytic, to hobnailed) and
architecture (solid to cystic or follicular)
Classically, has cells that are cells large, polygonal with
basophilic granular cytoplasm (contains zymogens→
highlighted by PASD).
Sometimes prominent lymphoid infiltrate
Usually in parotid. Can see in kids.

NR4A3 Translocations common

Stains: Positive for DOG-1 and SOX-10
Malignant, but generally not aggressive

Adenoid Cystic Carcinoma

Cribriform, tubular or solid growth

2 cell types: 1) Myoepithelial and 2) Ducts

Low-grade: Mostly myoepithelial (small cells with

oval to angulated nuclei), stain with p40 and SMA

High-grade: Mostly ductal cells (larger cells with

more vesicular chromatin), stain with CD117 and CK

Ducts can be inconspicuous in low-grade

(See image →)

Grading: give % Solid (ductal) component

Myoepithelial cells form pseudocysts that contain

Ducts
blue glycosaminoglycans or pink basement
(Most of the cells
membrane material (which are visible on FNA, with
are myoepithelial
“stromal exclusion” of myoepithelial cells)
in this case!)
Cytogenetics: Fusions of MYB or MYBL1 to NFIB
Infiltrative→ Extensive PNI→ Pain → Paralysis
Persistent local spread. OK 5yr survival, but poor
long-term survival.
Additional Basaloid tumors
Lymphadenoma: Encapsulated tumor with anastomosing cords of basaloid cells with abundant tumor-
associated lymphoid tissue.
Small cell neuroendocrine carcinoma: Like in the lung!
Sialoblastoma: Primitive-appearing basaloid cells. Seen in kids.
 Prominent Spindled Cells
Pleomorphic Adenoma
Benign, but can recur if not completely excised.
(aka Benign Mixed Tumor)
Most common tumor of salivary glands 1
Three components, encapsulated, well-circumscribed:
1) Ductular structures
2) Myoepithelial cells (can be spindled, epithelioid,
plasmacytoid, etc…), intimately admixed with stroma
3) Mesenchymal-like tissue (often myxoid stroma, but
can be chondroid, etc…) 3
Architecturally pleomorphic (cytologically bland!)
If ducts or myoepithelial cells dominate (but some
component is classic), can use the term “cellular” PA
Can see: tyrosine crystals, squamous metaplasia, cystic
degeneration
2
Cytogenetics: PLAG1-HMGA2 fusions very common

Cytology:
Prominent fibrillar, metachromatic stroma that
on a Diff-quick stain looks like “Troll Hair.”

Also visible ductal cells and myoepithelial cells

intimately admixed with the stroma

Metachromatic Stroma

Myoepithelioma Myoepithelial Carcinoma

Benign Malignant
Composed of entirely myoepithelial Composed of entirely myoepithelial
cells cells
Typically spindled to plasmacytoid
Presence of necrosis, atypical mitotic
Although may see some collagen, figures, invasion to surrounding
chondroid/myxochondroid stroma is parenchyma
absent

Also Consider
Carcinosarcoma Epithelial-myoepithelial carcinoma
Adenoid cystic carcinoma
 Squamoid
Squamous metaplasia
Can see in normal salivary glands or tumors (e.g., PA)
Classic Mimic of SCC!
In minor salivary gland often called:
“Necrotizing Sialometaplasia”
Lobular architecture is maintained
Smooth, rounded contours
Often associated inflammation and reactive changes
Acinar coagulative necrosis

Mucoepidermoid Carcinoma
Three components:
1) Mucinous cells (stain with PASD/mucicarmine)
2) Squamous cells
3) “Intermediate cells” (neither squamous nor 3
mucinous, with scanter cytoplasm) 1
Oncocytic variant exists, but is rare.

Most common malignant salivary cancer.

Often in parotid, but can get anywhere.
Broad age range, including kids

Cytogenetics: MAML2 gene fusions almost

definitional now

Must grade. Several systems, but often graded 2

intuitively (see table) Low-Grade High-Grade
Mostly cystic More solid
Well-circumscribed Infiltrative
More mucinous cells More squamous cells
Cytologically bland More atypical cytologically
Low mitotic count High mitotic count, Necrosis

Squamous Cell Carcinoma

If it is entirely squamous (with no mucinous cells or intermediate cells, and esp. when there are keratin
pearls), a metastasis needs to be excluded clinically
→ Often actually a metastasis from a Head or Neck squamous cell carcinoma (e.g., to an intra parotid
lymph node). Also consider extensive SCC differentiation of another salivary gland carcinoma.

Of note, higher grade Mucoep’s often are more squamous, so make sure the tumor is well-sampled.
 High-Grade
Salivary Duct Carcinoma
Resembles breast ductal carcinoma
(both invasive and in situ components)
Large ducts with comedonecrosis (like DCIS!)
Often apocrine/oncocytic

Stains: Androgen receptor (AR) and HER2 positive

Often in parotid, sometimes arising from a

pleomorphic adenoma (see below)

Very Aggressive

Carcinoma ex-pleomorphic adenoma

ex-PA
Carcinoma arising from a Pleomorphic Adenoma
May be a specific type of epithelial or myoepithelial
carcinoma→ most often Salivary Duct Carcinoma
Very pleomorphic, with lots of mitoses, necrosis and
destructive growth.
Cytogenetics: PLAG1-HMGA1 (in PA) and TP53 (in
carcinoma)
Usually older (time to de-differentiate) in parotid PA
Often long history of mass (i.e., a PA), now with rapid
enlargement.

Lymphoepithelial Carcinoma
Sheets and cords of polygonal large syncytial cells with
eosinophilic cytoplasm and vesicular nucleoli. Also, scattered
spindled cells.
Abundant lymphoplasmacytic infiltrate
Often EBV positive (like nasopharyngeal carcinoma, must
consider metastases!); Also stains with CK

Other High-grade
Carcinosarcoma→ Malignant epithelium and mesenchymal components
Metastases
Any other de-differentiated tumors
 Clear Cell
Clear Cell Carcinoma
Aka: Hyalinizing clear cell carcinoma

Sheets and tests of polygonal clear cells

Hyalinized/sclerotic stroma

EWSR1-ATF1 fusion

Unencapsulated, infiltrative

Usually intraoral salivary glands

“Clear” b/c full of glycogen→ stains with PAS

Stains: CK and p63 positive, Neg. myoep
markers

Epithelial-Myoepithelial Carcinoma
1
Malignant “EMC”
Biphasic:
1) Inner luminal ductal cells, with eosinophilic cytoplasm 2
2) Outer myoepithelial cells, with clear cytoplasm

Usually in parotid gland and indolent

Other Clear Cell

Acinic Cell Carcinoma Pleomorphic adenoma
Secretory Carcinoma
Mucoepidermoid carcinoma
 ABC’s Try Building a DDX from the ABC’s
A: Architecture Infiltrative (Malignant, usually)
Adenoid cystic
How are the nests of tumor arranged?
Acinic cell carcinoma
Encapsulated (Benign, usually) Circumscribed Basal cell adenocarcinoma
Pleomorphic adenoma Pretty much anything Mucoepidermoid carcinoma
Basal cell adenoma (Benign or Malignant) Oncocytic carcinoma
Myoepithelioma Intraductal carcinoma
Oncocytoma Clear cell carcinoma
Warthin tumor Epithelial-myoepithelial carcinoma
Epithelial-Myoepithelial carcinoma Carcinosarcoma
Carcinoma ex-PA
Myoepithelial carcinoma
Secretory carcinoma
Lymphoepithelial carcinoma

B: Bi-Phasic (Phases)
How many different types of cells are present?

Monophasic Biphasic Triphasic (or More!)

Myoepithelioma Adenoid cystic Pleomorphic adenoma
Myoepithelial carcinoma Basal cell adenoma/CA Mucoepidermoid carcinoma
Clear cell carcinoma Epithelial-Myoepithelial CA Acinic cell carcinoma
Polymorphous adenocarcinoma Warthin tumor Carcinosarcoma
Small cell neuroendocrine carcinoma Oncocytoma/CA Carcinoma ex-PA
Salivary duct carcinoma Intraductal carcinoma Secretory carcinoma
Canalicular adenoma Lymphoepithelial carcinoma

C: Cytology
Which types of cells are present? Ductal cells
PA
Acinar cells Clear cells Adenoid cystic
Acinic cell carcinoma Clear cell carcinoma Basal cell adenoma/CA
Acinic cell carcinoma Canalicular adenoma
Basal cells Secretory carcinoma Epithelial-myoepithelial carcinoma
Basal cell adenoma Salivary Duct carcinoma
Basal cell carcinoma Polymorphous Adenocarcinoma
Myoepithelial cells
Oncocytoma Secretory carcinoma
PA
Oncocytic carcinoma Carcinoma ex-PA
Adenoid cystic
Acinic cell carcinoma
Myoepithelioma/CA
Tumor-Associated Lymphoid
Basal cell adenoma/CA
Proliferations Mucous cells
Epithelial-myoepithelial
Mucoepidermoid carcinoma Mucoepidermoid carcinoma
carcinoma
Acinic cell carcinoma
Intraductal carcinoma Oncocytes
Lymphoepithelial carcinoma
Carcinoma ex-PA Oncocytoma/CA
Lymphadenoma
Clear cell carcinoma
Secretory carcinoma
Note: Modified from a presentation by Joaquín J. García MD, Warthin tumor
Division of Anatomic Pathology, Mayo Clinic Rochester
 Stains/Studies Warning: Morphology is still King!
Note: Many salivary gland tumors have at least some myoepithelial component
Myoepithelial markers: p63, p40, Calponin, SMA, GFAP, S100, SOX10
(but somewhat unpredictable!)

High-grade Salivary Tumors

p63/p40 SMA, CK8/18 CK5/6 Mucin AR Synaptophysin
Calponin
Mucoepidermoid, + - Focal + + - -
High-grade
Squamous cell carcinoma + - - + - - -

Salivary Duct Carcinoma - - + - - + -

Poorly-differentiated -/+ - Dot-like - - - +

neuroendocrine
carcinoma

Basaloid Salivary Tumors

p63 p40 SMA/ S100 CD117 LEF-1 PLAG1 MYB
Calponin
Pleomorphic adenoma + + + + +/- +/- + -

Basal cell + + + -/+ +/- + - -

adenoma/carcinoma
Adenoid cystic carcinoma +/- +/- + + + - - +

Myoepithelioma/carcinoma + + + + - - -/+ -

EMEC + + + + -/+ - - -

PLGA + - - + +/- - +/- -

Myoepithelial markers in “Abluminal” (outside) cells

 Stains/Studies
Clear Cell Salivary Tumors
p63/p40 S100 Sox10 DOG1
Myoepithelioma/carcinoma + + - -
EMEC + + - -
Acinic cell carcinoma - - + +
Mucoepidermoid carcinoma + - -/+ -/+

Oncocytic Salivary Tumors

P63 P40 S100 Mammaglobin Sox10 DOG1 GATA3 AR
Warthin & + - - - - - - -
Oncocytoma
Acinic cell - - - - + + - -
carcinoma
Secretory - - + + + - + -
carcinoma
Mucoepidermoid + + - - -/+ -/+ - -
carcinoma

Salivary duct - - - -/+ - - + +

carcinoma

Molecular testing
Tumor Most common molecular alteration
Adenoid cystic carcinoma MYB fusions
Clear cell carcinoma EWSR1-ATF1 Fusion
Intraductal carcinoma NCOA4-RET fusions
Mucoepidermoid carcinoma MAML2 fusions
Pleomorphic adenoma PLAG1-HMGA2 fusions
Polymorphous low-grade adenocarcinoma PRKD fusions/mutations
Secretory carcinoma ETV6 Fusions
Acinic cell carcinoma NR4A3 translocations
Epithelial-Myoepithelial Carcinoma PLAG1/HMGA2 translocations or HRAS mutations
Myoepithelial Carcinoma PLAG1/HMGA2 translocations or EWSR1 translocations
Basal cell adenoma/adenocarcinoma CTNNB1 or CYLD mutations

Tables Adapted from:

The Milan System for Reporting Salivary Gland Cytopathology. Faquin and Rossi. 2018.
Quick Reference Handbook for Surgical Pathologists. Rekhtman et al. 2019.
Grading Salivary Gland Tumors
Some tumors have “intrinsic” grade. Others have a variable grade and must be specifically graded.
Intrinsically graded tumors can still be up/down-graded (usually up) based on atypia, etc…

Low-grade Intermediate High-grade Variable grade

(Treated surgically like (Treated (Treated aggressively)
benign tumors) variably)
Acinic Cell Carcinoma Myoepithelial Salivary Duct Carcinoma Mucoepidermoid
Polymorphous Adenocarcinoma Carcinoma Neuroendocrine carcinomas Carcinoma
Basal Cell Adenocarcinoma Lymphoepithelial carcinoma Adenoid Cystic Carcinoma
Epithelial-Myoepithelial Primary squamous cell Adenocarcinoma, NOS
Carcinoma carcinoma Intraductal Carcinoma
Secretory carcinoma Carcinoma-ex Pleomorphic
Clear Cell Carcinoma Adenoma

High-grade Transformation
Low/intermediate grade tumors can undergo “High-grade Transformation” (i.e., De-differentiation)
• Lose recognizable conventional histomorphology, with increased mitotic activity and pleomorphism
• Transformed component usually high-grade carcinoma NOS or squamous cell carcinoma
• Tends to occur in patients older than the median age for individual neoplasms
• (Time for tumors to de-differentiate)
• More aggressive behavior→ Worse prognosis
Adapted from a presentation from Justin A. Bishop, MD Chief of Anatomic Pathology UT Southwestern Medical Center

Milan System On FNA’s, try to use the Milan system to guide clinical management and whenever
possible subtype the tumor and, if malignant, give a grade (high vs low).

Category Explanation Risk of Clinical

Malignancy Management
1. Non-diagnostic Insufficient material for Dx 25% Clinical and radiologic
correlation/repeat FNA
2. Non-Neoplastic Inflammatory/reactive changes (e.g., 10% Clinical follow-up and
reactive lymph node, infection) radiologic correlation
3. Atypia of Undetermined Indefinite for neoplasm (often 20% FNA or surgery
Significance inadequately sampled neoplasm) (e.g.,
rare atypical cells, abundant mucin)
4. Neoplasm: Benign E.g., Pleomorphic adenoma, Warthin <5% Surgery or follow-up
Tumor
4. Neoplasm: Uncertain E.g., “Basaloid neoplasm” (Favor 35% Surgery
Malignant Potential Monomorphic adenoma, cannot rule
out adenoid cystic)
5. Suspicious for Features suspicious for malignancy but 60% Surgery
Malignancy not unequivocal
6. Malignant Clearly malignant (e.g., Mucoep, 90% Surgery
Adenoid cystic, etc…). Try to subtype
and grade if possible.
 Prepared by Kurt Schaberg

Sinonasal/Nasopharyngeal Tumors
Benign
Sinonasal Papillomas aka Schneiderian papilloma
Morphology Location Risk of Molecular
transformation
Exophytic Exophytic growth; Nasal Very low risk Low-risk HPV
immature squamous epithelium septum subtypes

Inverted Inverted ‘‘ribbonlike’’ growth; Lateral Low to EGFR

immature squamous epithelium; wall and Intermediate risk mutations or
transmigrating intraepithelial sinuses low-risk HPV
neutrophilic inflammation subtypes
Oncocytic Exophytic and endophytic growth; Lateral Low to KRAS
multilayered oncocytic epithelium; wall and intermediate
microcysts and intraepithelial sinuses
neutrophilic microabscesses
Modified from: Weindorf et al. Arch Pathol Lab Med—Vol 143, November 2019

Oncocytic Sinonasal Papilloma

Note the abundant oncocytic epithelium with
numerous neutrophils

Inverted Sinonasal Papilloma

Note the inverted, “ribbon-like” growth
Respiratory Epithelial Adenomatoid Hamartoma aka “REAH”
Sinonasal glandular proliferation arising
from the surface epithelium (i.e., in
continuity with the surface).
Invaginations of small to medium-sized
glands surrounded by hyalinized stroma
with characteristic thickened, eosinophilic
basement membrane

Exists on a spectrum with seromucinous

hamartoma, which has smaller glands.

Should be able to draw a circle around all

of the glands though, if too confluent
→ consider a low-grade adenocarcinoma

Inflammatory Polyp
Surface ciliated, sinonasal mucosa,
possibly with squamous metaplasia.

Edematous stroma (without a

proliferation of seromucinous glands).

Mixed inflammation (usu. Lymphocytes,

plasma cells, and eosinophils)

Pituitary adenoma
Benign anterior pituitary tumor
Although usually primary to sphenoid bone, can erode into
nasopharynx or be ectopic
Can result in endocrine disorders, such as Cushing’s disease
or acromegaly.

Solid, nested, or trabecular growth of epithelioid cells with

round nuclei and speckled chromatin and eosinophilic,
granular chromatin.
Express CK, and neuroendocrine markers.
NO S100 sustentacular pattern
Can stain with hormone-specific markers (e.g., prolactin)
Can recur
 Small Round Cell DDX: MR. SLEEP’N
Malignant M: Melanoma, Mesenchymal chondrosarcoma
R: Rhabdomyosarcoma
S: SNUC, SCC, SMARCB1-deficient sinonasal carcinoma
L: Lymphoma
E: Esthesioneuroblastoma
E: Ewing sarcoma
P: Pituitary adenoma, Plasmacytoma
N: NUT Carcinoma, Nasopharyngeal Carcinoma, NEC,

Squamous cell carcinoma

Most common carcinoma!
Can be Keratinizing or Non-keratinizing
Associated with tobacco exposure.

High-risk HPV subtypes in a subset of tumors;

EGFR or KRAS mutations if papilloma–associated

Sinonasal Undifferentiated Carcinoma (SNUC)

Poorly differentiated carcinoma without squamous,
glandular, or neuroendocrine differentiation
(Dx of exclusion!).
Open to hyperchromatic nuclei. Somewhat monotonous.
Often prominent nucleoli.
CK+, but squamous markers negative
IDH2 codon R172 mutations in most tumors
Aggressive high-grade malignancy→ poor outcome

NUT (Midline) Carcinoma

Poorly-differentiated carcinoma (often small-round
blue cells), with often “abrupt keratinization” or
squamous differentiation.

Often younger patients, in the midline, often in the

head and neck.

NUT gene rearrangement→ stain with NUT IHC!

Aggressive high-grade malignancy→ poor outcome

 SMARCB1(INI-1)–deficient sinonasal carcinoma
Poorly-differentiated carcinoma with high N:C ratios
Similar morphology to SNUC but may show
prominent plasmacytoid/rhabdoid features
Biallelic inactivation of SMARCB1 (loss of INI-1
staining by IHC)

Poor long-term outcomes

HPV-related multiphenotypic sinonasal carcinoma

High-grade carcinoma with morphologic and
immunohistochemical evidence of myoepithelial
differentiation → often Adenoid cystic-like
Shows associated surface squamous dysplasia
Positive for HPV: High-risk subtypes (especially type
33)→ P16 IHC block positive, but must do
additional, more specific testing.
Although typically advanced disease at presentation,
clinical course is relatively indolent

Lymphoepithelial Carcinoma
Essentially non-keratinizing nasopharyngeal
carcinoma, undifferentiated type (if in the sinonasal
cavity, just call it NPC if in nasopharynx)
Sheets of malignant cells with vesicular chromatin,
indististinct cytoplasm, and abundant tumor-
infiltrating lymphocytes.
EBV-positive. Positive for CK, CK5/6, p40, p63

More common in Asians.

Teratocarcinosarcoma
Malignant tumor with features of teratoma (e.g.,
squamous or glandular epithelium, often including
immatures fetal-appearing squamous epithelium,
and immature neuroepithelium, sometimes with
rosette formation) and carcinosarcoma (with
spindled cells, possibly with rhabdomyoblastic, or
other differentiation) without germ cell components
 Neuroendocrine Carcinoma
Like Poorly-differentiated neuroendocrine
carcinomas of the lung.
Divided into: 1) Small cell neuroendocrine carcinoma
2) Large cell neuroendocrine carcinoma
Strong staining with a neuroendocrine stain (e.g..,
synaptophysin or chromogranin). Often perinuclear
“dot-like” keratin expression.

Mucosal Melanoma
Distinct from cutaneous melanomas biologically
(but must exclude metastatic melanoma clinically!)
Epithelioid to spindled cells with pleomorphic nuclei
and often prominent nucleoli.
Intracytoplasmic melanin
Melanoma markers: S100, SOX10, HMB45, MelanA,
MITF, Tyrosinase. Do many (as can be loss)!
Poor prognosis: Staging starts at T3-4.
No need for Clark/Breslow depth.

Adenocarcinoma
Salivary gland adenocarcinomas are the most common (particularly adenoid cystic→ see separate guide)
Sinonasal Adenocarcinomas
Intestinal type
Causal relationship with wood dust and leather dust (so, mostly men)
Morphology and IHC identical to colonic adenocarcinoma
(CK7-, CK20+, CDX2+)
Non-intestinal type
(CK7+, CK20-, CDX2-)
Low-grade:
Very bland cytologically (to the point where you wonder if it is malignant!)
Excellent prognosis
High-grade
Cytologically malignant. Diagnosis of exclusion (must exclude metastasis, etc…)
Poor prognosis
Nasopharyngeal papillary adenocarcinoma
Low-grade adenocarcinoma of the nasopharynx with predominantly papillary architecture
Papillae are lined by a single layer of bland cuboidal cells with scant cytoplasm
Complex, arborizing papillae (sort of looks like ovarian micropapillary serous borderline tumor)
Rhabdomyosarcoma Malignant tumor with primary skeletal muscle differentiation, several types
Stain with Desmin, MyoD1, Myogenin
Embryonal Rhabdo:
Variable numbers of round (“rhabdoid”), strap-, or tadpole-shaped
eosinophilic rhabdomyoblasts in a myxoid stroma
Can see cytoplasmic cross striations
Alveolar Rhabdo:
Larger, more rounded undifferentiated cells with only occasional
rhabdomyoblasts
Often arranged in an alveolar (nested) pattern
Distinctively strong and diffuse myogenin positivity
Characteristic FOXO1 translocations

Olfactory Neuroblastoma aka “Esthesioneuroblastoma”

Malignant neuroectodermal neoplasm
Confined to the cribriform plate (and
surrounding region)
Lobulated, nests to sheets of cells with
speckled chromatin. High N:C ratio
Fibrillary cytoplasm→ Neuropil!
Can see pseudorosettes.
IHC: Diffuse Synaptophysin/Chromogranin
S100→ Sustentacular pattern. CK negative.

Ewing Sarcoma aka Primitive Neuroectodermal Tumor (PNET)

Malignant tumor of neuroectodermal differentiation
Often have EWSR1 translocation (with FLI-1 or ERG) t(11;22)
Usually uniform, small, round, blue cells with sheet-like to lobular,
growth pattern with variable necrosis
Strong, membranous CD99 staining
(Sensitive, but not Specific staining)
Cytoplasmic glycogen stains with PAS

“Adamantinoma-like” variant can show diffuse staining with CK Can see

and p40! pseudorosettes

Lymphoma Plasmacytoma
Extranodal NK/T-cell lymphoma IHC: CD138+ with light chain restriction
IHC: CD3, CD56, EBER + May or may not be associated with multiple myeloma
Most common in Asians
 Unique (not benign) Mesenchymal Tumors
Glomangiopericytoma
Patternless proliferation of regular, syncytial spindled cells
with ovoid nuclei.
Prominent vascularity with perivascular hyalinization.
Can see “staghorn” vessels (hemangiopericytoma-like,
hence the name, in part)
Perivascular myoid phenotype (like a glomus tumor, hence
the name)
IHC: SMA+, Nuclear ẞ-catenin (CTNNB1 mutations)
Relatively indolent with good survival

Biphenotypic Sinonasal Sarcoma

Low-grade spindle cell sarcoma.
Cellular, submucosal spindle-cell proliferation.
Arranged in intersection fascicles, often herringbone.
Infiltrate into bone often.
Can induce epithelial proliferation.
“Biphenotypic” because has evidence of both neural
and muscular differentiation.
Neural→ S100 (focal to diffuse)
Muscle→ SMA (focal to diffuse)
PAX3-MAML3 translocations.
Slow, continuous growth, but no metastases.

Nasopharyngeal Angiofibroma
Richly vascular tumor with variably sized blood vessels set
in fibrotic stroma.
Vessels are usu. thin-walled and often dilated with
variable smooth muscle.
Stroma is myxoid to dense with stellate fibroblasts.
Almost exclusively young to adolescent boys (“Juvenile
angiofibroma”)→ classically causes epistaxis &
obstruction
Nuclear expression of ẞ-catenin and AR in stromal cells
Locally aggressive and can recur.
Treat with embolization and surgery
Immunohistochemistry

HPV-related multiphenotypic sinonasal

Sinonasal Undifferentiated Carcinoma

SMARCB1(INI-1)–deficient sinonasal

Neuroendocrine Carcinoma
Nasopharyngeal carcinoma
Squamous cell carcinoma

Olfactory Neuroblastoma
Rhabdomyosarcoma
Mucosal melanoma
NUT carcinoma

Ewing Sarcoma
Lymphoma
carcinoma

carcinoma
(SNUC)

CK
(AE1/AE3) + + + + + + + - - - - ±
CK5/6
+ - ± + + + - - - - - ±
P63 and
p40
+ - ± + + + - - - - - ±
Synapto/
Chromo
- - - - - - + - ± - + ±
CD56
- - - - - - + - ± ± + ±
CD99
- - - - - - - - - ± - +
P16
± ± - - + - ± - - - - -
S100
SOX10
- - - - + - - + - - + -
CD45
- - - - - - - - - + - -
Myogenin/
Desmin
- - - - - - - - + - - -
NUT
- - - + - - - - - - - -
INI-1
+ + - + + + + + + + + +
EBER
- - - - - + - - - ± - -
Note: Weak/focal staining with synaptophysin, CD56, and CK can be seen with many tumors and
should be taken in context. Look for strong, diffuse staining (think Christmas tree).
Algorithm for Nasal Small Round Blue Cell Tumors
Starting IHC Panel: 1) AE1/AE3, 2) p40, 3) synaptophysin, 4) SOX10, 5) CD45, 6) CD99, and 7) Desmin
Adapted from a presentation from Justin A. Bishop, MD Chief of Anatomic Pathology UT Southwestern Medical Center

CK

- or F ++

Desmin/myogenin SMARCB1
- or F ++ lost intact
CD99/NKX2.2 Alveolar SMARCB1-deficient
P40
- or F
Rhabdomyosarcoma sinonasal carcinoma ++
++ - or F
Melanoma Ewing Sarcoma Synaptophysin/Chromogranin NUT
markers
+ - - or F + + -
Melanoma Lymphoid Multilineage Differentiation Pituitary hormones/ NUT carcinoma EBER
+ markers sphenoid location
- - + + -
Lymphoma Synaptophysin/ - Lymphoepithelial Myoepithelial
Chromogranin Pituitary Neuroendocrine Carcinoma markers
SNUC
+ adenoma carcinoma +
Olfactory + Solid adenoid -
neuroblastoma cystic carcinoma
Teratocarcinosarcoma

CD99/NKX2.2

Start with the whole panel, and

-
then work through the ++
Non-keratinizing
algorithm and get additional squamous cell
stains/studies if necessary. carcinoma Adimantimoma-
like Ewing
sarcoma
 Prepared by Kurt Schaberg
Keratinocyte tumors
Actinic Keratosis
Precancerous, risk of malignancy ~8-20% per year
(progresses to SCC); Due to chronic sun exposure
Rough scaly plaque; typically due to sun exposure
Tx: liquid nitrogen, 5-FU, shave, curettage
• Atypical keratinocytes in lower third of epidermis
• Alternating orthokeratosis and parakeratosis
• Sparing of cutaneous adnexa
• Solar elastosis in dermis

Squamous cell carcinoma in situ (aka Bowen’s disease)

• No epidermal maturation
• Atypical cells at all levels of the epidermis Loss of granular layer
• Epidermis appears disorganized

Squamous Cell Carcinoma

Second most common form of skin cancer (20% of cutaneous malignancies)
Locally destructive; metastatic potential
Tx: Depends on size, location and depth of invasion: Excision, Mohs micrographic surgery, Radiation
• Nests of atypical squamous cells arise from the epidermis and invade the dermis
• Evidence of squamous differentiation (keratinization and intercellular bridges)
• Dyskeratotic cells = squamous differentiation
Risk factors for metastasis (high risk):
• Often associated with AK or SCCIS - location (ear, lip)
• Findings that suggest invasion - size (>2 cm)
• Jagged interface with dermis - depth
• Aberrant deep keratinization - evidence of perineural invasion
- evidence of desmoplastic
• Single cells invasion
features
Variants:
Keratoacanthoma - well-differentiated variant of SCC that spontaneously regresses in most cases.
Typically composed of large, crateriform (cup-like) lesion filled with abundant keratin debris
Acantholytic SCC – acantholysis with large epithelioid cells with dense eosinophilic cytoplasm and
scattered dyskeratotic (apoptotic) cells
Verrucous SCC – Extremely well-differentiated, low-risk with pushing border and acanthotic papilla.
NO infiltrative growth. Associated inflammation at base.
Desmoplastic SCC – tumor cells become spindled/sarcomatoid
HMWCKs, p63, and p40 are most sensitive markers for poorly differentiated and spindle
cell/sarcomatoid SCC (Pankeratin can be lost in poorly differentiated and spindle cell tumors)
 Basal Cell Carcinoma Most common malignancy in humans
Locally aggressive and destructive behavior
Very low metastatic potential (< 0.1%)
Pediatric BCC?  consider Gorlin’s Syndrome
• Basaloid cells with increased N/C ratio
• Nests with peripheral palisading
• Cleft formation between the tumor and surrounding stroma
Note: Some focal keratinization may be present!
May mimic adnexal structures, making margins challenging.
However, basal cell carcinoma tumor cells should have darker
chromatin, more apoptosis and mitoses, and paler cytoplasm than
the hair follicles.
Subtypes:
Nodular – Large, rounded nests Stains: BerEP4 will stain BCC but not SCC
Micronodular* – smaller nests
Superficial – superficial nests separated by uninvolved areas
Infiltrative*- small infiltrative cords
Sclerosing/morpheic* - infiltrative nests with desmoplastic stroma
Basosquamous* - Prominent areas of squamous differentiation
Infundibulocystic – resemble hair follicle
Fibroepithelioma of Pincus – anastomosing cords
* more aggressive variants Infiltrative

Seborrheic Keratosis
• Horn cysts
• Interlacing pigmented epidermal strands
• Acanthosis
• Hyperkeratosis

Solar lentigo aka lentigo senilis, age spot

“Dirty feet”
Finger-like proliferation of hyperpigmented rete growing down
from the epidermis. Keratinocytes, not melanocytes, are the
pigmented cells

Verruca vulgaris aka Wart

HPV-induced, circumscribed lesion
Cup-like rete ridges
Papillomatosis (“church spires”)
Hyperkeratosis often with parakeratosis
Koilocytes may be variably present
Verruca plana = flat wart
 Prepared by Kurt Schaberg
More Skin Tumors
Epithelial Cysts Epidermal Inclusion Cyst (EIC)
Acquired unilocular cyst due to trauma, etc..
Lined by squamous epithelium with granular layer
Contains laminated (basket weave) keratin
May rupture and become inflamed

Dermoid Cyst
Present at birth
Like EIC, but with hair follicles and sebaceous glands

Pilar (Trichilemmal) Cyst

Filled with dense, “wet” eosinophilic keratin
Stratified squamous epithelium
Granular layer generally absent

Sebaceous Tumors Ectopic sebaceous glands

Not associated with hair follicles
Sebaceous hyperplasia
Overgrowth of Sebaceous glands. Lobules of sebocytes
arranged around infundibulum of central hair follicle. 1 layer
of basaloid cells compressed at periphery of sebocytes. No
cytologic atypia
Sebaceous Adenoma
May have similar low-power architecture to sebaceous hyperplasia, but
typically larger nodular aggregates. Lobular downgrowth from epidermis.
Predominance (> 50%) of sebocytes. Cytologic atypia not prominent
Composed of > 50% germinative/basaloid cells Sebaceoma

Sebaceous Carcinoma
Aggressive tumors with high incidence of metastasis (> 30%)
Strong association with Muir-Torre syndrome if patients have multiple
sebaceous tumors (Genes implicated include MLH1, MSH2, MSH6, PMS2)
Eyelids are most common site (~ 75% of cases)
Clear cells often present but vary greatly in number
Show prominent cytologic atypia and pleomorphism
Mitotic figures, including atypical forms, are usually abundant
Stains: May stain with AR, EMA, and Factor XIIa
 (Eccrine) Spiroadenoma “blue cannonballs in the dermis”
Basophilic tumor nodules in dermis
Tumor lobules may be partially encapsulated
Biphasic appearance with 2 cell types:
1) Peripheral small cells with scant cytoplasm and small
hyperchromatic nuclei
2) Central larger cells with eosinophilic cytoplasm and oval,
vesicular nuclei
Tumor lobules sometimes surrounded by thickened basement
membrane, similar to cylindroma

Cylindroma
“jigsaw puzzle”
Also has basaloid (blue) nests in the dermis, also with
two cell populations and basement membrane
matrix.
Multiple nodules/lobules of basaloid cells
surrounded by dense eosinophilic basement
membrane
Tumor lobules have complex pattern, where tumor
lobules appear to fit together in irregular jigsaw
puzzle-like pattern

Chondroid Syringoma aka Cutaneous mixed tumor

Essentially a pleomorphic adenoma, but primary to the skin

Epithelial cells embedded in myxoid, chondroid, or fibrous stroma
Tumor shows eccrine and apocrine differentiation
Ductal structures of variable size and shape present
Ducts lined by 2 layers of cuboidal cells and peripheral layer of
myoepithelial cells

Small ducts, nests, cords, and cysts in superficial dermis Syringoma

Ducts and cysts lined by 1 or 2 layers of small, bland-
appearing cuboidal cells
Some ducts have tadpole-like appearance with comma-
like tails (like paisley)
Dilated ducts may have eosinophilic contents
Most common in head/neck, esp. eyelids
If deep/perineural invasion  consider Microcystic
Adenexal Carcinoma (MAC)
 Pilomatrixoma
Well-circumscribed with mixture of 1) basaloid and
2) shadow/ghost cells (abundant pink cytoplasm and open
space at their center where nucleus was)
Dystrophic calcification is frequently seen
Foreign-body giant cell reaction surrounding tumor is common
Infiltrative, prominent nucleoli, necrosis, mitoses? 
Pilomatrical Carcinoma

Trichofoliculoma
Cystic tumor that communicates to overlying epidermis
Cystic space filled with keratinous debris and hair shafts
Lined by squamous epithelium with thin granular layer
Numerous small, primitive follicles radiate around
periphery of tumor and communicate with central
cystic space

Trichilemmoma
Lobular proliferation of mature squamoid cells with pale-
to clear-staining cytoplasm
Peripheral palisading of basaloid cells
Cells are surrounded by thickened, glassy-appearing
basement membrane
Multiple broad connections to epidermis and follicles
Associated with Cowden’s Syndrome

COWden’s Syndrome Macrocephaly

& Uterine Cancer
PTEN mutation (tumor suppressor)

Multiple hamartomas (mouth, GI tract)

Thyroid carcinoma (usually Follicular)
Breast Cancer (very high risk)
Endometrial Cancer
Macrocephaly
trichileMMOOOOmas Thyroid Cancer

Breast CA
Last updated: 4/3/20 Prepared by Kurt Schaberg

Soft Tissue Tumors

Adipocytic
Lipoma

Benign adipocytic tumor

Most are mature “white fat” with a single large lipid droplet.
Common. Usually superficial/subcutaneous.
May recur.
Although clinically form a mass, may be indistinguishable
histologically from normal fat (so can sign out as “Mature adipose
tissue, compatible with lipoma”)
Molecular: Various chromosomal aberrations
Specific types:
Angiolipoma—Fat + prominent branching network of vessels, often with
fibrin thrombi. Usu. Tender nodule on forearm.
Spindle Cell Lipoma—Fat + bland spindle cells with a variably myxoid
background. Can be fat-poor.
Note, these two subtypes (↑↓) exist on a spectrum. Classically, they
are seen in older men in a “cape-like” distribution (neck, shoulder, back).
Spindled and floret cells stain with CD34.
Pleomorphic Lipoma—Spindle cell lipoma + scattered, bizarre giant cells
that frequently with floret-like arrangement of multiple hyperchromatic
nuclei

Chondroid Lipoma—Fat + round cells in a myxochondroid background.

Neural fibrolipoma—Fat+ fibrous tissue growing in nerves. Usu. in arms.

Myelolipoma—Fat + bone marrow elements. Most common in adrenal
medulla.

Lipoblastoma—Occurs in infants and resembles fetal adipose tissue.

Lobules of immature fat cells separated by connective tissue septa with
a loose myxoid appearance.
Myolipoma—Fat + smooth muscle bundles

Hibernoma—Brown fat (multiple small vacuoles within polygonal cells

with distinct cell membranes).
 Atypical Lipomatous Tumor/Well-Differentiated Liposarcoma
Most common adult sarcoma. Usually elderly.
Non-metastasizing (but recur/grow).
Deep soft tissue, most common in extremity, use ALT term, easier
to excise, curable and less likely to recur).
In retroperitoneum, use WDL term, harder to excise, basically
incurable.

Variable amount of lipoblasts (cytoplasmic lipid-rich droplets with a

hyperchromatic, indented/scalloped nucleus).

Can be lipoma-like (resembling mature fat), sclerotic (fibrous areas,

often with scattered hyperchromatic atypical cells), or
inflammatory (with associated brisk inflammatory infiltrate).
Molecular: Giant marker and ring chromosomes that contain
amplified regions of 12q including MDM2 and CDK4 → Test for
with MDM2 or CDK4 IHC, or, more commonly, MDM2 FISH for gene
amplification. P16 is a sensitive (but not specific) marker as it is
downstream from CDK4, so it is overexpressed.
Can De-differentiate (see below).

Fatty Tumors to FISH for MDM2

Lipomatous tumors with equivocal cytologic atypia
Recurrent lipomas
Deep lipomas without atypia that exceed 15 cm
Retroperitoneal or intra-abdominal lipomatous tumors lacking
cytologic atypia (Although retroperitoneal lipomas DO exist,
they are very rare and a diagnosis of exclusion)

(No need to FISH classic cases with lipoblasts and/or atypia)

Can
Dedifferentiated Liposarcoma Dedifferentiate
Contain an ALT/WDL component, with an abrupt transition to another
component, which is usually an undifferentiated pleomorphic sarcoma
(sometimes fibrosarcoma, or lower grade sarcoma).

Some say de-differentiated area should have a mitotic count of at least

5 mitotic figures per 10 high-power fields.

Molecular: Same 12q amplifications as in ALT/WDL (but with more

superimposed), so can use same FISH.

Has Metastatic potential in addition to being more locally aggressive.

 Myxoid Liposarcoma
Usu. younger and on the lower extremity

Resemble developing fat:

Multinodular proliferation of round cells
Abundant myxoid matrix,
Chicken-wire vasculature,
multivacuolar and univacuolar lipoblasts

As get higher grade→ lose myxoid

component → composed of primarily round
cells → “Round cell liposarcoma”
Molecular: FUS-DDIT3 fusions
(do FUS break apart FISH)
Higher
Outcome: Higher round cell component→
worse outcome. Grade
Can metastasize.

Pleomorphic Liposarcoma
Least common liposarcoma.
Essentially, an undifferentiated pleomorphic
sarcoma, but with scattered lipoblasts.
Extreme pleomorphism including bizarre giant cells.
Malignant with frequent metastases.
Molecular: Complex structural chromosomal
rearrangements.
 Fibroblastic/Myofibroblastic
Nodular Fasciitis
Benign, self-limited, “transient neoplasia.”
Rapidly growing, mass-forming subcutaneous lesion,
sometimes after trauma, that self-regresses. Often upper
extremity or head and neck of kids or young adults.
Can be misdiagnosed as a sarcoma because of rapid growth
and mitotic activity. Previously thought to be reactive.
Bland spindled to stellate cells with variably cellular “tissue
culture-like” pattern.
“Torn stroma” resembling “S” and “C” shapes.
Extravasated RBCs.
Pale nuclei with prominent nucleoli.
Older lesions may be scarred/collagenous.
Molecular: MYH9-USP6 gene fusions (do USP6 break apart
FISH).
IHC: Actin (+) (as myofibroblastic), but desmin (-).
Specific variants: Ossifying fasciitis (with metaplastic bone),
Cranial fasciitis (on scalp of infants), and intravascular
fasciitis (in vessels).

Proliferative Fasciitis/Myositis
Benign. Subcutaneous soft tissue of adults usu. on arm.
Like nodular fasciitis (tissue culture-like)
Prominent large, basophilic ganglion-like cells with one or
two vesicular nuclei and prominent nucleoli.

IHC: Similar to Nodular fasciitis. Not true ganglion cells

(negative S100, etc…)
If in muscle, use “Proliferative myositis.”

Ischemic Fasciitis
“Pseudosarcomatous” (Benign/reactive) proliferation overlying bony prominences of elderly and/or
immobile patients.
Often shoulder or sacral site→ intermittent ischemia with breakdown/regenerative changes.
Zonal growth with central necrosis surrounded by proliferating blood vessels and
fibroblasts/myofibroblasts.
Can see scattered hyperchromatic atypical cells and mitoses, but no atypical mitoses.
 Elastofibroma EVG
Benign (likely reactive/degenerative pseudotumor).
Usually under scapula of elderly patient.

Eosinophilic collagen and Elastin.

Occasional fibroblasts, myxoid material, and fat.
Elastic fibers have a degenerative, “beaded” appearance
that can fragment into flower-like disks
Stains: Can highlight Elastin with EVG.

Nuchal-type Fibroma
Benign. Usu. Posterior neck of adults. Painless mass.
Almost acellular densely collagenized with rare
fibroblasts. Somewhat ill-defined entrapping adjacent
structures.

IHC: Spindled cells usu. (+) CD34 and CD99. (-) actin.

Gardner-associated Fibroma
Benign. Usually back of younger patient.
Strong association with FAP and desmoid tumors (Gardner
syndrome).
Histologic overlap with nuchal-type fibroma.
Densely collagenized with sparse spindled cells with interspersed
lobules of fat.
Can entrap other structures at periphery.
IHC: Spindled cells usu. (+) CD34 and CD99. Often nuclear β-
catenin (like desmoids!)

Fibrous Hamartoma of Infancy

Benign superficial fibrous lesion occurring during first 2
years of life

3 components in organoid growth pattern: 3

1)Intersecting bands of mature fibrous tissue, comprising
spindle-shaped myofibroblasts and fibroblasts
2
2) Nests of immature round, ovoid, or spindle cells within
loose stroma
3) Interspersed mature fat
1
Molecular: EGFR exon 20 insertion/duplication
 Fibroma of Tendon Sheath
Benign. Slowly growing mass on tendon sheath or
aponeuroses.
Usu. adults, under 2 cm, and on extremities, often hand.
Well-circumscribed, lobulated.
Mostly hypocellular with spindled cells in densely
collagenized stroma.
Characteristic cleft-like areas spaces, possibly vascular.
IHC: variable actin and CD68

Calcifying Aponeurotic Fibroma

Benign. Primarily in Children. Can recur.
Slow-growing, painless mass on hands or feet attached
to aponeurosis, tendons, or fascia
Variable cellularity throughout lesion.
Plump, bland fibroblasts with dense collagen.
Distinct areas of calcification and cartilage formation.
Infiltrative growth.

Molecular: FN1-EGF fusions

Fibromatosis
Benign (never metastasize), but infiltrative with strong tendency to
recur.
2 Major Divisions:
Superficial: E.g., Palmar, plantar, penile. Small. Slowly-growing. Usu.
older.
Deep (“Desmoid-type”): E.g., Abdominal, mesenteric. More
aggressive. High-recurrence rate (>50%). Involve deep structures.
Usu. younger. Interestingly, microscopic margins do NOT predict
recurrence.
Infiltrative growth into surrounding structures (esp. skeletal muscle).
Broad, sweeping fascicles.
Uniform spindled cells with small, pale nuclei with pinpoint nucleoli.
Moderate amounts of collagen, surrounding cells, in slightly myxoid
background.
With age, less cellular and more collagen.
Microhemorrhages and scattered chronic inflammation.
IHC: Nuclear β-catenin (more cells with deep than superficial).
Some actin (+)
Molecular: Deep fibromatosis is associated with FAP and mutations in
the APC/β-catenin (CTNNB1) pathway
 Inflammatory Myofibroblastic Tumor
Borderline malignancy (tend to recur, rarely metastasize).
Most common sites: Lung, mesentery, omentum.
Any age, but more common in children.
Bland spindled to stellate cells in myxoid to hyalinize
stroma. Can have loose, fascicular, or storiform growth.
Prominent lymphoplasmacytic infiltrate.
Most cells bland, but sometimes large cells with
prominent nucleoli.
IHC: Variable staining with actin/desmin. ALK (+) in ~50%
Molecular: ~50% have ALK gene rearrangements.

Fibrosarcoma (Adult)
“Almost defined out of existence” – Dr. Richard Kempson
(Many tumors previously called fibrosarcoma have been re-
classified as synovial sarcoma, UPS, fibromatosis, or MPNST)
Now a diagnosis of exclusion! Must do work up to exclude
other diagnoses (IHC and FISH).
Uniform spindled cells with fascicular to herringbone growth.
Interwoven collagen fibers.

No specific IHC of molecular.

Can get Fibrosarcomatous transformation of DFSP→ Loses
storiform pattern and CD34 to become herringbone
fibrosarcoma.

Infantile Fibrosarcoma

Malignant. Newborns (congenital) or infants. Usu.

extremities.

Sheets of tightly packed spindled cells with herringbone

appearance. Little pleomorphism. Mitoses present.
Often lymphocytic infiltrate.

Molecular: ETV6-NTRK3 fusions (also seen in cellular

mesoblastic nephroma)
 Myxofibrosarcoma Old name: Myxoid Malignant Fibrous Histiocytoma (MFH)
Malignant. Slow-growing mass on extremity
of elderly.
Multinodular growth.
Myxoid background with varying cellularity
(usually low).
Stellate to spindled cells with
hyperchromatic, pleomorphic nuclei with
indistinct pink cytoplasm.
Characteristic curvilinear vessels that the
tumor cells attach to like “melting wax.”
IHC: focal actin

Molecular: Complex karyotype

Low-grade Fibromyxoid Sarcoma Old/alternative name: Hyalinizing Spindle Cell

Tumor with Giant Rosettes
Malignant. Deep soft tissues of extremity of
young to middle-aged adults.
Recur and can have late metastases.
Varying fibrous and myxoid areas, mostly
fibrous though.
Bland spindled cells with small hyperchromatic
nuclei.
Myxoid areas have curvilinear, branching
capillaries.
Can have large collagenous rosettes.

IHC: (+) MUC4, often EMA

Molecular: FUS-CREB3L2 fusions (do FUS FISH)

Sclerosing Epithelioid Fibrosarcoma

Malignant. Deep soft tissue of limbs.

Densely hyalinized stroma with epithelioid cells arranged in

cords and nests.
Cells have scant clear cytoplasm and angulated nuclei.

IHC: (+) MUC4, often EMA

Molecular: Somewhat diverse—many cases have FUS or

EWSR1 and CREB fusions
 Nerve Sheath Tumors
Schwannoma
Benign. Often associated with nerve. Usu. adults. Composed entirely of well-differentiated Schwann cells.
Very low risk of transformation.
Usually solitary and sporadic. NF2 associated with bilateral vestibular schwannomas.
Typically encapsulated.
Alternating compact spindle cells (Antoni A) and hypocellular less orderly areas (Antoni B)
Rows of nuclear palisading → Verocay bodies.
Axons not present in lesion→ pushed to periphery. Antoni B
Hyalinized blood vessels and lymphoid aggregates
common.
IHC: Strong, diffuse S100, scattered CD34,
moderate calretinin. Neurofilament highlights
displaced axons at periphery.
Subtypes: Antoni A
“Ancient change”- Degenerative atypia with
large, hyperchromatic nuclei, but no mitoses
Cellular – Exclusively Antoni A areas.

Melanotic – contain melanosomes, so stain with

melanocytic markers. Often epithelioid. Higher
risk of transformation.

Neurofibroma
Benign. Most commonly solitary and sporadic.
Multiple NF is a hallmark of neurofibromatosis type 1 (NF1), also
known as von Recklinghausen disease.
Higher, but still low, risk of transformation.
Can be cutaneous (most common), intraneural, or diffuse.
Plexiform NF→ almost exclusively in NF1; higher risk of MPNST.
Mixture of Schwann cells, perineurial-like cells, fibroblastic cells,
and entrapped axons.
Randomly oriented spindled cells with wavy, hyperchromatic nuclei.
Often hypocellular and variably myxoid
Thin and thick collagen strands (“shredded carrot collagen”)
Entrapped axons are overrun by lesion and scattered throughout.
IHC: Diffuse S100 (+) (but less so than schwannoma). Moderate
CD34. Neurofilament shows entrapped axons within lesion.
Types: Can be pigmented or show ancient change.
 Perineurioma
Benign. Can be intraneural or soft tissue. Sporadic.
Spindle cell proliferation with characteristic long,
thin, delicate, bipolar processes.
Wavy/tapering nuclei. Perivascular whorls.
IHC: EMA , Claudin-1, and GLUT-1 (+), Occasional
CD34. S100 (-)

Granular Cell Tumor

Benign neoplasm with neuroectodermal differentiation.
Epithelioid to spindled cells with abundant eosinophilic granular
cytoplasm highlighted by PASd
Full of lysosomes due to inactivating mutations in ATP6AP1 or 2
(makes it so can’t break down lysosomes)→ granular appearance
Stains: (+) S100, CD68, Inhibin, Calretinin
Congenital (Gingival) Granular Cell Tumor (Congenital Epulis):
Although looks similar, S-100 (-), located on gingiva at birth.

Ganglioneuroma
Benign. Usually posterior mediastinum or
retroperitoneum. No immature neuroblastic
element (unlike ganglioneuroblastoma).
Although some likely represent matured
neuroblastoma, it is thought that most are de novo.
Mature ganglion cells in neuromatous stroma
(unmyelinated axons with Schwann cells).
When multiple/diffuse and/or syndrome-related
(MEN 2b, Cowden, and NF1)→ Ganglioneuromatosis

Stains: Schwann cells (+) S100, Ganglion cells (+)

Synaptophysin, neurofilament

Traumatic (Amputation) Neuroma

Non-neoplastic nerve proliferation after
trauma (nerve is growing to try to
reestablish connection).

Haphazard proliferation of nerve fascicles

including axons and perineurial cells.
Damaged nerve often easily identified.
Malignant Peripheral Nerve Sheath Tumor (MPNST)
Malignant. Adults. Frequently in setting of NF1.
Often poor prognosis.

Must arise from a peripheral nerve or pre-existing

peripheral nerve sheath tumor or display histologic/IHC
evidence of nerve sheath differentiation.

Variable appearance, can resemble undifferentiated

pleomorphic sarcoma or fibrosarcoma.

Spindled cells arranged in sweeping fascicles.

Densely cellular areas alternate with less cellular areas
giving a “marble-like” effect.
Can have herringbone architecture.
Wavy, buckled nuclei.
Geographic necrosis and/or mitotic activity (often
greater than 10/10 HPFs)

IHC: Patchy S100 and SOX10.

Loss of H3K27me3 expression (associated with worse
prognosis. Not entirely specific—see with SUZ12 and
EED gene inactivation)

Subtypes:
MPNST with rhabdomyoblastic differentiation
(“Malignant triton tumor”)

MPNST with glandular differentiation

Epithelioid MPNST—composed of polygonal, epithelioid

cells. Unique strong, diffuse S100 staining

Other Nerve Sheath Tumors

Nerve Sheath Myxoma: Benign. Superficial, myxoid. Irregular, slow-growing nodules separated by
fibrous bands containing spindled cells in myxoid matrix. S100 (+)

Ectopic Meningioma: Benign. Essentially a meningioma in soft tissue. Whorled architecture. Oval
nuclei. Occasional nuclear pseudoinclusions. IHC: EMA, PR, and SSTR2A (+)

Palisaded encapsulated neuroma (Solitary circumscribed neuroma): Benign. Dermal tumor, often on
head/neck. Lobular with sharply demarcated borders. Composed of axons, Schwann cells, and
perineural fibroblasts.
 Perivascular Tumors
Glomus
Benign. Tumor derived from glomus body (specialized AV
anastomosis that regulates heat).
Often red-blue nodules in the deep dermis of extremities.
fingers/toes. Often painful.

Very richly vascular network separating tumor cell nests.

Distinctive cells with round nuclei and eosinophilic cytoplasm.

IHC: Actin (+) other smooth muscle markers variable.

Myopericytoma/Myofibroma
Benign. Exist on a spectrum.

Myofibroma: Usu. Head/neck in first year of life.

Multinodular, well-circumscribed.
Biphasic: 1) immature-appearing plump spindled cells with
staghorn vessels, 2) areas of more mature spindled cells in
bundles and whorls.
Myopericytoma: Superficial mass in adults.
Nodular, well-circumscribed.
Concentric, multilayered growth of spindled cells around
vessels.
Very richly vascular

IHC: Actin (+) other smooth muscle markers variable.

Perivascular Epithelioid Cell Tumor (PEComa)

Benign.
Often areas of epithelioid tumor cells with abundant
granular eosinophilic to clear cytoplasm with round
nuclei.
Associated with vessel walls in radial arrangement.
IHC: Express melanocytic (usu. HMB45, variable MelanA),
and smooth muscle (Actins, desmin, etc..) markers.
A subset of cases are associated with Tuberous Sclerosis.
Can see in many sites/organs.
Includes Angiomyolipoma, Clear cell “sugar” tumor, and
lymphangioleimyomatosis.
 Smooth Muscle IHC: SMA, Desmin, H-Caldesmon, Calponin (+)

Leiomyoma
Benign.
Can see commonly in dermis (derived from pilar muscles
and vessels).
Very uncommon in deep soft tissue.

Cytologically bland spindled cells with cigar-shaped

nuclei. Fascicular architecture.
No nuclear atypia. At most very rare mitoses (<1/50 HPF)

Pilar Leiomyoma
Ill-defined, dermal nodule composed of haphazardly
arranged smooth muscle bundles/fascicles
Fascicles often dissect between dermal collagen
Often painful.

Angioleiomyoma
Well-circumscribed neoplasm composed of mature
smooth muscle cells arranged around prominent blood
vessels

Leiomyosarcoma
Malignant. Poor prognosis.
Often in retroperitoneum of adults.
Often arise from veins.
Similar appearance to leiomyoma (fascicular
architecture)
But often notable pleomorphism.
Mitotic activity, often atypical mitoses.
Necrosis.
Molecular: Complex karyotype

EBV-associated Smooth Muscle Tumor

Benign, but patients can get multiple primaries.
Seen in setting of immunodeficiency (e.g., HIV, post-transplant, etc…)

Mostly typical smooth muscle appearance (fascicular architecture,

blunt-ended nuclei). Can see tumor-infiltrating lymphs and more
“round cell” areas.

Molecular/IHC: Need to confirm EBV in tumor with EBER

 Skeletal Muscle Tumors IHC: Most specific Myogenin, MyoD1
Also smooth muscle markers (e.g., Desmin, Actin)
Rhabdomyoma
Benign. But location/growth may cause problems (especially in
heart)
Cardiac-type Rhabdomyoma:
Occur in hearts of infants and young children, often in the
setting of Tuberous sclerosis.
Large, polygonal, vacuolated, cleared out, “spider cells”
Adult-type Rhabdomyoma:
Mature skeletal muscle differentiation.
Usu. Head and neck. Often pharynx or tongue.
Large, polygonal cells with abundant granular eosinophilic
cytoplasm. Some spider cells
Unencapsulated, lobular growth.

Fetal-type Rhabdomyoma:
Usu. Head and neck. Any age.
Irregular bundles of immature skeletal muscle.
Myxoid background.

Embryonal Rhabdomyosarcoma
Malignant.
Most common soft tissue sarcoma in kids.
Occasional adult.
Usu. Head/Neck (e.g., nasal, tongue, etc..) or
Genitourinary (e.g., bladder, prostate, etc…)

Resembles embryonic skeletal muscle cells.

Some areas are hypercellular “small round blue cells.”
Other areas maturing with rhabdoid cells with abundant,
eccentric eosinophilic cytoplasm, “tadpole cells,” and
“strap cells” (with cross striations)
Set in myxoid stroma

Botryoid type: Densely cellular layer below epithelial

surface (“cambium layer”) separated by hypocellular
area. Polypoid surface nodules (“grape-like”). Usually
projecting into mucosa-lined spaces (like vagina or nasal
cavity)
 Alveolar Rhabdomyosarcoma
Malignant. More aggressive than Embryonal
Rhabdo.
Often adolescents and young adults in deep soft
tissue of extremities and sinuses.
Highly cellular “small round blue cell” tumor.
Monomorphous round nuclei.
Often nest-like arrangement (hence “alveolar”).
Notable absence of strap cells, tadpole cells,
etc…
Molecular: FOXO1 fusions with either PAX3 or
PAX7

IHC: Strong, diffuse Myogenin suggests this Dx

(often patchier in embryonal). Often patchy
neuroendocrine staining.

Pleomorphic Rhabdomyosarcoma
Malignant. Adults. Deep soft tissue.

High-grade cytologically: sheets of large, atypical cells.

Eosinophilic polygonal cells to tadpole-like.

No embryonal or alveolar component. Resembles

heterologous differentiation in carcinosarcomas.

Spindle Cell Rhabdomyosarcoma

Malignant. Likely a variant of embryonal.
Usu. Young boys, esp. paratesticular.
Exclusively spindled cells with cigar-shaped nuclei.
Better prognosis than other Rhabdomyosarcomas.

Sclerosing Rhabdomyosarcoma
Malignant. Usually adults in soft tissue.

Nests of small round blue cells in nests and single file.

Abundantly hyalinized, eosinophilic to basophilic
matrix.

IHC: Of note, MyoD1 is strongly positive, while

Myogenin and desmin are only focal often.
 Fibrohistiocytic Tumors
Tenosynovial Giant Cell Tumor
Benign, but can be locally destructive. 4
Mixture of 1) bland mononuclear cells, 2) foamy macrophages, 3)
hemosiderin-laden macrophages, and 4) osteoclast-like giant cells.
Mononuclear cells are spindled to round with reniform/grooved
nuclei. Mitoses common. 2
IHC: Mononuclear cells CD68, CD163 (+), scattered desmin.
Molecular: CSF1 gene rearrangements 1
Localized-type:
L

Discrete, rounded proliferation. Usually occurs in digits. Less

aggressive. Often cure with excision.
Diffuse-type:
Grows in expansive sheets. Often in or around knee. Often
intraarticular. Large. Destructive.
Aka “Pigmented Villonodular Synovitis” (PVNS)
Need to treat more aggressively.
3

Fibrous Histiocytoma
Benign (generally). Neoplasm or Neoplasm-like (some seem to
occur after trauma)

Fibroblastic and histiocytic cells arranged in short fascicles.

Dermatofibroma
In Dermis (most common site by far)
Looks like a “blue haze” in the dermis
Tumors are grossly circumscribed but microscopically have
irregular, often jagged borders Collagen trapping at periphery
Overlying epithelial basilar induction with hyperpigmentation
(may mimic BCC)
Lots of variants: Epithelioid, Cellular, Aneurysmal, etc…
IHC: FXIIIA(+), CD163(+), CD68(+), CD34(-)

“Deep Benign Fibrous Histiocytoma:” If in deep soft tissue.

Very rare.

Plexiform Fibrohistiocytic tumor: Plexiform architecture in

deep soft tissue/dermis
 Vascular Tumors Endothelial cells stain with: CD31, ERG, FLI1,
often CD34
Vascular Malformations
Developmental abnormalities (occur during embryogenesis in
utero), that grow with the host. Static. Do not regress.
Arteriovenous Malformation (AVM)
Large, tortuous arteries with fragmented elastic lamina and
associated with thick-walled veins. Variable small vessel
component.
Most common in head/neck and brain.
Venous Malformations (Venous Hemangiomas)
Poorly-circumscribed collection of abnormal veins
Vary in size/proportion.
Often abnormally thick or thin walls for size.
Includes: Cavernous hemangiomas (collection of large, dilated
veins with thin walls)
Cutaneous Capillovenous Malformation
E.g. Telangiectasia. Often diagnosed clinically.
Associated with a variety of conditions (e.g., Osler-Weber-
Rendu)
Intramuscular hemangioma
Small vessels within muscle. Often parallel.

Papillary Endothelial Hyperplasia aka Mason’s Tumor

Intravascular exuberant proliferation of endothelial cells

with fibrin.
Small papillae covered by a single layer of endothelium
with a collagenized fibrin core. No atypia or mitoses.
Papillae can fuse, forming anastomotic channels.
Main importance is that it can mimic angiosarcoma
histologically. However, can be distinguished by exclusively
intravascular growth and lack of mitoses/atypia.

Bacillary Angiomatosis
Pseudo-neoplastic vascular proliferation caused by Bartonella
(Gram-negative bacilli, also causes Cat scratch disease).
Almost exclusively in immunocompromised adults, often AIDs.
Often in skin/soft tissue.
Lobules of capillary-sized vessels with plump endothelium with
clear cytoplasm. Associated neutrophilic infiltrate.
Stains: Warthin-starry highlights organisms
Hemangiomas
Benign vascular neoplasms. Often grow faster than patient.
Categorized by vessels size/appearance.

Lobular Capillary Hemangioma (“Pyogenic granuloma”)

Polypoid, exophytic on skin and mucosal surfaces.
Unclear if truly neoplastic.
Lobular arrangement of small capillaries with larger “feeder”
vessel.
Myxoid stroma with inflammatory cells.

Infantile (Juvenile) Hemangioma

Starts as flat, red mark soon after birth→ grows to look like
“strawberry” over several months → regress over several years.
Multinodular masses fed by single arteriole.
Appearance varies depending on phase.
IHC: Unique expression of GLUT1 (not in other hemangiomas)

Rarer subtypes
Hobnail hemangioma
Anastomosing hemangioma
Spindle cell hemangioma

Epithelioid Hemangioma aka Angiolymphoid hyperplasia with eosinophils

Benign.
Often young adults in superficial head and neck.
Circumscribed, subcutis. Large and deep.
Lobules of capillaries centered around larger vessel.
Endothelial cells are plump (“epithelioid”), projecting
like tombstones into vessels. Round nuclei. Abundant
eosinophilic cytoplasm. Associated inflammatory
infiltrate rich in eosinophils.

Lymphangioma
Benign. Often in kids during the first year of life.
Associated with Turner syndrome (XO).
Thin-walled, dilated lymphatic vessels of different
sizes, lined by flattened endothelium. Frequently
surrounded by lymphoid aggregates.
Contain grossly “milky” lymphatic fluid.
IHC: Endothelium expresses D2-40 and PROX1
(specific for lymphatics). Also CD31.
Kaposiform Hemangioendothelioma
Locally aggressive vascular tumor.
Exclusively in children.
Often associated with Kasabach-Merrit
phenomenon (consumption of
platelets→ thrombocytopenia)

Infiltrate soft tissue in “cannon-ball

fashion.” Different areas have features of
both capillary hemangioma and Kaposi
sarcoma (spindled cells).

Tightly coiled glomeruloid-like areas.

Epithelioid Hemangioendothelioma
Malignant (but less aggressive than angiosarcoma).
In soft tissue, often angiocentric, expanding wall and obliterating
lumen. Also common in liver.
Cords of epithelioid endothelial cells in myxohyaline stroma.
Eosinophilic cells with vacuoles containing erythrocytes (“Blister
cells”).
IHC: CAMTA1 stain specific

Molecular: recurrent CAMTA1-WWTR1 fusions

Kaposi Sarcoma
Locally aggressive. Often multiple cutaneous lesions
Caused by Human Herpes Virus 8 (HHV8) in all cases.
Can be Classic/Endemic, which are usually indolent, or
associated with immunosuppression (either
iatrogenically for organ transplantation or by AIDs),
which is more aggressive often.
Proliferation of bland spindled cells with slit-like
vascular spaces containing erythrocytes.
Often associated inflammatory infiltrate and hyaline
globules.

IHC: HHV8
Pseudomyogenic Hemangioendothelioma
Rarely metastasize. Often develop additional nodules in
same anatomic region. Often young men on leg.
Infiltrative sheets and fascicles of plump spindled cells.
Abundant brightly eosinophilic cytoplasm (resembling
rhabdomyoblasts, hence the name!). Vesicular nuclei.
IHC: CK AE1/AE3 (+), ERG(+), FOSB (+). CD31 (+/-),
INI1 intact.
Molecular: SERPINE1 and FOSB genes fusion

Atypical Vascular Lesion

Benign. Occur in irradiated skin (often of breast).
Often small/multiple.
Irregularly-shaped thin-walled vessels with branching and
anastomosing growth. Lined by a single layer of endothelium
with some hobnailing and hyperchromasia.
NO endothelial cell multilayering or true cytologic atypia
IHC/Molecular: No MYC overexpression/amplification.

Angiosarcoma
Malignant. Very aggressive. Typically elderly.

Variable degrees of vascular differentiation.

Some areas show well-formed anastomosing
vessels, while other areas may show solid sheets
of high-grade cells.
Can be epithelioid or spindled.
Often extensive hemorrhage.

Unlike benign lesions: significant cytologic atypia,

necrosis, endothelial cells piling up, and mitotic
figures (although mitoses can be seen in some
benign tumors)

Grade does not predict prognosis (all aggressive)

Post-radiation angiosarcoma of the breast:

Occurs after radiation (usu. ~5yrs).
High-level amplification of MYC (by IHC or FISH) is
a hallmark of this lesion.
Tumors of Uncertain Differentiation
Myxoma
Benign. Adults.
Uniform, cytologically bland, small spindled to stellate cells in
abundant myxoid stroma.
Can show cystic change and/or have more slightly more cellular
areas. Grossly look like jelly.
Notably: No atypia or mitoses (otherwise consider
myxofibrosarcoma)

Intramuscular:
Within muscle. Frequent GNAS mutations.
Intramuscular myxoma + fibrous dysplasia = Mazabraud
syndrome (both have GNAS mutations)
Juxta-articular:
Vicinity of a large joint (usu. Knee)
Lacks GNAS mutations.

Deep (“Aggressive”) Angiomyxoma

Benign (despite name!), but frequent recurrences
Adult women in pelvicoperineal region.
Small spindled to stellate cells in a loosely collagenized,
myxoid stroma. Scattered vessels of varying size.
Scant eosinophilic cytoplasm.
Larger spindled myoid cells congregate around larger
vessels and nerves.

IHC: ER, PR (+), Variable desmin and actin.

Molecular: HMGA2 rearrangements frequently.

Extrarenal Rhabdoid Tumor

Malignant. Very aggressive! Mainly infants and children.
Characteristic “rhabdoid” cells (Large, round/polygonal
cells with abundant, eccentric, glassy eosinophilic
cytoplasmic inclusions and vesicular nuclei with prominent
nucleoli)
Morphologically/genetically identical to Rhabdoid tumors
in kidney and brain of kids.
IHC/Molecular: SMARCB1 (INI1) loss/inactivation
CAM5.2 (+) in inclusions.
 Ossifying Fibromyxoid Tumor
Usually benign with potential with recurrence.
Lobules of uniform, monomorphous round to
spindled cells arranged in cords surrounded by
fibromyxoid stroma.
Circumscribed mass with peripheral zones of
metaplastic bone.
IHC: S100 (+), Desmin (+/-)
Molecular: PHF1 rearrangements

Angiomatoid Fibrous Histiocytoma

Indolent with very rare recurrence. Most commonly young.

Often pericapsular cuffing of lymphocytes (mimicking a lymph node)

Nodules of spindled/histiocytoid cells with syncytial growth.
Pseudoangiomatoid spaces full of blood. Thick fibrous capsule.
IHC: Variable desmin and EMA.

Molecular: EWSR1-CREB1 fusions.

Ectopic Hamartomatous Thymoma

Benign. Exclusively in the lower neck region. Often adults.
Despite name, no evidence of thymic origin/differentiation.
Haphazard blending of spindle cells, epithelial islands and
adipocytes.
Some spindled cells show “lattice-like” growth. Islands of often
squamous epithelium blend with spindled cells.
IHC: Epithelium stains with keratins. Plump spindled cells express
actin. Delicate spindled cells express CD34.

Phosphaturic Mesenchymal Tumor

Most tumors are benign (but cause significant side-effects!).
Produce FGF23 → causes tumor-induced osteomalacia by
inhibiting renal proximal tubule phosphate reuptake.

Bland spindled to stellate cells with produce unusual

hyalinized “smudgy” matrix with “grungy” or flocculent
calcifications.

FGF23 can be demonstrated by testing blood or by IHC.

 Clear Cell Sarcoma of Soft Tissue aka Malignant Melanoma of Soft Parts
Malignant. Typically young adults.
Characteristic nested growth with dividing collagenous
bands.
Epithelioid (mostly) to spindled cells with palely eosinophilic
to amphophilic (despite name) with vesicular nuclei and
prominent nucleoli. Scattered multinucleated giant cells.

IHC: Expresses melanocytic markers (S100, HMB45, MITF,

etc..)
Molecular: EWSR1-ATF1 fusions

Extraskeletal Myxoid Chondrosarcoma

Malignant. Prolonged survival, but frequent, metastases.
Despite name, no overt cartilaginous differentiation!
Abundant myxoid matrix with cords, clusters, networks, and
nests of cells with modest amounts of eosinophilic cytoplasm
and round/oval nuclei.
“AT&T tumor”→ “reach out and touch someone” → cells are
often reaching out to touch each other.
Molecular: NR4A3 fusions, often with EWSR1 or TAF15

Pleomorphic Hyalinizing Angiectatic Tumor/ Think: PHAT

Hemosiderotic Fibrolipomatous Tumor
Malignant. Usually adults in soft tissue. Often on foot.

PHAT:
Prominent thin-walled ectatic blood vessels lined by fibrin.
Embedded in spindled to pleomorphic cells with
intranuclear inclusions and fine hemosiderin granules.

Hemosiderotic Fibrolipomatous Tumor:

Thought to represent early PHAT. Can be by itself or at
periphery of PHAT.
Adipocytes with admixed hemosiderin-laden spindled
cells, hemosiderin-laden macrophages, and scattered
inflammation.

IHC: CD34 (+)

Molecular: Both have recurrent TGFBR3 and/or MGEA5

rearrangements
 Synovial Sarcoma
Malignant. Usually young adults.
Often soft tissue, but also common in Thorax and
Head/Neck.
Monophasic SS→ Just spindled component.
Biphasic SS→ Spindled and epithelioid component.

Fairly uniform spindled cells with relatively little

cytoplasm.
Ovoid, “stubby,” nuclei with hyperchromatic granular
chromatin and small nucleoli. Can see “Stag-horn”
vessels.
Epithelial cells arranged in nests and glands with
paler cytoplasm and vesicular nuclei.
IHC: Patchy EMA and CK (particularly strong in
epithelial areas). Usu. CD99 (+). TLE-1 (+)
Molecular: SS18-SSX gene fusions t(X;18)

Epithelioid Sarcoma
Malignant. Often youngish adults.
Classic/conventional type:
Cellular nodules of epithelioid to spindled cells with central
degeneration/necrosis→ looks vaguely granulomatous.
Vesicular chromatin and eosinophilic cytoplasm.
Proximal type:
Multinodular and sheet-like growth of large pleomorphic cells large
vesicular nuclei and prominent nucleoli. Often Rhabdoid-appearing.
IHC: INI1 loss; Cytokeratin/EMA and CD34 (+)
Molecular: Complex, but SMARCB1 (INI1) deletions/loss.

Alveolar Soft Part Sarcoma

Malignant. Often young adults.
Organoid nests of large, uniform, epithelioid cells with
abundant, eosinophilic, granular cytoplasm. Round
nuclei with prominent nucleoli.
PAS demonstrates rhomboid or rod-shaped
intracytoplasmic inclusions.
IHC: TFE3 (+), S100 and Desmin (-/+)

Molecular: ASPSCR1-TFE3 Fusion

Ewing Sarcoma
Malignant. Variable neuroectodermal differentiation.
Often arises in the bone of young (but can see in many
organs; Chest wall = Askin tumor).
Usually uniform, small, round, blue cells with sheet-like
to lobular, growth pattern with variable necrosis

IHC: Strong, membranous CD99 staining (Sensitive, but

not specific staining)
Cytoplasmic glycogen stains with PAS

Molecular: EWSR1 fusion (with FLI-1 or ERG) t(11;22)

Can see pseudorossettes

CIC-rearranged Sarcomas
Malignant. More aggressive the Ewing.
Often young adults in soft tissue.

Solid proliferation of small round cells (like

Ewing sarcoma).
Scant eosinophilic to clear cytoplasm.
Geographic necrosis usually present.

IHC: WT1 (+), variable CD99

Molecular: CIC-DUX4 fusions

BCOR-rearranged Sarcomas
Malignant. Outcome similar to Ewing.
Often in bone or soft tissue of young.

Solid proliferation of mostly small round cells with

monomorphic round nuclei, fine chromatin, and
delicate capillary network.
Sometimes partially spindled.

Molecular: BCOR fusion with either CCNB3 or MAML3

or a BCOR internal tandem duplication.

IHC: SATB2
Solitary Fibrous Tumor (“SFT”) Old name: Hemangiopericytoma
(referred to cellular tumors on a spectrum with SFT)
Usually benign.
Adults in deep soft tissue or serosal surfaces (classically
lung/pleura).

“Patternless pattern” of varying cellularity of bland

spindled cells with varying amounts of collagenized
stroma.
Prominent “Staghorn vessels” (dilated, thin-walled,
branching vessels).
Can be hyalinized or myxoid.

IHC: STAT6 (+). Also, CD34, CD99 (+, but variable).

Molecular: NAB2/STAT6 gene fusion

Factors associated with malignant behavior:

Numerous mitoses (esp. >4/10 HPF), Large size (esp. >15
cm), and tumor necrosis.

Intimal Sarcoma
Malignant.
Arises in large blood vessels of systemic and pulmonary circulation. Characteristic predominantly
intraluminal growth with obstruction of blood flow and seeding tumor emboli.
Mild to severely pleomorphic spindled cells with necrosis, nuclear pleomorphism, and mitoses. Can have
myxoid or fascicular areas.
IHC: MDM2 (+)
Molecular: Amplification of MDM2/CDK4 (like in ALT/WDL)

Undifferentiated Sarcoma
A sarcoma with no identifiable line of differentiation.
Heterogeneous group and diagnosis of exclusion.
Subclassify based on histologic appearance.

Undifferentiated Pleomorphic Sarcoma

(aka Malignant Fibrous Histiocytoma (MFH)
Wildly pleomorphic cells.
Complex karyotypes
Undifferentiated Spindle Cell Sarcoma
Undifferentiated Round Cell Sarcoma
Undifferentiated Epithelioid Sarcoma
 Pattern-Based Approach Modified from/inspired by: “Practical Soft Tissue Pathology”
by Jason Hornick
General Comments: Although a pattern-based approach is very useful, in many cases you might have a
good idea of the Dx via “instant pattern recognition.” Nevertheless, it can be helpful to judiciously
consider mimickers and other diagnoses based on a pattern-based approach.

Myxoid IHC to consider: S100, Desmin, CK AE1/AE3

Myxoma Low-grad fibromyxoid sarcoma

Neurofibroma Myoepithelioma
Perineurioma Myoepithelial carcinoma
Neurothekeoma Myxoinflammatory fibroblastic sarcoma
Spindle cell lipoma Aggressive angiomyxoma
Nodular fasciitis Chordoma
Ossifying fibromyxoid tumor
Myxoid liposarcoma
Myxofibrosarcoma
Extraskeletal myxoid chondrosarcoma
Note: Some people prefer SOX10 over S100

Pleomorphic IHC to consider: S100, Desmin, CD45, CK AE1/AE3, MDM2, ERG

Undifferentiated pleomorphic sarcoma Extraskeletal osteosarcoma

Pleomorphic leiomyosarcoma Pleomorphic fibroma
Pleomorphic liposarcoma Pleomorphic dermal sarcoma
Pleomorphic rhabdomyosarcoma Atypical fibroxanthoma
Dedifferentiated liposarcoma Schwannoma/Neurofibroma with ancient change
Myxoinflammatory fibroblastic sarcoma Metastatic carcinoma
Pleomorphic angiectatic tumor
Myxofibrosarcoma
Angiosarcoma

Round cell IHC to consider: S100, Desmin, CK AE1/AE3, CD45, CD99, TdT, WT-1, Synaptophysin,

Ewing sarcoma BCOR-rearranged sarcomas

Alveolar rhabdomyosarcoma Lymphoma/Leukemia
Round cell liposarcoma Wilm’s tumor
Desmoplastic small round cell tumor Neuroblastoma
Synovial sarcoma
Mesenchymal chondrosarcoma
CIC-rearranged sarcomas
Spindled Cells IHC to consider: S100, Desmin, SMA, CK AE1/AE3, p40, β-catenin,
MUC4, CD34, CD31, CD117
Nodular fasciitis Low-grade fibroblastic sarcoma
Inflammatory myofibroblastic tumor Embryonal/Spindled rhabdomyosarcoma
Myofibroma/myopericytoma Kaposi sarcoma
Fibrous hamartoma of infancy Angiosarcoma
Calcifying aponeurotic fibroma Fibrous histiocytoma
Fibromatosis Dedifferentiated liposarcoma
Schwannoma Follicular dendritic cell sarcoma
Neurofibroma Solitary fibrous tumor
Perineurioma Aggressive angiomyxoma
Ganglioneuroma Myxofibrosarcoma
Spindle cell lipoma Fibroma (several kinds)
Leiomyoma Myofibroblastoma (mammary-type)
Leiomyosarcoma Hemosiderotic fibrolipomatous tumor
GIST
MPNST
Synovial sarcoma
Biphenotypic sinonsasal sarcoma
DFSP

Epithelioid IHC to consider: S100, Desmin, CD45, CK AE1/AE3, ERG, CD68,

INI1,
Epithelioid schwannoma Clear cell sarcoma
Epithelioid hemangioma Alveolar soft part sarcoma
Epithelioid sarcoma Ossifying fibromyxoid tumor
Extrarenal rhabdoid tumor Granular cell tumor
Epithelioid MPNST Juvenile xanthogranuloma
Tenosynovial giant cell tumor Glomus tumor
Myoepithelioma/carcinoma Epithelioid angiosarcoma
GIST Metastatic carcinoma
PEComa Metastatic melanoma
Meningioma

Biphasic IHC to consider: S100, CK AE1/AE3, MDM2, SMA, H3K27me3

Carcinosarcoma
Biphasic synovial sarcoma
MPNST (with heterologous differentiation)
Ectopic hamartomatous thymoma
Dedifferentiated liposarcoma
Myoepithelioma/carcinoma
 Tumor Behavior “Beyond Benign and Malignant”
Soft tissue tumors can have varied behavior that often exits more on a spectrum than carcinomas
making specific subtyping (if possible) of considerable clinical importance. While some tumors (e.g.,
fibromatosis) are benign (meaning that they do not metastasize), they can nevertheless be locally
destructive and recurrent.

For sarcomas, which are by definition malignant, histologic type alone often does not provide sufficient
information for predicting clinical behavior and treatment planning. As such, the tumors must also be
graded, most often using the French Federation of Cancer Centers Sarcoma Group (FNCLCC) system.

French Grading System (FNCLCC) Histologic Type Score

Tumor Differentiation ALT/WDL 1

Score 1 Sarcomas closely resemble normal adult tissue Myxoid liposarcoma 2

Round cell liposarcoma 3
Score 2 Sarcomas for which histologic typing is certain
Pleomorphic liposarcoma 3
(e.g., myxoid liposarcoma)
Dedifferentiated liposarcoma 3
Score 3 Embryonal or undifferentiated sarcomas,
sarcomas of doubtful subtype Fibrosarcoma 2

Mitotic Count (per 40x field) Myxofibrosarcoma 2

Score 1 0-9 mitoses per 10 HPF Undifferentiated Pleomorphic Sarcoma 3

Well-differentiated leiomyosarcoma 1
Score 2 10-19 mitoses per 10 HPF
Conventional leiomyosarcoma 2
Score 3 ≥20 mitoses per 10 HPF
Poorly-differentiated leiomyosarcoma 3
Tumor Necrosis
Low-grade fibromyxoid sarcoma 3
Score 0 No necrosis
Sclerosing epithelioid sarcoma 2
Score 1 <50% necrosis
Synovial sarcoma 3
Score 2 ≥50% N
DFSP 1
Pleomorphic rhabdomyosarcoma 3
Mesenchymal chondrosarcoma 3
Extra-skeletal osteosarcoma 3
Total Score Grade
Ewing sarcoma 3
2-3 Grade 1 Malignant rhabdoid tumor 3

4-5 Grade 2 Undifferentiated sarcoma, NOS 3

The following tumors are not graded: GIST, alveolar

6-8 Grade 3 and embryonal rhabdomyosarcoma, MPNST,
angiosarcoma, extraskeletal myxoid
chondrosarcoma, clear cell sarcoma, alveolar soft
part sarcoma, and epithelioid sarcoma.
 Prepared by Kurt Schaberg
Last updated: 1/3/2021
Upper Aerodigestive Tract
Squamous Lesions
General
Both benign and malignant conditions can sometimes have similar clinical appearances.
“Leukoplakia”—clinical term for a white plaque on a mucous membrane
“Erythroplakia”—clinical term for a red plaque. Higher risk of dysplasia.
“Speckled Erythroplakia”—clinical term for a mixed red and white lesion.
May represent a wide spectrum of histologic changes often falling within the general category of
keratosis (abnormal presence and/or excessive keratin) with or without dysplasia.
Any type of lesion may be biopsied to evaluate for malignancy/dysplasia.

Non-neoplastic Lesions May mimic cancer clinically, often with leukoplakia or ulceration

Candidiasis
Most common oral fungal infection.
Often occurs in immunocompromised patients, but can
occur in healthy individuals.
Often appears clinically like a white plaque.
Dimorphic fungi with yeast forms and
hyphae/pseudohyphae→ hyphal form causes tissue
invasion/symptoms so look for hyphae to make Dx (yeast
only is not good enough!)
Often seen with parakeratosis and acute inflammation
(so consider this Dx and do stains whenever you see this).
Can highlight with PASd or GMS
May see accompanying reactive epithelial changes like
hyperplasia.

Herpes Simplex Virus

Virus infects epithelial cells and ganglion cells.
Two types classically infecting different sites:
Type 1= Oral, Type 2=Genital, but not always true.
Infected cells show classic ground glass
intranuclear inclusions with “3 M’s”: Molding,
Margination, Multinucleation.
Often associated ulceration with acute and
chronic inflammation.

CMV can cause similar ulcers, but is much

rarer, usually only seen in the
immunocompromised, and the eosinophilic
intranuclear inclusions are seen in
mesenchymal cells.
 Lichen Planus
Same as on the skin (often also involves mucous membranes).
Chronic, self-limited inflammatory reaction.
Multifocal (if focal → consider Lichenoid keratosis)
“Band-like” T-cell infiltrate below epithelium
“Saw-tooth” rete ridges
Often hydropic degermation and/or degenerating keratinocytes
NO significant atypia (otherwise consider dysplasia)
Variable thickness and keratinization
Unknown etiology. Associated with many medications and Hep C.
Clinical 5P’s: Purple, Pruritic, Polygonal, Planar, Papules.

Hairy Leukoplakia
Epithelial hyperplasia induced by Epstein-Barr virus (EBV).
Often on the lateral tongue of immunocompromised patients.
Acanthosis and parakeratosis
“Balloon” cells in spinous layer with viral cytopathic effect
including eosinophilic nuclear inclusions and ballooning
degeneration→ highlighted by EBER in situ hybridization
Often coinfected with candida.
Little inflammation. No dysplasia.

Geographic Tongue
aka “Benign migratory glossitis”
Idiopathic inflammatory condition, primarily on tongue.
Often asymptomatic→ self-resolves
Multiple, well-defined erythematous islands with
raised whitish yellow borders that rapidly appear→
migrate around tongue.
Epithelium with hyperparakeratosis, acanthosis,
spongiosis, elongated rete ridges, and collections of
neutrophils (Monro abscesses).
Lamina propria acute and chronic inflammation
 Reactive vs Dysplastic Changes
Benign/Reactive Dysplastic
“Think Eggs” “Think Boulders”
Cytology: Although they may enlarge, nuclei are Cytology: Nuclei are big, irregular, jagged,
still rounded with smooth nuclear contours. rough, and dark.

Low N:C ratios (More cytoplasm) High N:C ratios (mostly nucleus!)

Nuclei are smooth Nuclei are Dark

Round/oval, often with with Irregular
speckled chromatin crinkled contours

Sometimes have a Dyskeratotic cells

prominent nucleolus
(think Yolk) Usually no nucleoli
(unless perhaps
invasive)

Lots of inflammation? If so, raise your threshold

to account for reactive changes!
Maturating

Architecture: No maturation in traditional High-

grade dysplasia. Many cells don’t know which way
is up.
Architecture: Often matures towards surface, with
However, can see maturation in low-grade
highest N:C ratio cells confined to the base
dysplasia and keratinizing dysplasia.
Cells seem to “Know which way is up”
 Squamous Neoplasms, Non-HPV related
Majority of oral cavity, larynx, and pharynx cancers are squamous cell carcinoma.
Major risk factors: smoking (most important cause), alcohol, and betel-quid chewing.
→ synergistically increase risk together exponentially (not just additive)
Often clinically appear white to erythematous. Erythematous lesions are more frequently dysplastic.
Genomically unstable with chromosome gains/losses. Frequent mutations in TP53.

Squamous Dysplasia
Epithelium with accumulated genetic changes→ risk of progression to squamous cell carcinoma.
Non-obligate precursor→ most cases of dysplasia do not progress to SCC (higher grade = higher risk)
Features of nuclear/cellular “atypia”: marked variation in size/shape, marked hyperchromasia, prominent
nucleoli
Epithelium may be atrophic or acanthotic, keratinizing or non-keratinizing.
Grade using scheme below based on maturation, but if there is severe atypia it is acceptable to upgrade
to high-grade dysplasia even if it matures at the surface.
Not always reproducible! (So consider showing another person if it’s important)

Low-Grade Dysplasia
(previously mild dysplasia)
Low Malignant Potential (may regress or not advance)
Limited to LOWER half of epithelium, with surface maturation
Architectural Stratification preserved with retained orientation
criteria (vertical cells at bottom, horizontal cells at top)
Cytologic Criteria At most minimal cellular atypia
Rare mitoses, in or near basal layer.
Few dyskeratotic cells

High-Grade Dysplasia
(previously moderate to severe dysplasia or CIS)
Pre-malignant lesion
Involves at least half of the epithelium, and may be full thickness
Architectural Abnormal maturation
criteria Altered cells involve ≥1/2 of thickness
Disordered stratification
Can be keratinizing or non-keratinizing
Intact basement membrane
No stromal alterations
Cytologic Criteria Conspicuous cellular atypia
Increased N:C ratio
Increased mitoses at or above basal layer
Dyskeratotic or apoptotic cells throughout

Adapted from: WHO Classification of Head and Neck Tumors. 2017.

 Proliferative Verrucous Leukoplakia
Multifocal, progressive disorder→ very high rate of recurrence and
transformation to SCC. Often older females. Unknown etiology.
Oral cavity: often involves gingival,
alveolar mucosa, and palate.
Appearance changes with time:
Starts with localized flat or verrucous
hyperorthokeratosis
Often lichenoid interface mucositis.
Eventually becomes multifocal and
develops dysplasia.
Dx often requires clinical and pathologic
correlation as findings on one biopsy are
not diagnostic (must know multifocal,
progressive).
May progress to traditional or verrucous
SCC.

Conventional Squamous Cell Carcinoma

Malignant epithelial tumor with squamous differentiation.
→ Keratinization (±keratin pearls) and/or intercellular
bridges

Features of invasion: downward growth of islands, cords

and isolated tumor cells, irregular interface, desmoplastic
response, lymphovascular invasion, perineural invasion.
Grading is irrespective of keratinization.
Well-differentiated: closely resemble normal squamous
mucosa (matures somewhat normally), few mitoses.
Moderately-differentiated: more pleomorphism and
mitoses.
Poorly-differentiated: basal-type cells predominate with lots
of mitoses. Often lose expression of HMWCKs.
Depending on location, can present with mass (oral cavity),
hoarseness (supraglottic larynx) or dyspnea/stridor
(subglottic larynx), etc..

Frequently metastasizes to cervical lymph nodes→ lymph

node mets is the single most adverse prognostic factor.
Extracapsular extension is a particularly associated with
regional recurrence and worse survival.
 Verrucous Squamous Cell Carcinoma
Variant of Well-differentiated Squamous Cell Carcinoma
Dramatic acanthosis with club-shaped projections and
invaginations. Marked “church-spire” keratinization.
No significant cytologic atypia
Proliferative basal cell layer only 1-2 cells thick.
Only very rare mitoses in basal layer.
Well-defined “Pushing” invasion, often with
associated lymphocytic inflammation.
NO infiltrative growth.
Often need to see nearby epithelium to show relative
invasion beneath basal layer of nearby epithelium.
Locally destructive/invasive, but does not metastasize
May be very hard to Dx on small biopsies, requiring
clinical correlation. If clinically concerned for
malignancy, but biopsy looks like benign→ consider this
Dx!
If infiltrative growth→ conventional SCC

Spindle Cell Squamous Cell Carcinoma aka “Sarcomatoid carcinoma” or

“Carcinosarcoma”
Squamous cell carcinoma variant with predominantly
malignant spindle and/or pleomorphic cells.
Often an ulcerated polypoid mass.
Epithelial→ mesenchymal transition
Can have heterologous differentiation.
Must have evidence of epithelial differentiation,
either by morphology (e.g., adjacent conventional
SCC or dysplasia) or by IHC (e.g., CK, p40, etc..)
Similar prognosis to conventional SCC.

Basaloid Squamous Cell Carcinoma: Basaloid, hyperchromatic appearance (high N:C ratio) often with a
conventional component. HPV-negative. Rounded nests with peripheral palisading and admixed
hyalinized stroma. Frequent mitoses and comedonecrosis. May mimic a salivary gland neoplasm and be
SOX10 positive, but diffuse p63/p40 (which is often patchy in adenoid cystic carcinoma). More aggressive.
Papillary Squamous Cell Carcinoma: Exophytic papillary growth pattern with thin fibrovascular cores
covered by severely dysplastic basaloid cells. Uncommon. May be HPV-related in oropharynx, but not
elsewhere. Better prognosis.
Adenosquamous Carcinoma: Arises from squamous epithelium but shows both squamous and glandular
differentiation.
Lymphoepithelial Carcinoma: Sheets of pleomorphic cells with a prominent intratumor chronic
inflammatory infiltrate. Like nasopharyngeal carcinoma, but not often associated with EBV.
 HPV-related Squamous Lesions
Verruca Vulgaris
Benign squamous proliferation in oral cavity
Caused by low-risk HPV (e.g., Type 2 and 4)
Identical to on the skin.
Exophytic and papillomatous.
Hyperkeratosis and acanthosis.
Elongated and “cup-like” rete ridges. Condyloma Acuminatum: Oral equivalent of anogenital
Cytologically bland with prominent granular condyloma. HPV types 6 or 11. Often sexually transmitted.
layer and occasional koilocytes. Often larger than verruca vulgaris.

Multifocal Epithelial Hyperplasia aka “Heck’s Disease”

Multifocal benign squamous proliferation in oral cavity caused by HPV.
Most common in children/adolescent girls.
HPV types 13 or 32 often.
Often located on lips or buccal mucosa→ multiple papules.

Mild hyperkeratosis, prominent acanthosis, normal cell

maturation. Occasional koilocytes.
“Mitosoid” figures are hallmark (not often seen in other
conditions)

Squamous Papilloma
Benign exophytic squamous proliferations with
branching fibrovascular cores.
Usually associated with HPV types 6 or 11.
Can get through sexual or non-sexual contact.
Variable koilocytes (may be obvious or subtle)
Often solitary.
Malignant transformation is very rare.

If multiple, especially if young, consider:

Recurrent Respiratory Papillomatosis (RPR)—
multiple, recurrent papillomas in the respiratory
tract of children and young adults→ high
morbidity as can obstruct breathing, swallowing,
etc…
Squamous Cell Carcinoma, HPV-Positive
Squamous cell carcinoma associated with High-risk HPV’
>90% caused by HPV type 16 → associated with oral sex
Incidence rising: Frequently white men in 50’s
Strong predilection to oropharynx: Base of Tongue (BOT) and
Tonsils
Often presents at high clinical stage with a small/occult
oropharyngeal primary and cervical lymph node metastases,
which are often large and cystic.
Distinct morphology:
Non-keratinizing, high N:C ratios→ basaloid appearance.
Frequent mitoses and/or apoptotic figures.
Frequent associated lymphocytes/lymphoid stroma.
Some morphologic spectrum as can be papillary, etc…
Arises is crypts of tonsils→ grows/invades as nests/lobules.
No recognizable in situ component/background dysplasia.

Grading is NOT applicable!!

HPV can be detected by: In situ hybridization or PCR.
Diffuse “block positive” staining with p16 is used as a reliable
surrogate marker for the presence of high-risk HPV in
oropharyngeal carcinomas (if appropriate morphology).
Significantly better prognosis than conventional SCC

“Block Positive” P16

Characteristic HPV-Positive SCC HPV-Negative SCC

Median Age ~50 yrs ~65 yrs
Risk Factors Sexual behavior Smoking and Alcohol
Background Dysplasia Rare Frequent
Morphology Commonly non-keratinizing Conventional, often keratinizing
with high N:C ratio
Grading Not Applicable Applicable
P16 IHC Positive (“Block”) Negative
Lymph node Frequently cystic Uncommonly cystic
metastases
Postulated origin Reticulated epithelium of Surface epithelium
invaginated crypts
3-year survival ~80% ~60%
Adapted from: WHO Classification of Head and Neck Tumors. 2017.
Important Staging Details:
Use the right Checklist!
There are separate checklists and staging criteria for the Oral Cavity & Lip, Pharynx, and Larynx. Make
sure you use the right one as they are very different!

Depth of invasion:
1) First draw a horizontal
Particularly in oral cavity, predictive of regional line from the basement
lymph node metastasis. membrane of the nearby
epithelium
Measure by drawing a horizontal line from the
basement membrane of adjacent epithelium and 2) Then drop a vertical
then dropping a “plump line” from this (see →) “plumb line” from that to the
deepest point of invasion →
Depth of Invasion (DOI

Perineural invasion (PNI):

Poor prognosis at all sites (associated with
recurrence and metastasis), so concurrent
chemoradiation is often considered.
Any size nerve counts.
Tumor should “have a relationship” with the nerve
(not just be near the nerve or passing by the nerve)

Extranodal extension (ENE):

Nodal status is the most important prognostic factor
in upper aerodigestive tract SCC. All macroscopically
negative or equivocal lymph nodes should be
entirely submitted.
ENE is defined as of extension of metastatic tumor,
present within the confines of the lymph node,
through the lymph node capsule into the
surrounding connective tissue, with or without
associated stromal reaction.

Soft tissue deposits appear to be the equivalent of a

positive lymph node with ENE and should be
recorded as such
 “Small Round Blue Cell Tumors”
(in kids) Prepared by Kurt Schaberg

Leukemia/Lymphoma Always a consideration! Do several heme markers and show a

hematopathologist.

Ewing Sarcoma
Malignant tumor of neuroectodermal differentiation that is often
arises in the bone (but can see in many organs; Chest wall = Askin
tumor)
Often have EWSR1 translocation (with FLI-1 or ERG) t(11;22)
Usually uniform, small, round, blue cells with sheet-like to lobular,
growth pattern with variable necrosis
Strong, membranous CD99 staining
(Sensitive, but not Specific staining)
Can see
Cytoplasmic glycogen stains with PAS
pseudorossettes

Rhabdomyosarcoma Malignant tumor with primary skeletal muscle differentiation, several types
Stain with Desmin, MyoD1, Myogenin
Embryonal Rhabdo:
Variable numbers of round (“rhabdoid”), strap-, or tadpole-shaped
eosinophilic rhabdomyoblasts in a myxoid stroma
Can see cytoplasmic cross striations
Alveolar Rhabdo:
Larger, more rounded undifferentiated cells with only occasional
rhabdomyoblasts
Often arranged in an alveolar (nested) pattern
Distinctively strong and diffuse myogenin positivity
Characteristic FOXO1 translocations

Wilms Tumor aka nephroblastoma

Malignant tumor originating in Kidney
3 key elements: 1)Primitive epithelial tubules, 2)Blastema
(sheets of small high N:C ratio cells), 3)Stroma
In some cases may only see 2 (or possibly even 1) element
3 component stain differently with IHC stains
Epithelium: ⊕ WT-1, CK
Blastema: ⊕ WT-1, Desmin
Stroma: Weak WT-1, (plus heterologous elements)
 Neuroblastoma Maturing Ganglioneuroblastoma Maturing Ganglioneuroma
Most primitive/aggressive Intermediate differentiation Most mature; Benign
Malignant Neuroblastoma + Ganglion cells Ganglion cells set in
SRBCT +/- rosettes, fibrillary stroma
neurofibrillary matrix NO neuroblastoma

Peripheral neuroblastic tumors derive from the sympathetic nervous system (therefore develop anywhere
along the distribution of the sympathoadrenal neuroendocrine system)
Positive stains: synaptophysin, chromogranin, CD56, NB84, and neuron-specific enolase
staining for S-100 protein has been used to identify cytodifferentiated cells such as Schwann cells
MYCN amplification  Poor prognosis!

Desmoplastic Round Cell Tumor

Malignant tumor of uncertain histogenesis often found in the peritoneal
cavity; often in young men
Characteristic EWSR1 – WT-1 translocation
Basaloid nests of tumor that are surrounded by cellular desmoplastic
stroma
Stains: Positive CK, Desmin, WT-1 (but C-terminus—opposite of Wilms!)

For all pediatric tumors, consider in addition to Formalin-Fixed Tissue:

1) Flow cytometry, 2) Cytogenetics, 3) Freezing some (depends on quantity, etc..)

CD45 TdT CK Desmin MyoD1 Synapto. CD99 WT-1

AE1/AE3 Myogenin Chromo
Leukemia/ + +/- - - - - -/+ -
Lymphoma
Ewing Sarcoma - - Usu. - - - - + -

Rhabdomyosarcoma - - -/+ + + Rare -/+ -

Wilms’ Tumor - - + -/+ - -/+ - +

Neuroblastoma - - - - - + - -

Desmoplastic Round - - + + - - -/+ C-terminus

Cell Tumor
Last updated: 6/11/2020 Prepared by Kurt Schaberg

Stomach Tumors
Benign Tumors
Fundic Gland Polyps
Benign. Most common stomach polyp.
Hyperplastic expansion of deep oxyntic mucosa with
cystically dilated oxyntic glands and foveolar hypoplasia.
Parietal cell hyperplasia
Usually asymptomatic and incidental.
Associated with PPI use
Can have CTNNB1 (β-catenin) mutations
If numerous (esp. >20) in a young patient, consider a
polyposis syndrome, such as FAP.

Hyperplastic Polyps
Benign. Second most common gastric polyp
Elongated, tortuous, hyperplastic foveolar epithelium
Cystically dilated glands
Inflammatory changes and edema
Often eroded at surface.
Small, haphazardly distributed smooth muscle
Hyperproliferative response to tissue injury.
Usually arise in setting of long-standing gastritis
Precursor lesion = polypoid foveolar hyperplasia

May be hard to differentiate from hamartomatous

polyps (e.g., Cronkhite-Canada syndrome)

Pyloric Gland adenoma

Polypoid proliferation of pyloric-type gastric glands
(cuboidal to columnar cells with foamy, ground-
glass cytoplasm) and no well-formed apical mucin
cap. Often dilated glands. Basal round nuclei.
Usually older individuals with atrophic/metaplastic
autoimmune gastritis and/or H. pylori
Sometimes syndromic (e.g., FAP, GAPPs, etc…)
Activating GNAS and/or KRAS mutations and
inactivating APC mutations.
Can develop high-grade dysplasia → carcinoma

Stain with MUC6

 Dysplasia Low-grade foveolar-type dysplasia

Neoplastic change of gastric epithelium without stromal invasion.

Can be gastric/foveolar or intestinal-type (or mixed):

Intestinal-type dysplasia: looks like a colonic adenoma with tall
columnar cells with hyperchromatic nuclei

Gastric/Foveolar-type dysplasia has tubulovillous or serrated fronds

lined by cuboidal to columnar cells resembling gastric foveolar cells.
Nuclei are round to oval. There is apical neutral mucin.

Regardless of type, graded as high vs low:

Low-grade dysplasia: preserved polarization (basal nuclei), relatively
preserved architecture
Intestinal: nuclei hyperchromatic, elongate (“cigar-shaped”)
Foveolar: nuclei round to oval

High-grade dysplasia: Prominent cytologic atypia with enlarged nuclei,

high N:C ratios, sometimes prominent nucleoli. Loss of polarity.
Complex architecture.

Indefinite for dysplasia: Not a biologic entity. Used when there are
questions as to if a lesion is neoplastic or reactive. Often very inflamed.

Intramucosal carcinoma
→ Invasion into lamina propria
Characterized by gland crowding, excessive branching, and budding.
Can see: Single cell infiltration, trabecular growth, intraglandular
necrotic debris, and irregular gland fusion.
High-grade intestinal-type dysplasia

Intestinal-type Adenoma
Localized, polypoid lesion (whereas dysplasia can be flat and
multifocal/non-localized) with dysplastic intestinalized epithelium.
Third-most common type of gastric polyp.
Any cause of gastric intestinalization is a risk factor (e.g., H. pylori,
autoimmune gastritis, etc…)

Look similar to colorectal adenomas and have similar genetics.

Rarer Polyps
Foveolar-type adenoma: Similar to foveolar dysplasia (discussed above), but localized, polypoid lesion.
Usually syndrome-associated (FAP or GAPPs), with no background of inflammation (unlike intestinal-type
adenomas)

Oxyntic gland adenoma: Neoplasm composed of columnar cells with chief cell differentiation (pale
basophilic cytoplasm) with mild nuclear atypia, mimicking oxyntic glands. High rate of progression to
invasive adenocarcinoma.
 Malignant Tumors
Adenocarcinoma
Malignant epithelial neoplasm with invasion of lamina propria (or beyond) by neoplastic glandular cells.
Risk factors:
H. pylori—very strong risk factor. Chronic infection→ chronic inflammation → intestinal metaplasia →
dysplasia → carcinoma.
Also—smoking, EBV-infection, and dietary factors

Morphological subtypes:
Tubular—most common subtype. Branching tubules of variable
diameter. Solid growth with barely recognized tubules is included in
this group.

Poorly cohesive (including signet ring)—Second most common.

Neoplastic cells are isolated or arranged in small aggregates without
well-formed glands.
Signet-ring cell type is composed predominantly or exclusively of
signet ring cells, which are characterized by a central, optically clear,
globoid droplet of cytoplasmic mucin with an eccentric nucleus.

Mucinous—malignant epithelium in extracellular mucin pools. Must

be >50% of tumor. Tumor cells may be in glands or single cells.

Papillary—Relatively rare. Exophytic growth with elongated finger-

like processes lined by cuboidal to columnar cells supported by
fibrovascular cores. Well-differentiated with pushing invasion, but
nevertheless has a worse prognosis.

Gastric (adeno)carcinoma with lymphoid stroma—(aka

“lymphoepithelial-like carcinoma” or “medullary carcinoma”)
Syncytial growth of irregular sheets and tubules of polygonal tumor
cells with rich lymphocytic infiltrate. Often EBV-associated. A
separate subset are MMR-deficient (so get EBV and MMR IHC on any
case you are considering for this).

Hepatoid carcinoma—resemble liver (large polygonal eosinophilic

cells). May stain with Hepar-1 and/or AFP. Usually Arginase-1
negative.

Micropapillary adenocarcinoma—small clusters of tumor cells

without fibrovascular cores protruding into clear spaces. Worse
prognosis (like micropapillary carcinomas in other organs).

Fundic-gland type—develop from oxyntic gland adenomas. Very rare!

Mixed—contain two or more subtypes. Often worse prognosis.

Molecular subtypes:
Chromosomally unstable: Predominantly intestinal type morphology with extensive DNA copy
number variations. Frequent TP53 mutations. Most common subtype.

Genomically stable: Predominantly diffuse (signet-ring) morphology. Fewer genetic alterations.

Frequent CDH1 and RHOA alterations/mutations.

Microsatellite instability (MSI): mutations or promoter methylation of mismatch repair enzymes

(often MLH1). Better prognosis.

EBV-positive: usually histologically gastric carcinoma with lymphoid stroma. PIK3CA and ARID1A
mutations. Often PD-L1 amplified. Better prognosis.

Staging:
Tumors with an epicenter within 2 cm of the GE junction should be staged as esophageal cancers.
All tumors in the stomach that do not cross the GE junction (or have an epicenter in the stomach >2
cm from the GE junction) should be staged as gastric.

Stage Finding
Tis Carcinoma in situ = High-grade dysplasia
T1a Tumor invades lamina propria or muscularis mucosae
T1b Tumor invades submucosae
T2 Tumor invades muscularis propria
T3 Tumor invades subserosa
T4a Tumor perforates serosa
T4b Tumor invades adjacent structures

Predictive biomarkers:
Anti-HER2 (ERBB2) therapy is used in patients with unresectable or metastatic tumors. (see
esophageal guide for grading scheme)

EBV and MSI: tumors that are EBV-positive or MSI-high are better prognosis.
 Well-Differentiated Neuroendocrine Tumors “NET”
Proliferation of cells with round nuclei, “salt and pepper” (speckled) chromatin and abundant
eosinophilic cytoplasm, arranged in nests, acini, trabeculae, and ribbons.

Express neuroendocrine (NE) markers: Synaptophysin, Chromogranin, INSM1

3 main clinical settings/types (see chart below):

Type 1: Associated with autoimmune gastritis→ destruction of parietal cells→ decreased stomach acid
→ compensatory hyperplasia of antral G-cells (to try to signal to make more acid)→ secrete gastrin →
ECL cell hyperplasia and NET formation
Type 2: Zollinger-Ellison syndrome with a duodenal or pancreatic gastrin-secreting NET, which stimulates
ECL cell hyperplasia and stomach NET formation
Type 3: Sporadic, often higher stage and more aggressive.

Size Requirements: (this can vary a little by source, but generally…)

NE cell hyperplasia: collections of >5 NE cells. Can be linear (chain) or micronodular (clusters), <0.15mm
NE cell dysplasia: nodules > 0.15 mm, fused nodules, or infiltrative nodules (pTis)
Micro-NET: cellular proliferation filling lamina propria. Nodule >0.15mm, but < 0.5mm (pTis)
NET: >0.5mm or invasion into submucosa

Grading: Ki67 Proliferation index based on evaluation of ≥ 500 cells in a “hot spot.” Mitotic count based
on evaluating 50 Hpfs, but reported per 10 Hpfs.

Grade Ki67 Proliferation Mitotic index

Index
Grade 1 <3% <2
Grade 2 3-20% 2-20
Grade 3 >20% >20

Type 1 Type 2 Type 3

Cause Autoimmune gastritis Zollinger-Ellison syndrome, Sporadic
often MEN1
Focality Multifocal Multifocal Unifocal
Cell of origin ECL (body/fundus) ECL (body/fundus) D,G, ECL, and EC-cells
% of Gastric NET’s ~85% ~5% ~10%
Hypergastrinemia Yes (secondary) Yes (primary) No
ECL-cell proliferation Yes Yes No
Acid secretion Low High Normal
Background mucosa Atrophic gastritis Parietal cell hyperplasia Normal
Stage at Dx: Low (Tx = EMR) Low (usually) Often advanced
5-year survival ~100% ~75% <50%
 Neuroendocrine Carcinoma
Often arise from non-neuroendocrine tumors (and subsequently develop neuroendocrine differentiation.
Sheet-like growth
Not Graded. Ki67/Mitotic index >20% (often much higher).
Malignant! Very metabolically active/rapidly growing
→ see on normal FDG-PET scan
Molecular: p53, RB1 (and other carcinoma-associated mutations)
Treatment: Platinum-containing chemotherapy

Small Cell Neuroendocrine Carcinoma

Morphology: Fusiform nuclei, finely granular chromatin, scant
cytoplasm, and nuclear molding. Extensive necrosis.
Tons of mitoses. Ki67 almost 100%.

Large Cell Neuroendocrine Carcinoma

Morphology: Large, round nuclei, with prominent nucleoli, and
moderate amounts of cytoplasm. Sheet-like to nested growth.
Ki67 often in 60-80% range.

Other Malignancies
Lymphoma
The GI tract is the most common site of extranodal lymphomas and the stomach is the most commonly
involved site. The two most common are DLBCL and extranodal marginal zone lymphoma.
Diffuse Large B-Cell Lymphoma (DLBCL)—Diffuse infiltrate of atypical large lymphoid cells that show
immunoreactivity to B cell markers (CD20, PAX5, CD19, CD79a) and are negative for EBV. Most cells
resemble centroblasts. Tend to localize to one anatomical site and are less aggressive than their nodal
counterpart. However, like nodal disease, must still do full work-up to classify as Germinal center (GCB)
or Activated B Cell (ABC) subtypes and look for MYC and BCL2 alterations.
Extranodal Marginal Zone Lymphoma of Mucosa-associated Lymphoid Tissue (“MALT lymphoma”)—
Often associated with H. pylori infection. Diffuse to perifollicular infiltrate of small centrocyte-like to
monocytoid lymphocytes. Positive for B-cell markers (CD20, PAX5). CD43 and MNDA1±. Negative for
mantle cell markers (CD5, SOX11, and CyclinD1), CLL/SLL markers (CD5, CD23, LEF1), and Follicular
Lymphoma markers (CD10, BCL6). Indolent course. Often cured by eradication H. pylori.

Squamous cell carcinoma—carcinoma with exclusively squamous differentiation, with keratinocyte-cells

with intercellular bridges and/or keratinization. Very rare.
Adenosquamous carcinoma—carcinoma with both glandular and squamous differentiation (with each at
least 25%).
Undifferentiated carcinoma—carcinoma composed of anaplastic cells without histologic or
immunophenotypic evidence of differentiation. Diffuse malignant cells. Often patchy keratin. Dx of
exclusion—must rule out lymphoma, melanoma, EBV-associated gastric carcinoma, etc…
Gastroblastoma—Often young men. Biphasic tumor of gastric muscularis propria with spindled cells and
nests of epithelial cells. MALAT1-GLI1 gene fusion
Last updated: 10/12/2020 Prepared by Kurt Schaberg MD

Testicular Tumors
Germ Cell Tumors
3 main subtypes depending on age and if they are derived from germ cell neoplasia in situ (GCNIS).
Most common: Germ cell tumors derived from GCNIS (Post-pubertal type) (Type 2, below), which is
often sub-grouped into seminoma and non-seminoma germ cell tumors
Although only 1% of all male cancers, they are the most common cancers among young men between
puberty and 40s.
Risk factors: Family history, cryptorchidism, subfertility, pesticides, marijuana, microlithiasis.
Although can be aggressive tumors, with current treatments can often be cured as very responsive to
chemoradiation.
Type Tumors Age Derived Genotype Behavior
from GCNIS
1 Teratoma (prepubertal) Usually < 6 yrs No Diploid or Very good.
Yolk sac tumor (prepubertal) aneuploid. Mostly
Dermoid cyst No i12p gains benign.
2 Seminoma Post-pubertal Yes Aneuploid Malignant,
Embryonal carcinoma Usually 20s-30s Frequent gains but
Choriocarcinoma and losses. responsive to
Yolk sac tumor Overexpression of therapy
Mixed Germ cell tumor isochrome 12p
3 Spermatocytic Tumor Usually > 50 yrs No Aneuploid Excellent
No i12p gains

Germ Cell Neoplasia In situ (“GCNIS”)

Proliferation of atypical germ cells within seminiferous
tubules
Large, angulated nuclei with coarse chromatin
(resemble seminoma cells)
Often located at base of tubules with prominent halos
Often present in nearby parenchyma adjacent to most
associated germ cell tumors.
Often absent spermatogenesis.
Identical IHC profile to seminoma: OCT3/4, cKit (+)
Precursor lesion: ~50% progresses to overt Germ Cell
Tumor within 5yrs.

Intermediate stages between GCNIS and invasion:

Intratubular seminoma→ complete filling of expanded Intratubular non-seminoma→ Same concept,
seminiferous tubule by neoplastic cells with obliteration but almost exclusively embryonal carcinoma.
of normal components. Thought to be reprogrammed GCNIS cells.
 Seminoma Think: Clear/White color
Most common germ cell tumor (~50%).
Present with mass. Usually unilateral.
Grossly solid, fleshy, lobulated, cream-colored.
Large polygonal cells with clear to eosinophilic cytoplasm
(full of glycogen), distinct cell membranes, vesicular
chromatin, and prominent nucleoli
Fibrous septae and nested architecture
Lymphocytic infiltrate; Sometimes granulomas.
GCNIS usually in residual tubules. Rare syncytiotrophoblasts.
IHC: (+) OCT3/4, CD117, D2-40, SALL4
Elevated serum LDH, rarely hCG.
First site of metastases often retroperitoneal lymph nodes.
Molecular: majority have isochrome 12p; ckit mutations in
many.
Prognosis: Good if treated.

Embryonal Carcinoma Think: Purple color

Second-most common testicular GCT.
Usually part of a mixed GCT
Rudimentary epithelial differentiation
Large, crowded, “Primitive” pleomorphic cells
Vesicular nuclei with prominent nucleoli.
Coarse, basophilic chromatin. Amphophilic cytoplasm.
Variable architecture (nests, sheets, papillae, glands)
Prominent mitoses and apoptotic bodies.
IHC: (+)CD30, OCT3/4, AE1/AE3, SALL4
Molecular: Isochrome 12p amplification
Aggressive, but often responds to chemotherapy

Choriocarcinoma Think: Red color

Usually part of a mixed GCT.
Malignant cytotrophoblasts and trophoblasts
(mononuclear with light cytoplasm) and
syncytiotrophoblasts (multinucleated with deeply
eosinophilic cytoplasm). Abundant Hemorrhage
IHC: (+) hCG. Syncytiotrophoblasts: (+) inhibin, glypican-3.
Cytotrophoblasts: (+) SALL4, p63, GATA3
Very elevated Serum hCG → (similar to LH and TSH)→
gynecomastia, thyrotoxicosis
Most aggressive GCT. Frequent hemorrhagic metastases.
Less responsive to treatment.
Yolk Sac Tumor, Postpubertal-type Think: Pink color

aka: “Endodermal Sinus Tumor” or “YST”

Almost always a component of mixed GCT
Many patterns/architecture (often combined)
Most common = reticular/microcystic
(Honeycomb meshwork)
Can also be solid, papillary, glandular, etc…
Often hypocellular myxoid areas
Schiller-Duval Bodies (endodermal sinus)(→)
Refractile eosinophilic hyaline globules (→)
Band-like intercellular basement membrane
material
Can have “hepatoid” areas resembling liver that
stains with liver markers.
IHC: (+)AFP, Glypican-3, SALL4, AE1/AE3,
Elevated Serum AFP
Post-chemo can get sarcomatoid YST

Teratoma, Postpubertal-type
Composed of tissues from one or more germinal layers.
May be composed of differentiated mature tissue or immature,
embryonic-type tissue. Often part of a mixed GCT.

In contrast to ovary, pretty much all teratomas in postpubertal testis

are malignant!
Can see virtually all tissue types including epithelial and mesenchymal.
Often multiple cysts lined by glandular or squamous epithelium.
Frequent immature neuroectodermal structures.
IHC: Differentiated elements express profile of that tissue type.
Often areas of cytologic atypia, including primitive mitotically active
stroma cuffing glands.
If a dysplastic component forms a nodule that is larger than a 4X field (5
mm)→ somatic-type malignancy arising in a teratoma. Usually a
sarcoma, most commonly rhabdomyosarcoma.
Most common component in a treated GCT.

Rare situation where can be benign teratoma in an adult: Dermoid

cysts, or, organoid morphology with prominent components of ciliated
epithelium and smooth muscle and no GCNIS, isochrome 12p, or
testicular scarring.
 Mixed Germ Cell Tumor
Malignant tumors with more than one germ cell tumor component.
Clinically regarded as “non-seminoma” (even if seminoma present).
Majority of all non-seminomatous GCT are mixed.
Must report approximate % of each component.
Note: Syncytiotrophoblasts ≠ choriocarcinoma (can see in other
tumors, like seminoma)
Special subtypes:
Polyembryoma→ combination of embryonal carcinoma and YST
resembling an embryo
Diffuse embryoma→ orderly combination of embryonal carcinoma
and YST in parallel flat layers (pictured→).

Regressed Germ Cell Tumors

Germ cell tumors that have undergone either partial
or complete regression (“burnt-out”), leaving behind
a well-delineated nodular focus of scaring fibrosis in
the testis.
Can present with metastatic disease, but primary has
completely regressed. Can be seminoma or Non-
seminoma.
Scar findings: Well-demarcated scar, Coarse
calcifications within tubules, chronic inflammation,
hyalinized tubular ghosts.
Nearby findings: GCNIS, tubular atrophy, microliths

Spermatocytic tumor
Relatively rare. Generally excellent prognosis.
NOT associated with GCNIS or cryptorchidism
NOT a component of mixed GCT
Usually occurs in OLDer men (>50yo)
Polymorphous cell population (3 cell types: small,
medium, and large)
Poorly-defined cell membranes. Dense cytoplasm.
Round nuclei with dense to granular chromatin.
Diffuse to multinodular pattern of growth.
Frequent cystic change/edema.
No significant inflammation/granulomas
IHC: Negative for usual seminoma markers (e.g.,
OCT3/4). (+) cKit and SALL4
Can undergo sarcomatous transformation.
 Teratoma, Prepubertal-type
Composed of elements resembling somatic tissues from one or more
germ cell layers.
Primarily occurs in prepubertal males <6 years old
(but can see in older)
In contrast with Postpubertal-type:
Benign behavior. Do not recur or metastasize.
NO association with GCNIS or isochrome 12p amplification.
NO cytologic atypia. NO association with mixed GCT.
As such, they are most akin to the mature cystic teratomas seen in the
ovary.
Frequently include skin structures, ciliated epithelium, fat, cartilage,
bone, and muscle in organoid structures. No significant cytologic atypia.
Normal surrounding testicle: No GCNIS, tubular atrophy, scars,
microlithiasis, necrosis, or impaired spermatogenesis (which might
suggest a GCNIS-derived GCT)

Specialized variants:
Dermoid Cyst: replicate skin in an organoid arrangement. Squamous
epithelium with adnexal structures. Cured by excision.
Epidermoid Cyst: Unilocular cyst with squamous lining and keratinaceous
debris. No adnexal structures or other elements. Cured by excision.
Well-differentiated Neuroendocrine Tumor: Similar morphology to
elsewhere. Often pure. Usually good behavior. Only variant that can
behave aggressively.

Yolk Sac Tumor, Prepubertal-type

Rare. Usually in young boys <6 years old
Identical morphology and IHC profile to postpubertal-type.
Secretes AFP
However, unlike postpubertal YST:
NOT associated with GCNIS. NO isochrome 12p amplification.
Excellent survival, even with advanced stage.

Usually pure, but can see in combination: Mixed teratoma and

yolk sac tumor, prepubertal-type
Immunohistochemistry of Germ Cell Tumors

Embryonal Carcinoma

Metastatic Carcinoma
Spermatocytic Tumor
Choriocarcinoma
Yolk Sac Tumor

Other Tumors
Seminoma

Teratoma
GCNIS

AE1/AE3 - ± + + + + - + Many!

OCT3/4 + + + - - - - - Rare NSCLC and RCC and large cell

lymphoma
CD30 - - + - - - - ± Lymphomas, melanoma,
nasopharyngeal carcinoma,
mesenchymal tumors
Glypcian-3 - - - + + ± ± HCC, gastric cancers,
syncytiotrophoblasts
D2-40 + + ± - - ± - ± Gliomas, meningiomas, mesothelial
tumors, lymphatic tumors,
PLAP + + + ± + - - ± Numerous adenocarcinomas (colon,
endometrium, etc..)
SALL4 + + + + ± ± + ± Hematologic malignancies, rhabdoid
tumors, Wilms tumor, lots of GI
adenocarcinomas among others
βhCG - - - - + - - ± Other trophoblastic tumors,
syncytiotrophoblasts
cKIT + + - ± - - ± ± Lots of tumors
(CD117)
AFP - - ± + - ± - ± Hepatocellular tumors, etc..

CK7 ± ± + - + + ± Many carcinomas

Modified from: WHO classification of Tumors of the Urinary System and Male Genital Organs. 4th ed.
Sex Cord-Stromal Rare. More common in kids. Vast majority are benign.
A little variable, but often stain with some combination of: Inhibin, calretinin, SF-1, FOXL2, Melan A

Leydig Cell Tumor

Abundant, eosinophilic granular cytoplasm.
Diffuse growth. Uniform round cells.
Round, central nuclei with prominent nucleoli.
Frequent Reinke crystals (→)
Usually asymptomatic, but children can present with
precocious puberty as the tumor can secrete steroid
hormones (e.g., testosterone).
Most common testicular sex cord-stromal tumor.
Vast majority are benign.

Sertoli Cell Tumor

Often shows at least focal tubular differentiation.
Usually moderate pale cytoplasm.
Rarely diffuse growth.
Unique IHC: Frequent nuclear β-catenin, WT-1, CK
AE1/AE3, and neuroendocrine markers.
Vast majority are benign.

Variant:
Sclerosing Sertoli Cell Tumor—extensively hyalinized
stroma with cells arranged in tight cords and clusters

Factors associated with Malignant behavior in Sex Cord-Stromal Tumors:

Cytologic Atypia, Abundant Mitoses, Large size, Vascular Invasion, Necrosis, Infiltrative growth
(Pretty common-sense bad findings ;-)
 Granulosa Cell Tumors
Similar to the more common ovarian counterpart
Adult Granulosa Cell Tumors
Rare.
Often asymptomatic, but can secrete estrogen
Cells: Scant pale architecture with grooved nuclei
Varied architecture: Sheet-like, trabecular, ribbon-like,
microfolicular (with “Call-Exner bodies” filled with pink secretions).
Molecular: Frequent FOXL2 point mutations
Juvenile Granulosa Cell Tumors
Rare. Almost all in first decade, often before 6 months old.
Usually presents as a mass.
Macrofollicles with mucinous secretions
Round nuclei with NO GROOVES

Large Cell Calcifying Sertoli Cell Tumor

Large Sertoli cells with abundant granular
eosinophilic cytoplasm
Calcifications (focal, psammomatous to
large, plaque-like)
Often prominent neutrophilic infiltrate.
NO nuclear β-catenin
Frequently associated with Carney complex
Frequent PRKAR1A mutations

Other Tumors
Intratubular Large Cell Hyalinizing Sertoli Cell Neoplasia:
Expanded seminiferous tubules with large Sertoli cells with pale
cytoplasm accompanied by prominent basement membrane
deposits around and within tubules (→).
Almost exclusively in Peutz-Jegher’s syndrome (think: like SCTATs!).
Often present as prepubertal males with gynecomastia (aromatases
made by tumor convert androgens→ estrogen).
Always benign.

Fibroma/Thecoma:
Resemble ovarian counterparts. Benign. Rare.
Unencapsulated proliferation of spindled cells with scant
eosinophilic cytoplasm.
 Miscellaneous Tumors
Gonadoblastoma
Germ cells resembling GCNIS cells and spermatogonium
Sex cord cells resembling immature granulosa cells
Arranged in round nests with round deposits of
eosinophilic basement membrane
Frequent calcifications
Develop in individuals with gonadal dysgenesis.
Can progress to a germ cell tumor, often seminoma.

Hematolymphoid Tumors
Most common testicular tumor in men over 50 years old.
Can be primary or part of systemic involvement.
Often obliterate the seminiferous tubules centrally with peripheral
intertubular spread.
Diffuse Large B-Cell Lymphoma comprises ~90% of primary
testicular lymphomas.
Same stains as elsewhere.

Other Tumors
Ovarian-type Epithelial Tumors:
Resemble entire spectrum of ovarian type epithelial tumors. Most commonly Serous and Mucinous,
with most being Serous Borderline Tumors, which do not recur or metastasize.

Rete Testis Adenoma:

Very rare. Benign tumor of rete epithelium that spans the spectrum from packed tubules (adenoma) to
tumors with a cystic component (cystadenoma), papillary architecture (papillary cystadenoma), or
glands with prominent fibrous tissue (adenofibroma).

Rete Testis Adenocarcinoma:

Very Rare. Malignant. Diagnosis of exclusion. Malignant gland forming tumor of rete epithelium. Must
be centered in hilum of testis, patient must have no other similar primary, and other Dx’s (e.g.,
mesothelioma), must be excluded. Poor prognosis.

Myoid Gonadal Stromal Tumor:

Spindle cell tumor near rete testis with features of gonadal stroma and smooth muscle. Circumscribed
with densely packed spindled cells arranged in short fascicles. IHC: (+)SF1, FOXL2, SMA, S100.
 Paratesticular Tumors
Adenomatoid Tumor
Benign Mesothelial tumor.
Most common neoplasm of paratesticular region
Often based in the epididymis and < 2cm.
Irregularly shaped gland-like microcystic spaces
composed of flattened or cuboidal cells with
associated fibrous stroma and lymphoid aggregates.
Bland cytologic features.
Helpful feature: "thread-like bridging strands“ (→)
Sometimes signet ring-like vacuolated cells.
Solitary, localized.
IHC: Mesothelial markers: D2-40, Calretinin, WT-1,
CK5/6 , CK AE1/AE3.

Mesothelioma
Rare. Malignant proliferation of mesothelial cells arising
from tunica vaginalis.
Mass envelops testicle, often invading it.
Like in the pleura, variable appearance. Often epithelioid
with papillary or tubulopapillary architecture.
Less associated with asbestos.

IHC: Usual mesothelial markers (see above)

Papillary Cystadenoma of the Epididymis

Rare. Benign Tumor of Epididymal ducts.
Associated with von Hippel-Lindau syndrome (but is more often
sporadic)
Cystic structures that are focally papillary.
Clear columnar/cuboidal cells with abundant clear cytoplasm.
Frequent reverse nuclear polarity.
Colloid-like secretions.
Morphologically (and immunophenotypically) resembles
papillary clear cell RCC (see separate Kidney guide)
Adipocytic Tumors
Lipoma:
Benign. Most common mesenchymal tumor of region.
Consist of entirely mature adipocytes.

Well-differentiated Liposarcoma:
Common paratesticular sarcoma. Recur, but won’t
metastasize unless dedifferentiate.
Varying proportion of adipocytes, fibrous bands with
enlarged, hyperchromatic stromal cells, and occasional
lipoblasts. Can see inflammation/myxoid change.
Giant marker and/or ring chromosomes→ MDM2
amplification.

If large or questionable atypia→ consider getting FISH

to help differentiate.

Smooth Muscle Tumors

Leiomyoma:
Benign. Somewhat common.
Consist of entirely bland smooth muscle (like in other
locations).

Leiomyosarcoma:
Common paratesticular sarcoma.
Fascicles of spindled cells with brightly eosinophilic
cytoplasm and “cigar-like” blunt nuclei.
Significant atypia, mitoses, and/or tumor necrosis.

IHC: Desmin, SMA, H-Caldesmon, Calponin

Skeletal Muscle Tumors

Rhabdomyoma:
Benign. Very rare. Most often adolescents.

Rhabdomyosarcoma:
Often in children or young adults and Embryonal
subtype with primitive round or spindled cells and
variable eosinophilic rhabdomyoblasts with abundant
eccentric cytoplasm. Often good prognosis.

IHC: MyoD1, Myogenin, Desmin.

 Algorithmic Diagnosis of Testicular Tumors
Algorithms modified from: Urologic Surgical Pathology. Liang Chen et al. 2020.

Clear Cytoplasm:
Start
Nests polygonal cells Yes GCNIS Present? No Predominantly
arranged with fibrous Intertubular
septae with Growth?
lymphocytes? Yes No
Yes No
3 Distinct Cell
Seminoma Large, Focal Types?
irregular Glandular
[Oct3/4+, partially clear Architecture?
CD30-, nuclei? No
Yes Yes Yes
Glypican3-] No
No

Yolk Sac Sertoli Cell

Embryonal Metastatic Lymphoma Tumor Spermatocytic
Tumor Adenocarcinoma Tumor
[Oct3/4+, [CD45+, [Inhibin+,
CD30+, [Oct3/4-, [CK+, SALL4-,
CD30-, Oct3/4-, SF1+, [Oct3/4-, CD30,
Glypican3-] Oct3/4-, CD30-, inhibin-] Nuclear β- Glypican3-]
Glypican3+, Glypican3-]
AFP+] catenin]

Glandular and/or Tubular growth:

Start Predominantly
Cells with large Yes GCNIS Present? No intertubular and
crowded, irregular intralymphatic
nuclei lining gland-like growth??
spaces? Yes
No
Yes No
Metastatic Tubular growth
Embryonal Variably sized cells, Adenocarcinoma with solid tubules?
hyaline globules,
[Oct3/4+, variable patterns? [CK+, SALL4-,
CD30+, Oct3/4-, CD30-, Yes No
Glypican3-] Glypican3-]
Yes No
Rete Testis
Sertoli Cell
Neoplasm
Tumor
Yolk Sac Tumor Seminoma [centered in
[Inhibin+,
hilum, CK+,
[Oct3/4-, CD30-, SF1+,
[Oct3/4+, CD30-, PAX8-, CEA+,
Glypican3+, AFP+] Nuclear β-
Glypican3-] EMA+]
catenin]
Microcystic:
Start Prominent cords of
Yes GCNIS Present? No tumor cells, Lipid
Variably sized nuclei and
flattened nuclei linin rich cells, and
cysts? Sertoli Cell Yes hyalinized stroma?
Tumor No
Yes No
Yes Neonate?
[Inhibin+,
Yolk Sac Tumor SF1+,
Seminoma No
(post-pubertal) Nuclear β- Juvenile Granulosa
[Oct3/4+, CD30-, catenin] Cell Tumor
[CK+, Oct3/4-, Abundant
Glypican3-, CK-] eosinophilic
CD30-, Glypican3+,
[Inhibin+, AFP-, cytoplasm?
AFP+, PLAP+]
Glypican3-]

Yes No

Yolk Sac
Leydig Cell Tumor: Oct3/4+, CD30+, Glypican3- Tumor (pre-
Adenomatoid Tumor: CK+, Calretinin+ pubertal)

[CK+, Oct3/4-,
CD30-,
Glypican3+,
AFP+, PLAP+]
Pink Cells with Abundant cytoplasm (Oxyphil):
Start
Leydig Cell Tumor No Fibromyxoid stroma with
Yes Round nuclei
with prominent neutrophils and calcifications?
[Inhibin+]
nucleoli, ±
Yes No
lipofuscin or
Reinke Crystals? Presence of other patterns,
Large Cell
Lots of mitoses, and
Calcifying Sertoli
associated GCNIS?
Cell Tumor
Yes
Consider: [Inhibin+]
Metastatic Carcinoma, Melanoma,
Hematolymphoid tumors No
Hepatoid Yolk Sac Tumor

Yes [CK+, Glypican3+, AFP+, Oct3/4,

CD30-, Inhibin-]
Highly pleomorphic
nuclei, Prominent
intratubular No Insular and trabecular
Adenomatoid growth? patterns, coarse chromatin,
Tumor ± teratomatous elements?
No Well-differentiated
[CK+, Calretinin-] Neuroendocrine Tumor Yes
[CK+, Synaptophysin+, Inhibin-]
Spindle Cells: Start
Round nuclei
with prominent
nucleoli, ±
lipofuscin or
Leydig Cell Tumor Yes Reinke Crystals? No Bland Nuclear
[Inhibin+] Cytology with no
Mitoses?
Yes
No
Fibrothecoma
Smooth Muscle Actin Keratin, S100,
[SMA-, S100-] and S100 staining? Desmin staining?

Myoid Gonadal Stromal Tumor

[SMA+, S100+]
Sarcomatoid MPNST,
Melanoma, Leiomyosarcoma,
Carcinoma or Rhabdomyosarcoma
Mesothelioma Liposarcoma

[S100+ at least [Desmin+]

[CK+]
partial]
 Prepared by Kurt Schaberg

Thyroid Cytology
Adequacy Criteria Must see at least 6 groups of well-visualized follicular
epithelial cells, each consisting of at least 10 cells.
Exceptions:
1) Abundant colloid with radiographic findings compatible
with a colloid nodule
2) Abundant inflammation with a solid nodule
(lymphocytes, granulomas, or neutrophils)
3) Atypia
Ideally, follicular epithelium should be in nice big, flat (“monolayered”) sheets, with evenly
spaced (“Honeycomb-like”) dark, round nuclei with uniformly granular chromatin.

Benign Follicular Nodule Watery Colloid

Histologically represent nodular goiter, adenomatoid
nodules, and colloid nodules.
Variable amounts of: colloid, bland follicular cells,
Hürthle cells, and macrophages.
Should be sparse to moderately cellular with a good
amount of colloid (easiest to see on diff-quick)
Watery colloid – thin, watery, like cellophane
Dense Colloid – thick, hyaline
Cystic degeneration: macrophages, “reparative” stretched cells Dense Colloid

Lymphocytic Thyroiditis
Hypercellular smear with abundant, polymorphic lymphocytes.
Hürthle cell metaplasia common (Large cells with abundant
granular cytoplasm and prominent nucleoli).
Advanced cases may be hypocellular (due to fibrosis).
Often middle-aged women with associated circulating
autoantibodies.

Granulomatous Thyroiditis Aka subacute or de Quervain’s

Self-limited inflammatory condition, usually diagnosed clinically
Clusters of epithelioid histiocytes (i.e., granulomas) and
multinucleated giant cells, often ingesting colloid
Early can have neutrophils and eosinophils. Later have lymphocytes.
 Papillary Carcinoma
Most common malignant thyroid neoplasm
Relatively good prognosis. Spreads via
lymphatics.
Classic findings:
-Intranuclear pseudoinclusions
-Powdery, pale chromatin with marginal
micronucleoli
-Enlarged, irregular nuclei
-Longitudinal nuclear grooves
-Dense, squamoid cytoplasm
-Multinucleated giant cells
-Dense, “Bubble gum” colloid
-Septate cytoplasmic vacuoles
-Papillary structures w/ and w/o fibrovascular
cores

Some findings, but “not enough”?

Consider Atypia of Undetermined Significance
(AUS) or Suspicious for Malignancy.

Follicular Neoplasm/Suspicious for Follicular Neoplasm

Cannot differentiate between Follicular Adenoma
and Carcinoma on cytology specimens (need to
see capsular or vascular invasion on resection
specimen!)
Moderately or Markedly cellular
Significant alteration in follicular architecture
→ Repetitive microfollicular pattern or cell
crowding/overlapping in trabeculae
→ Minimal colloid
Minimal cytologic atypia. Microfollicle: less than 15 cells
arranged in a circle that is at
Hürthle Cell Lesions: least 2/3 complete
Look for: 1) nonmacrofollicular
architecture, 2) absence of colloid, 3) Some findings, but “not enough”?
absence of inflammation, and 4) presence Consider Follicular Lesion of Undetermined
of “Transgressing blood vessels” Significance (FLUS)
 Medullary Carcinoma
Can be sporadic or inherited (part of MEN 2A&B)
Derived from Parafollicular C cells→ stain with Calcitonin!
Moderate to Marked Cellularity. Often discohesive.
Plasmacytoid, polygonal, to spindled cells.
Mild to moderate pleomorphism.
“Salt and Pepper” chromatin.
Granular cytoplasm with small granules.
Occasional intranuclear pseudoinclusions or amyloid fragments
Undifferentiated (Anaplastic) Carcinoma
Extremely aggressive. Poor prognosis.
Classically older women with rapidly growing, hard
neck mass → trouble breathing
Variable cellularity. Often discohesive.
Epithelioid to Spindled cells.
Enlarged, pleomorphic nuclei.
Often associated necrosis and inflammation.
Can see osteoclast-like giant cells
The Bethesda System and Genetics
With rare exception, FNAs should be classified into one of the Bethesda Categories.
If you have an equivocal AUS/FLUS case, consider sending for molecular testing.
Papillary Thyroid Carcinoma:
MAPK Pathway Diagnostic Category Risk of Management
BRAF (most classic PTC’s) Malignancy
V600E (most common)
I Unsatisfactory Repeat US-guided FNA
RAS (associated with
follicular variant & NIFTP)
II Benign 0-3% Clinical follow-up
Medullary Carcinoma:
RET (think MEN2A&B) III AUS/FLUS ~5-15% Repeat FNA and/or
Molecular testing
Follicular Neoplasms:
RAS most common IV Follicular 15-30% Lobectomy
PAX8/PPARG Neoplasm
PTEN
V Suspicious for 60-75% Near total or total
Poorly Differentiated and Malignancy thyroidectomy
Anaplastic
TP53 VI Malignant 97-99% Thyroidectomy
CTNNB1
(and others mentioned above)
Last updated: 8/10/2020 Prepared by Kurt Schaberg

Thyroid & Parathyroid Lesions

Thyroid Tumors
Papillary Thyroid Carcinoma “PTC”
Malignant tumor with follicular epithelial cell differentiation and distinct nuclear features.
Most common form of thyroid cancer in both adults and children. More common in women.
Risk factor: Ionizing radiation. Often relatively indolent cancer.
Often presents with a painless thyroid mass.
Nuclear Features: (Definitional)
- Nuclear enlargement and elongation
- Nuclear overlapping
- Irregular nuclear contours
- Intranuclear pseudoinclusions (→)
- Longitudinal nuclear grooves
- Nuclear chromatin clearing
Conventional (classic) PTC: Papillary architecture (hence the name!).
May have mixed in other architectures like follicles. Frequent
psammoma bodies. Occasional squamous metaplasia. Often cystic
degeneration. Densely eosinophilic colloid.
Papillary microcarcinoma: Tumor variant ≤ 1 cm. Often missed
grossly/incidental. Malignant, but excellent prognosis.
Encapsulated variant: Totally surrounded by a fibrous capsule (intact or
focally infiltrated). Excellent prognosis.
Follicular variant: Exclusively (or almost exclusively) follicular
architecture. Can be infiltrative or encapsulated with invasion.
Tall Cell variant: Cells 2-3x as tall as they are wide with abundant
eosinophilic cytoplasm. Must account for ≥30% of tumor. More
aggressive behavior.
Columnar cell variant: Rare. Columnar cells with prominent
pseudostratification. Lack conventional nuclear features. Resembles
endometrioid/intestinal adenocarcinoma morphologically. IHC: CDX2+!
Diffuse sclerosing variant: Rare. Diffuse involvement with sclerosis and
solid nests of tumor cells. Also background lymphocytic inflammation
and psammoma bodies.
Cribriform-morular variant: Mixture of cribriform, follicular, papillary,
trabecular, and solid growth with round squamoid structures (morules).
Frequent vascular invasion. Almost exclusively in females. Association
with FAP→ nuclear β-catenin. IHC: LEF-1 positive.
Other variants: Hobnail, solid/trabecular, oncocytic, spindle cell, clear
cell, Warthin-like, and PTC with fibromatosis/fasciitis-like stroma
IHC: (+)TTF-1, PAX8, Thyroglobulin, CK7,
Molecular alterations: BRAF (most common by far, often V600E), RET,
RAS, TERT promoter→ often mutually exclusive→ MAPK activation
 Follicular Adenoma
Benign neoplasm with thyroid epithelial differentiation
Completely surrounded by a fibrous capsule (→).
Variety of architectural patterns: normo-, micro-, or
macrofollicular, solid, and/or trabecular, but different than
surrounding parenchyma
Cells are cuboidal with round, basally located nuclei.
Smooth nuclear contours and uniform chromatin.
ABSENT: capsular/vascular invasion, PTC-like nuclei
(Must submit entire capsule to exclude invasion)
Molecular: Most frequently RAS mutations.
Associated with Cowden syndrome and Carney complex
Variants:
Hyperfunctioning—hyperthyroidism. Papillary projections.
Lipoadenoma—mature adipose tissue is sprinkled throughout
Signet-ring cell—cells with cytoplasmic vacuoles Capsular and/or
Other variants: clear cell, spindle cell, black
Vascular Invasion
Follicular Carcinoma
Malignant. Nuclear features of PTC are absent.
Risk factors: insufficient iodine, ionizing radiation
Often present with painless mass.
Requires either capsular or vascular invasion!
Otherwise, cytology and architecture is identical to
follicular adenoma
Often surrounded by thick fibrous capsule.
Most require that tumor penetrate the entire capsule→
classically has a “mushroom” appearance.
For vascular invasion, tumor cells should be adherent to
the vessel wall either with covering endothelium or in a
thrombus with fibrin (this is to distinguish from artifactual Thrombus
tumor “misplacement”). Controversial (see next page)
Invasion must occur in the capsule or beyond
Subclassified into 3 groups: Tumor
1) Minimally invasive → capsular invasion only →
excellent prognosis
2) Encapsulated angioinvasive→ risk of hematogenous
metastasis (often bone/lung)
3) Widely invasive → extensive involvement of thyroid
and soft tissues, often with prominent vascular invasion
Molecular: RAS point mutations and PAX8-PPARγ gene fusions most common.
Associated with Cowden syndrome
IHC: (+)TTF-1, PAX8, Thyroglobulin, CK7, (More on next page!)
 Is that “good enough” for capsular invasion?
Most require complete transgression of the capsule
(labeled “Yes”→)
Some pathologists are more lenient, and may accept
those labeled “Not yet”
When in doubt, get multiple deeper histologic levels.
Remember, a prior FNA may disrupt the capsule.
Also, as the tumor grows and extends into the
parenchyma, it can induce a new stromal reaction
forming a secondary fibrous band (example D). So,
instead of just the fibrous capsule itself, look at the
gland contour. If the invasive tongue of tumor
extends outside of the usual contour (even if there is
a thin capsule), many would consider this invasive.

From the CAP Protocol for the Examination of Specimens From Patients With Carcinomas of the Thyroid Gland

Is that “good enough” for vascular invasion?

PTC→ usually spreads via lymphatics (no RBCs, stain with D2-40) to lymph nodes.
Follicular Carcinoma→ spreads via veins (luminal RBCs, stain with CD31) hematogenously to lungs/bones
Vascular invasion must be outside of the tumor—either in the capsule or beyond.
According to the WHO, tumor cells should be adherent to the vessel wall either with covering
endothelium or in a thrombus with fibrin.
However, newer data suggests tumor cells within vascular lumina unassociated with thrombus and tumor
cells underlying intact endothelium could represent “pseudoinvasion” given the fenestrated endothelial
network of endocrine organs.
Stricter CAP unequivocal definition: invasion of tumor through a vessel wall accompanied by fibrin
thrombus→ correlates more closely with aggressive disease.

These examples have fibrin associated with tumor,

so they are unequivocal vascular invasion
Controversial, WHO would say Yes. Stricter CAP would say NO.
Consider “Uncertain Malignant Potential” (next page)

May represent tangential

example B, get deeper levels

Tumor bulging and indenting

the vessel wall does not count

(Blue = endothelium) →
(Red = fibrin)
From the CAP Protocol for the Examination of Specimens From Patients With Carcinomas of the Thyroid Gland
 Hürthle (Oncocytic) Cell Tumors
Neoplasms composed of oncocytic cells with abundant
eosinophilic granular cytoplasm.
Hürthle cell adenoma→ essentially a follicular adenoma
composed of Hürthle cells. Encapsulated. Benign.
Hürthle cell carcinoma→ contains vascular and/or capsular
invasion (essentially a follicular carcinoma with Hürthle cells)

Most use term only if “majority” (greater than 75%) of

tumor has this morphology (otherwise use term “Hürthle
cell features”)
Hürthle cells are large with abundant eosinophilic granular
cytoplasm and large central nuclei with prominent nucleoli.
Full of mitochondria.
Variable architecture: follicular, trabecular, or solid
Larger tumors are more likely to be malignant.

Tumors of “Uncertain Malignant Potential”

Some encapsulated neoplasms with a follicular architecture can have questionable capsular/vascular
invasion or nuclear changes that are mild, where it is unclear if they are sufficient to justify a diagnosis
of papillary thyroid carcinoma→ In such diagnostically uncertain cases, one can use the diagnosis of
“Uncertain Malignant Potential” (UMP)
For example: Tumor cells invade into, but not completely across the capsule, or, Tumor cells are in a
blood vessel, but are not covered by endothelium or thrombus.
Follicular Tumor of Uncertain Malignant Potential→ encapsulated or well-circumscribed follicular-
patterned tumor lacking nuclear features of PTC with equivocal vascular or capsular invasion (and no
PTC-like nuclear features). Essentially between follicular adenoma and carcinoma.

Well-differentiated Tumor of Uncertain Malignant Potential → Encapsulated or well-circumscribed

follicular-patterned tumor well-developed or partially developed PTC-type nuclear changes and with
questionable capsular or vascular invasion. If invasion is totally excluded→ NIFTP (next page)

Capsular or Vascular Invasion

Present Questionable Absent
Invasive Encapsulated Non-invasive
Present Follicular Variant of Well-differentiated Follicular Thyroid
Nuclear PTC Tumor of Uncertain Neoplasm with
features Well-Differentiated Malignant Potential Papillary-like nuclear
of PTC Questionable features (NIFTP)
Carcinoma, NOS
Follicular Tumor of
Absent Follicular Carcinoma Uncertain Malignant Follicular Adenoma
Potential
Modified from: WHO Classification of Tumors of the Endocrine Organs. 2017.
 Non-invasive Follicular Thyroid Neoplasm
with Papillary-like Nuclear Features (“NIFTP”)
Diagnostic Requirements:
1) Encapsulated or Clear demarcation
2) Follicular pattern of growth with:
- No true papillae
- No psammoma bodies
- <30% solid, trabecular, or insular growth pattern
3) Nuclear features of papillary carcinoma (nuclear score 2-3)
4) No lymphovascular or capsular invasion
5) No tumor necrosis
6) No significant mitotic activity (<3 mitoses/10 HPF)

Score nuclear features using table below. If present +1, if absent

= 0. Need a score of 2-3 to qualify. May be patchy/focal.

However, nuclear features of PTC are usually only partially

developed in NIFTP. So, if they are very well-developed,
reconsider the diagnosis and consider testing for BRAF
mutations (present in PTC, not in NIFTP)
The entire tumor (or at least the Nuclear Alteration Findings
entire capsule) should be submitted
Size and Shape nuclear enlargement, overlapping,
for histologic evaluation
crowding, elongation
Molecular: RAS mutations (like Nuclear membrane irregular contours, grooves,
follicular adenomas/carcinomas). irregularities pseudoinclusions
BRAF mutations (like in PTC) are
notably absent, which can be useful Chromatin clearing with margination, glassy
diagnostically with challenging cases. characteristics nuclei

Prognosis: Very low risk of

progressive disease. Can be treated Encapsulated Follicular Tumor Algorithm
with lobectomy alone.
Invasive?

Yes Questionable

Carcinoma No Uncertain
Malignant
Potential

Papillary Carcinoma Nuclear Features?

Yes No Questionable

NIFTP Follicular Use Nuclear Assessment

Adenoma Guide
Score: 2-3 Score: 0-1

Modified from: WHO Classification of Tumors of the Endocrine Organs. 2017.

 Poorly-Differentiated Thyroid Carcinoma
Thyroid carcinoma with morphology, genetics, and behavior
between differentiated carcinomas (i.e., papillary and follicular)
and anaplastic carcinoma. Applies to Hürthle cell tumors also.
Turin Criteria:
1) Carcinoma of follicular cell origin
2) Solid, trabecular, or insular growth pattern
3) Absence of conventional nuclear features of papillary thyroid
carcinoma
4) At least of one of the following:
- Convoluted nuclei (dedifferentiated PTC nuclear features)
- ≥3 mitoses per 10 high-power fields
- Tumor necrosis
Tumor cells are small and uniform with round hyperchromatic
nuclei or convoluted nuclei. Mitoses are common. Extensive
tumor necrosis can give a peritheliomatous pattern.
Some arise from via dedifferentiation of PTC or follicular
carcinoma (which may be visible in the lesion), while others
appear to be de novo.
Often widely invasive into soft tissue and vessels
IHC: (+)TTF1, PAX8, Thyroglobulin, often express HMW-CKs

Prognosis: Intermediate prognosis

Malignant thyroid tumor

of follicular cells

Follicular Carcinoma Solid, Trabecular, or

Papillary Carcinoma, Etc.. No Insular Pattern

Yes

Solid Variant of Typical PTC nuclei

Yes
Papillary Carcinoma throughout

No

Presence of one of the following:

Follicular Variant 1) Convoluted nuclei,
No
(solid growth pattern) 2) Necrosis, 3) Mitoses

Yes

Poorly Differentiated Thyroid

Carcinoma
Modified from: WHO Classification of Tumors of the Endocrine Organs. 2017.
 Anaplastic Thyroid Carcinoma
Highly aggressive thyroid malignancy composed of
undifferentiated follicular epithelial cells.
Classically older women with rapidly growing firm, fixed, highly
infiltrative neck mass→ Pain, hoarseness, dysphagia
Can occlude airway!
Many cases seem to arise from dedifferentiation of a pre-existing
thyroid tumor (may have history of long-standing nodule)
Variable morphology with 3 main patterns:
Sarcomatoid→ spindled cells resembling pleomorphic sarcoma,
Giant cell→ highly pleomorphic cells some of which have multiple
nuclei, Epithelial→ Squamoid nests
Common findings: Necrosis, mitoses, invasive growth.
Often inflammatory cells.
IHC: PAX8 often maintained. Frequent loss of TTF1, CK
Molecular: Frequent TP53 mutations. Also, BRAF, RAS, PTEN
Prognosis: Very aggressive with often <1 yr survival

Squamous Cell Carcinoma

Malignant epithelial tumor with entirely squamous differentiation.
Clinical features and prognosis similar to anaplastic carcinoma
Notably, both PTC and Anaplastic carcinoma can have squamous
areas, so the tumor should be sampled well to exclude squamous
differentiation of another tumor.
Often extensive infiltration of soft tissue/vessels.

Thyroid Carcinoma Immunohistochemistry

CK Thyroglobulin TTF1 PAX8 Ki67 P53 Calcitonin,
synaptophysin
Normal Thyroid + + + + <3% Wt -
Follicular cells
Well-differentiated + + + + <10% Wt -
thyroid carcinoma
Poorly-differentiated + -/+ + + 10-30% + -
thyroid carcinoma
Anaplastic thyroid +/- - -/+ +/- >30% + -
carcinoma
Medullary carcinoma + - + -/+ Wt +
Modified from: WHO Classification of Tumors of the Endocrine Organs. 2017.
 Medullary Thyroid Carcinoma
Malignant tumor of the thyroid with parafollicular C-cells
differentiation.
Uncommon. Although mostly sporadic, associated with
Multiple Endocrine Neoplasia (MEN) type 2 (germline RET
Inclusion
mutations).
Often present with painless mass. Frequent LN metastases
at presentation with elevated serum calcitonin.
Wide morphologic spectrum! Common patterns of growth
include: solid, lobular, trabecular, and/or insular.
Tumor cells can appear: round, polygonal, plasmacytoid, or
spindled. Nuclei are “Neuroendocrine” (round, speckled
“salt and pepper”) with occasional pseudoinclusions.
Cytoplasm is eosinophilic to amphophilic and granular. Amyloid

Although scattered markedly atypical cells may be present

(“Endocrine atypia”), generally not too pleomorphic.
Frequent stromal amyloid.
In familial tumors (e.g., MEN 2b) → more frequently
multifocal with C-cell hyperplasia.
IHC: (+) Calcitonin (most specific), Neuroendocrine
markers (synaptophysin, chromogranin), TTF-1. (+/-) PAX8.
(-) thyroglobulin.
Molecular: Frequent RET mutations. Occasional RAS mutations.
Prognosis: Intermediate aggressive behavior.
Rare variant: “Mixed medullary and follicular thyroid carcinoma”

Hyalinizing Trabecular Tumor

Extremely good prognosis. Follicular-derived neoplasm. Rare.
Solid, well-circumscribed nodule.
NO capsular, vascular, or thyroid parenchymal invasion.
Wide trabeculae and nests separated into bundles by stroma.
Cells may be enveloped by hyalinized PAS-d positive basement
membrane material.
Large polygonal/elongated cells. Eosinophilic finely granular
cytoplasm. Occasional perinuclear yellow bodies.
Nuclei are vesicular and mostly round, but with frequent
grooves, inclusions (→), and membrane irregularities.
(Can be mistaken for PTC, particularly on FNA!!!)
IHC: (+)TTF-1, thyroglobulin; (-) Calcitonin
Unique membranous staining with MIB1 (Ki67 clone)
 Mucoepidermoid Carcinoma
Low-grade malignant/indolent. Very rare.
Unclear origin, but favored to represent metaplastic
differentiation of follicular derived carcinoma in most
cases. Associated with PTC in ~1/2 of cases
Two required cell types: 1) Squamoid cells ,
2) Mucin-producing goblet cells.
IHC: Most cases express PAX8, TTF-1, thyroglobulin
Molecular: Occasional MAML2 rearrangements.

Sclerosing Mucoepidermoid Carcinoma with Eosinophilia

Malignant with sometimes aggressive behavior.
Rare. Strong female predominance.
Consistently associated with fibrosing Hashimoto’s thyroiditis.
Small nests and strands of epidermoid cells infiltrating sclerotic
stroma. With interspersed mucous-secreting cells.
Rich inflammatory infiltrate with lymphocytes, plasma cells, and
prominent eosinophils.
Frequent PNI and LVI.
IHC: (+/-)TTF1, (-/+) Thyroglobulin.

Mucinous Carcinoma
Malignant. Extremely Rare.
Unknown origin/etiology.
Abundant pools of mucin with floating trabeculae/
tumor clusters. Cells have large nuclei with nucleoli.
Other typical carcinomas should be absent.
Must clinically exclude a metastasis.
IHC: Focal staining with thyroglobulin, TTF-1, PAX8

Ectopic Thymoma
Very Rare. Typical mediastinal thymoma histology, but
located ectopically within the thyroid gland.
Arises from ectopic thymus tissue.
Jigsaw puzzle-like lobules separated by sclerotic septae.
Intimate admixture of ovoid to spindled epithelial cells
with a variable amount of small lymphocytes.
IHC: Epithelium—cytokeratins, p63, PAX8
Lymphocytes—immature T cells (TdT+, CD1a, CD99)
 Spindle Epithelial Tumor with Thymus-like Differentiation (“SETTLE”)
Malignant. Intermediate behavior. Rare.
Highly cellular. Lobulated architecture.
Spindled epithelial cells that merge into glandular
structures.
May have glomeruloid glands/papillae, reticulated
fascicles, or be exclusively spindled.
IHC: Both cell types stain with HMWCK and CK7.
Spindled cells rarely show myoepithelial staining.

Intrathyroid Thymic Carcinoma

Old name: Carcinoma showing thymus-like
differentiation (“CASTLE”)
Very Rare. Malignant tumor with thymic epithelial
differentiation (malignant counterpart of intrathyroidal
thymoma).
Appears identical to thymic carcinoma of mediastinum:
essentially a squamous cell carcinoma with
lymphocyte-rich stroma.
IHC: (+) CD5, p63, CD117, Cytokeratins, PAX8, calretinin
(-) TTF-1, Thyroglobulin; Ki67 10-30%

Other Thyroid Tumors

Paraganglioma Langerhans Cell Histiocytosis
Peripheral Nerve Sheath Tumors Rosai-Dorfman Disease
Hemangioma Follicular Dendritic Cell Sarcoma
Angiosarcoma Diffuse Large B-cell Lymphoma
Smooth Muscle Tumors MALT lymphoma
Solitary Fibrous Tumors Teratoma
Metastases
 Parathyroid Tumors IHC: These are (+) PTH, GATA3, Synaptophysin, Chromogranin
(-) TTF1, Thyroglobulin, Calcitonin; (+/-) PAX8

Normal Parathyroid
Regulates calcium levels with parathyroid hormone PTH 3 1
Three main components:
1- Chief cells: main cell type, round central nucleus, clear to
amphophilic cytoplasm
2-Oxyphil cells: large cells with abundant pink cytoplasm 2
3-Fat (and fibrous tissue) dividing cells into lobules

Parathyroid Adenoma
Benign parathyroid neoplasm. Relatively common.
Often present with primary hyperparathyroidism→ hypercalcemia
(metabolic bone disease, kidney stones, fatigue, etc.)
Can arise in any of the 4 glands, or be ectopic.
A minority of cases are associated with MEN1/2A
Well-circumscribed, often encapsulated
Composed of chief cells (most common), oncocytes, or a mixture.
Cells have round, central nuclei with dense chromatin.
Unlike normal parathyroid, there is typically NO FAT
Occasional mitoses acceptable. Sometimes follicular architecture.
Many variants: Oncocytic, water-clear cell, lipoadenomas (contain
fat and other parenchymal elements)
Remember, the surgeon often wants a weight!

Parathyroid Carcinoma
Rare. Malignant neoplasm derived from parathyroid cells.
Usually presents with hyperparathyroidism.
Requires evidence of one of the following:
- Invasive growth involving adjacent structures (e.g., thyroid or soft tissue)
- Invasion of vessels in capsule or beyond (attached to wall)
- Metastases
Usually subdivided by broad fibrous bands. Variable pleomorphism/mitoses.
Ki67 usually 6-8% (vs <4% in adenomas)
“Atypical Parathyroid Adenoma”
Adenomas that exhibit some features of parathyroid carcinoma but lack
unequivocal invasive growth→ essentially “Uncertain Malignant Potential.”
Frequent findings: bands of fibrosis, adherence to other structures, tumor in
capsule, solid/trabecular growth, nuclear atypia, increased mitotes.
Usually benign clinical course with close clinical follow-up.
Fibrous bands
Last updated: April 17, 2021
Prepared by Dr. Kurt Schaberg
Mesenchymal Tumors of the Uterus

Smooth Muscle Tumors

Stain with: Desmin, SMA, Caldesmon
Leiomyoma
Benign smooth muscle tumor. Most common uterine tumor.
If tons, particularly at a young age, consider hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome.
Classically these have staghorn vessels, eosinophilic nucleoli with halos, and rhabdoid inclusions.
Show loss of fumarate hydratase
Still have metastatic potential—“Benign metastasizing leiomyoma”
Variants:
Cellular leiomyoma—significantly increased cellularity compared to normal myometrium
Leiomyoma with bizarre nuclei—bizarre nuclei (smudged, hyperchromatic, pleomorphic) in an otherwise normal
leiomyoma (no mitoses or tumor necrosis)
Mitotically active leiomyoma—increased mitoses, but no atypia or tumor necrosis

Smooth Muscle Tumor of Uncertain Malignant Potential (“STUMP”)

Smooth muscle tumor whose features preclude a definitive diagnosis of leiomyoma vs. leiomyosarcoma
(Either equivocal mitoses or necrosis often; Many IMT’s were previously mistakenly Dx'd as this!)
Relatively low risk of recurrence

Leiomyosarcoma
Malignant smooth muscle tumor. Typically spindle cell, but can be epithelioid.
Want to see: 1) High-grade cytologic atypia, 2) Increased mitoses (typically >2/10 HPF), and 3) Tumor-type necrosis
Genetically complex chromosomal aberrations
Very poor prognosis

Endometrial Stromal Tumors

Low-grade/benign tumors stain like normal endometrial stroma with CD10 and ER/PR; High-grade stains with Cyclin-D1

Endometrial Stromal Nodule

Benign tumor resembling proliferative endometrial stroma with a relatively well-circumscribed margin

Low-grade Endometrial Stromal Sarcoma

Malignant tumor composed of cells resembling proliferative endometrial stroma with infiltrative growth into
myometrium and/or lymphovascular invasion—Often have “tongue-like” growth
Fusion of JAZF1 and SUZ12 (think “Jazzy Suzie”)
Intermediate prognosis, mostly depending on stage

High-grade Endometrial Stromal Sarcoma

Malignant tumor derived from endometrial stromal cells with high-grade round cell morphology. Frequently myxoid.
Typically confluent, permeative, destructive growth. Usually high mitotic activity, necrosis, and LVI.
Fusions: YWHAE-associated or BCOR-associated
Other Tumors
Undifferentiated Uterine Sarcoma
Malignant tumor arising in the endomyometrium with high-grade cytologic atypia and no specific line of differentiation.
Destructive invasion. Marked cytologic atypia and brisk mitotic activity. Diagnosis of exclusion.
IHC: Variable CD10, Often Cyclin-D1 (+). May see focal SMA.
Complex genetically
Most patients present at high stage. Poor prognosis.

Uterine Tumor Resembling Ovarian Sex Cord Tumor (“UTROSCT”)

Neoplasms resembling ovarian sex cord tumors without endometrial stromal component
Usually well-circumscribed.
IHC: Frequently WT-1 positive, variable expression of Inhibin, calretinin, and Melan-A
Recurrent NCOA translocations
Benign course typically.

Rhabdomyosarcoma
Malignant tumor showing skeletal muscle differentiation (like rhabdomyosarcomas elsewhere)
IHC: (+) desmin, myogenin, MyoD1

Perivascular Epithelioid Cell Tumor (PEComa)

Mesenchymal tumor containing epithelioid cells with clear to eosinophilic, granular cytoplasm demonstrating
melanocytic and smooth muscle differentiation, thought to be derived from so-called “Perivascular Epithelioid Cells.”
Mixture of spindled and epithelioid cells, many with granular cytoplasm.
IHC: (+) HMB45, Melan-A, and Cathepsin K; Variable smooth muscle markers
Some have TFE3 fusions→ clear nested epithelioid morphology
Features to evaluate malignancy: 1)≥5cm, 2)High-grad atypia, 3)>1 mitoses/50HPF, 4)Necrosis, 5)LVI
<3→ Benign/Uncertain malignant potential
≥3→Malignant

Inflammatory Myofibroblastic Tumor (IMT)

Spindled to polygonal cells growing in fascicles. Often have myxoid stroma.
IHC: ALK1 positive; variable smooth muscle markers
ALK molecular rearrangements.
Features that predict aggressive behavior: Size >7cm, Necrosis, Moderate to severe cytologic atypia, Mitoses, LVI.

NTRK-Rearranged Cervical Spindle Cell Neoplasm

Spindled cells with variable architecture, brisk mitotic activity, and often prominent lymphocytic infiltrate.
IHC: (+)CD34, S100

Tumors with a Glandular Component

Carcinosarcoma
Biphasic tumor with malignant carcinomatous and sarcomatous elements.
Usually old women with a mass prolapsing out of the cervix
Carcinoma: Often serous, sometimes endometrioid
Sarcoma: Often high-grade non-specific sarcoma, but can make heterologous elements (osteosarcoma,
chondrosarcoma, rhabdosarcoma, etc…)
Often advanced stage and poor prognosis

Adenosarcoma
Mixed epithelial and mesenchymal tumor with a benign epithelial component and stroma is low-grade malignant.
(Think phyllodes tumor)
Papillary/polypoid projections of cellular stroma (often with condensation, “cuffing” around glands).
Can show heterologous elements and sarcomatous overgrowth.
MDM2/CDK4 and TERT gene amplifications.

Misc.
Adenomatoid tumor
Benign tumor of mesothelial origin.
Inter-anastomosing pseudo glands with variably sized tubules (sometimes with a signet ring appearance) with associated
smooth muscle hypertrophy (so can be mistaken for a mesenchymal tumor!)
IHC: Tumor cells express CK AE1/AE3 and Mesothelial markers (D2-40, WT-1, Calretinin)
Last updated: 8/10/2021 Prepared by Kurt Schaberg

Vascular Diseases
Vasculitis Inflammation of the blood vessel walls.
Can be infectious or non-infectious.
Clinical findings are diverse and depend on the organ(s) involved.
Generally have constitutional symptoms (fever, myalgias, malaise), +/- localized tissue damage due to
ischemia or bleeding (leading to single or multiorgan dysfunction). Elevated CRP and ESR.
Classified mostly based on this size of the vessel usually involved and the organs involved.
Many systemic rheumatologic diseases (e.g., Rheumatoid arthritis, sarcoidosis, and Systemic Lupus
Erythematosus) can have associated vasculitis.

Main immunological mechanisms of Non-infectious vasculitis:

1) Immune Complex-associated Vasculitis—Antigen-antibody/complement complexes deposit in the
vessel wall→ recruit inflammatory cells. Seen with many systemic immunological conditions (e.g., SLE),
drug hypersensitivity, and viral infections.

2) Antineutrophil Cytoplasmic Antibodies (ANCA) —Antibodies react with neutrophil cytoplasmic

antigens (ANCAs)→ activate neutrophils → degranulate → damages vessels.
2 types of ANCA: MPO-ANCA (formerly p-ANCA) seen with microscopic polyangiitis and Churg-Strauss,
and PR3-ANCA (formerly c-ANCA) seen in Wegner’s.

3) Anti-endothelial Cell Antibodies — Antibodies to endothelial cells

Variable Vessels
Behςet’s disease
Cogan’s syndrome

Small Vessels
Immune complex
IgA vasculitis (Henoch-Schönlein purpura)
Medium Vessels Cryoglobulin vasculitis, SLE, Goodpasture disease
Immune complex ANCA
Large Vessels
Polyarteritis nodosa Microscopic polyangiitis
Granulomatous
Giant-cell arteritis Anti-endothelial cell Granulomatosis with polyangiitis (Wegner’s)
Takayasu arteritis Kawasaki disease Eosinophilic granulomatosis with polyangiitis (Churg-Strauss)

Capillaries only
Anti-endothelial cell
Anti-GBM disease Based on the Chapel Hill Consensus Conference of 2012
 Large Vessel Vasculitis
Involves large vessels (not inside of organs) with some medium-sized vessels
Histologically see lymphohistiocytic inflammation of vessel wall with frequent granulomas/giant cells.
Fragmentation of internal elastic lamina (IEL; best seen on EVG stain)
Patchy→ so get lots of levels and an EVG in biopsies. Nodular thickening of intima with medial scarring.

Takayasu Arteritis
Predominantly impacts aorta (particularly the arch)
and its major branches
Onset usually before age 50
Transmural fibrous thickening of aorta, with lumen
narrowing, particularly of branching vessels→ loss of
pulses in upper extremities.
Giant cell (Temporal) Arteritis
Usually impacts aorta and/or its major branches,
with a predilection for the branches of the carotid
and vertebral arteries, especially the temporal artery
Onset usually after age 50.
Most common vasculitis in elderly in US.
Often associated with polymyalgia rheumatica
Involvement of ophthalmic artery can cause
permanent blindness, so considered a medical Normal IEL
emergency requiring prompt Dx and treatment with
corticosteroids.
As these processes are histologically
indistinguishable, they are often identified clinically,
primarily by age. IEL fragmentation

Medium Vessel Vasculitis

Involves main visceral arteries and their branches.
Inflammatory aneurysms and stenoses are common.
Polyarteritis Nodosa (PAN)
Transmural necrotizing arteritis of medium or small arteries
(without glomerulonephritis or vasculitis of arterioles, capillaries, or
venules) with mixed inflammation, fibrinoid necrosis, and
thrombosis. Frequently involves renal artery and GI tract.
Often patchy/segmental.
Immune complex mediated.
~30% have chronic Hepatitis B
Kawasaki Disease (“Mucocutaneous lymph node syndrome”)
Arteritis impacts medium and small arteries.
Usually < 4 years old, presenting with oral, conjunctival and
palmoplantar erythema (“strawberry tongue”) with a desquamative
rash and cervical lymphadenopathy. Often post-infectious.
Predominantly coronary arteries involved→ aneurysms & MI.
Autoantibodies to endothelial/smooth muscle cells.
Treat with IVIG and aspirin.
 Small Vessel Vasculitis
Often neutrophil-predominant and leukocytoclastic→
fibrinoid necrosis, thrombosis, RBC extravasation.
ANCA-mediated
Microscopic Polyangiitis (MPA)
Necrotizing vasculitis of small/medium vessels.
Mixed inflammation with fibrinoid necrosis
Very commonly involves kidney and lung.
MPO-ANCA usually positive.

Granulomatosis with Polyangiitis (Wegner’s)

Necrotizing granulomatous inflammation.
Commonly impacts lung, nasal cavity, and kidney.
In lung/head see granulomas with geographic central
necrosis and associated vasculitis→ form ulcers and
nodules. In kidney can see crescentic glomerulonephritis.
PR3-ANCA positive.

Eosinophilic Granulomatosis with Polyangiitis

(Churg-Strauss)
Eosinophil-rich and necrotizing granulomatous
inflammation. Often impacts the lung. Associated with
asthma and eosinophilia. MPO-ANCA usually positive.

Immune complex-mediated
IgA Vasculitis (Henoch-Schönlein purpura)
Vasculitis with IgA1-dominiant immune deposits.
Often involves skin (palpable purpura), GI tract
(abdominal pain), kidney, and joints (arthritis).
Most common systemic vasculitis in kids. Usually self-
limited and post-infectious (often after URI).

Cryoglobulinemic Vasculitis
Serum cryoglobulins (Ig that precipitate out of solution at
< 37°C)→ vessel deposits→ vasculitis. Often involves
skin, kidney, and peripheral nerves. Highly associated
with Hep C and monoclonal gammopathy.

Hypocomplementemic Urticarial Vasculitis

(Anti-C1q)
Associated with anti-C1q antibodies. Immune complex→
activate complement cascade→ mast cell degranulation
and neutrophil activation→ urticaria and small vessel
vasculitis

Anti-Endothelial Cell Antibody-mediated

Anti-Glomerular Basement Membrane (GBM)
Disease (Goodpasture Syndrome)
Impacts capillaries in kidney, lung, or both. In lung→
hemorrhage. In kidney→ crescentic glomerulonephritis.
 Variable Vessel Vasculitis
Behςet’s Disease
Vasculitis involving arteries or veins of any size.
Recurrent oral and/or genital aphthous ulcers, accompanied by cutaneous, ocular, articular, GI, and/or
CNS lesions. Can get thrombosis or aneurysms.
Most common along “ancient silk road” (Middle East→ Asia)
Cogan’s Syndrome
Systemic vasculitis with predominantly ocular and inner ear findings. May also involve aorta & heart.

Infectious Vasculitis
Most often due direct extension of infected tissue. Can cause aneurysms→ “Mycotic” aneurysms
Examples where vasculitis is an important component of disease:
Syphilis→ luminal obstruction and perivascular infiltrate of lymphocytes and plasma cells.
Fungi→ Aspergillus and Mucor can cause disseminated infection with angioinvasion. Usually
immunocompromised patients. Causes obstruction→ tissue necrosis.
Other examples: Rocky mountain spotted fever, Q fever, Typhus, Meningococcus, Lyme disease

IgG4-related Aortitis/Periaortitis
Characteristic findings in adventitia: 1) Dense
lymphoplasmacytic infiltrate, 2) Storiform-type fibrosis,
3) Obliterative phlebitis.
Must see >50 IgG4-positive plasma cells in a single HPF.
Most often older men.

Coagulopathic Disorders Look for “bland” (non-inflamed) thrombi in vessels

Disseminated Intravascular Coagulation (DIC)—Consumptive

coagulopathy where systemic activation of the coagulation cascade leads
to thrombosis of small vessels throughout the body (and also bleeding).
Can occur in many settings (e.g., sepsis, trauma, etc…). See fibrin thrombi
in small vessels.
Thrombotic Thrombocytopenic Purpura (TTP)—thrombotic
microangiopathy with widespread platelet thrombi in small vessels→
hemolytic anemia, purpura, thrombocytopenia, renal dysfunction. Results
from ADAMTS13 deficiency. See platelet-rich occlusive thrombi.
Hemolytic Uremic Syndrome (HUS)—Similar to TTP (thrombotic
microangiopathy), but thrombi mostly limited to kidneys. Usually in Kids
after eating E. Coli O157:H7 (makes Shiga-like toxin toxic to endothelial
cells), which also causes bloody diarrhea.
Heparin Induced Thrombocytopenia (HIT)—antibodies recognize heparin
+ platelet factor 4 complexes→ activate platelets→ thrombocytopenia and
thrombus formation. Usually thrombi are in large vessels (e.g., DVT→ PE).
 Vascular Deposition Disorders H&E Congo
Red
Amyloidosis
Deposits of abnormally folded protein (rich in β-
sheets) in vessels and tissues→ obstructs flow and
makes rigid (impaired vasoreactivity) → ischemic
injury; Also make vessel brittle→ hemorrhage.
Extracellular eosinophilic amorphous material (H&E)
Congo Red Stain → “Apple green” birefringence
Trichrome → greyish (vs Fibrosis→ bright blue)
Can subtype (see below) to determine etiology using
IF, Mass spectrometry, immunoblotting, IHC, etc…
Category Associated Disease Amyloid Protein Precursor Protein
Systemic Amyloidosis
Plasma cell dyscrasia (1°) Multiple myeloma AL Immunoglobulin light
chain (usually λ)
Reactive systemic Chronic inflammatory conditions AA SAA
amyloidosis (2°)
Hemodialysis-associated Chronic Renal Failure Aβ2m Β2-microglobluin
Localized Amyloidosis
Senile Cerebral Alzheimer disease Ab APP
Endocrine Type 2 Diabetes AIAPP Islet amyloid peptide
Medullary thyroid CA A Cal Calcitonin
Isolated atrial AANF ANP
Hereditary
Familial Mediterranean AA SAA
Fever
Familial amyloidotic ATTR Transthyretin
neuropathy
Systemic Senile ATTR Transthyretin
Modified from: Robbins and Cotran’s Pathologic Basis of Disease,

Vascular Calcification (Mönckeberg’s Arteriosclerosis)

Calcification of arterial media layer.
Common and often incidental in older patients.
Associated with age, diabetes, renal failure, and
hyperparathyroidism.

Note: Calcification of the intima (and subsequently the

media) is very common in Atherosclerosis (discussed
separately)
 Other Deposition Disorders
Light-Chain Deposition Disease—Immunoglobulin light chains deposit in tissue in non-amyloid
form. Seen with immunoglobulin-producing neoplasms. Looks similar to amyloid on H&E, but not
Congo red positive with Apple-green birefringence. Often due to κ light chains.

Calciphylaxis—progressive skin necrosis due to calcification of small and medium-sized vessels.

Usually a result of hyperparathyroidism seen with chronic renal failure. Also see thrombi, soft tissue
calcifications, panniculitis, necrosis, and ulceration.

Oxalosis– Deposition of calcium oxalate crystals in vessels and tissues→ occlude lumen→
ischemia. Can be 1° (due to enzyme deficiency) or 2° (due to ingestion of oxalates or ethylene
glycol—antifreeze!). Birefringent crystals associated with foreign body giant cell reaction.

Common Aging-associated Disorders

Atherosclerosis
Development of atheromatous plaques in arteries.
Often most noteworthy in coronary arteries→ Myocardial
infarction or cerebral arteries→ Stroke.
Can also cause peripheral vascular disease.
Endothelial injury/inflammation → accumulation of lipoproteins
→ ingested by macrophages → foamy macrophages in intima
(“Xanthoma”) with a fibrous cap, calcifications, and smooth
muscle proliferation → gradually grows and narrows lumen →
can rupture → triggers thrombosis of rest of lumen → ischemia
→ infarction
Risk factors: obesity, diabetes, smoking, hypercholesterolemia,
men, hypertension, inflammation

Hypertensive Changes
Most commonly associated changes with “Benign” hypertension
(but also generally seen with aging!).
1) Intimal fibroplasia of small arteries (Arteriolosclerosis)
Deposition of collagenous extracellular matrix and vascular
smooth muscle cell growth between endothelium and IEL →
thickening of intima → narrowing of vessel lumen
2) Hyalinization of arterioles (Hyalinosis)
Amorphous eosinophilic material (PASd+, Congo red -) made up of
plasma proteins with matrix. Also associated with diabetes.
In “malignant” hypertension→ see hyperplastic arteriolosclerosis
→ small arteries have thickened “onion skin-like” intima
(concentric layers) with fibrinoid necrosis and thrombosis.
Intimal Proliferative Disorders
Expansion of intima by smooth muscle cells and myofibroblasts. This is a common consequence of
vascular injury and vascular activation (i.e., a common endpoint of many diseases).

Hypothenar Hammer Syndrome

Direct mechanical injury of superficial vessels
(classically of ulnar artery on hypothenar surface of
hand from overuse of a hammer)
→Lumina occlusion/thrombosis with scarring and
ingrowth of capillaries into the media
→ Present with signs of vascular insufficiency (e.g.,
cold pale or cyanotic hand)
PMID: 23887165

Moyamoya Disease
Most common in Japan. Idiopathic. Multiple spontaneous occlusions of cerebral arteries.
Secondary development of adjacent net-like systems of collaterals→ Looks like a “puff of smoke” on
angiography → can rupture → stroke

Arterial Dissections
Disruption of vessel lumen→ blood can enter “false lumen” and dissect between layers or rupture.
Frequently caused by trauma, but can be sporadic.
Common sites:
Cervical (carotid/vertebral arteries): Often younger adults.
Coronary arteries
Aorta: Often older males with history of hypertension. Also False
associated with Marfan Syndrome and bicuspid aortic valve. lumen
Stanford Type A: involves ascending aorta (more common).
Stanford Type B: only descending aorta.
With sporadic cases, microscopically often see “Cystic
Medial Degeneration” with 1)Marked loss of elastic
lamellae (best seen with elastic stain) and 2)Deposition of
proteoglycans (best seen with colloidal iron stain)

Proteoglycan accumulation

Normal elastic layers

Loss of
elastic layers

EVG stain Colloidal Iron

 Miscellaneous Disorders
Fibromuscular Dysplasia
Replacement of normal component (usually smooth
muscle) by loose fibrous tissue → causes narrowing
and weakening/aneurysm formation (like beads on a
string).
Often involves large to medium-sized blood vessels,
especially renal arteries (causing hypertension due to
renin/angiotensin system). Often middle-aged
women.

Thromboangiitis Obliterans aka “Buerger disease”

Almost exclusively in middle-aged males who are heavy smokers.
(Thought to be a pathologic response to smoking)
Acute thrombosis of peripheral vessels→ invokes inflammatory response (not a true vasculitis, IEL intact)

Angiodysplasia of the Gastrointestinal Tract

Arteriovenous malformation, often in the cecum of elderly patients.
Causes GI bleed. Thought to be degenerative.
Dilated capillaries and veins in submucosa/mucosa.
Sometimes called “vascular ectasia.”

Cerebral Aneurysms aka “Berry Aneurysm”

Saccular aneurysm from localized structural degeneration
(loss of IEL and muscle layers)
Typically occur in circle of Willis
Relatively common (~5% of population)
Associated with connective tissue disorders, polycystic
kidney disease, hypertension, etc…
→ rupture→ subarachnoid hemorrhage
PMID: 30760624

Aortic Aneurysms
Abdominal Aortic Aneurysm (AAA): Associated with atherosclerosis. Most common in older, male
smokers (screen this population with ultrasound). Often just above bifurcation with plaque, thinned
media, and bland, laminated mural thrombus. If rupture→ massive fatal hemorrhage (risk is
proportional to size).

Thoracic Aortic Aneurysm: Usually associated with hypertension (and sometimes Marfan syndrome).
As dilates→ encroaches on nearby structures (harder to swallow/breathe) and leads to aortic valve
insufficiency. Can rupture→ massive hemorrhage
 Idiopathic Myointimal Hyperplasia of Mesenteric Veins
Rare.
Usually young to middle-aged men with GI pain
and/or bleeding. Most common in left colon.
Can clinically look like IBD.

On resection: mural mesenteric veins have

concentric proliferation of smooth muscle cells in
the intima and media. (Arteries normal)

On biopsy: Arteriolized capillaries, subendothelial

fibrin deposits, fibrin thrombi, and perivascular
hyalinization. Reactive epithelium (mucin-depleted).
+/- usual ischemic changes.

Enterocolic phlebitis
Localized lymphocytic perivenular circumferential cuff of
inflammation → venous engorgement, hemorrhage, and necrosis.
Usually right-sided in middle-aged or elderly.
Can be necrotizing and/or granulomatous.
Last updated: 7/23/2020 Prepared by Kurt Schaberg

Lesions of the Vulva

Non-Neoplastic Lesions
Lichen Sclerosus (formerly lichen sclerosus et atrophicus)
Most common in postmenopausal women. 4
Autoimmune disease. 4
Clinically appears as white to red plaques with 1
wrinkling and hypopigmentation resembling 1
“tissue paper.”
Causes pruritis and pain.
Sclerosis of papillary dermis and atrophy of
overlying epithelium.
3
1) Hyalinization and edema in papillary dermis
(“homogenization”)
2) Some degree of vacuolar degeneration of
basal keratinocytes
3) Band-like lymphocytic infiltrate beneath 3
2
homogenized collagen.
4) Epidermal atrophy
Increases risk of differentiated VIN.

Lichen Simplex Chronicus

Non-specific pattern in response to chronic rubbing/scratching.
Can be seen in association with other disorder (e.g., Candida
infection, contact dermatitis) or due to clothing or other
irritation.
Clinically looks thickened, leathery, scaled (“Lichenification”)
Marked hyperkeratosis (sometimes parakeratosis)
Hypergranulosis
Irregular epidermal hyperplasia
Papillary dermis is thickened with vertical dense collagen
between papillae
Lots of spongiosis? → consider contact dermatitis
Neutrophils in stratum corneum? → consider fungal → PAS/GMS

Bartholin’s Cyst Bartholin Glands

(can be seen in wall of Bartholin cyst)
Vulvar cyst due to Bartholin gland duct outlet
obstruction with subsequent retention of mucinous
secretions (Duct→ Cyst).
Located in posterior vestibule.
Unilocular with smooth inner lining of nonkeratinizing
squamous, transitional, or mucinous epithelium.
 Tumors in the Epithelium
Seborrheic Keratosis
Benign. Clinically, “Stuck-on” look

Varying degrees of: Acanthosis, hyperkeratosis,

interlacing pigmented epidermal strands,
papillomatosis, and horn cysts

Hidradenoma Papilliferum
Benign. Often presents as an
asymptomatic nodule.
Virtually identical to intraductal
papilloma of the breast
Well-circumscribed subepithelial nodule
Papillary proliferation with tubular glands
Apocrine differentiation with apical snouts
Two cell layers (inner epithelial and outer
myoepithelial) can be seen on IHC.

Squamous Intraepithelial Lesion (SIL)

Intraepithelial (in situ, non-invasive), squamous dysplasia due to HPV infection.
Clinically, can be flat or plaque-like, white to reddish-brown in color, and asymptomatic or pruritic
Low-grade Squamous Intraepithelial Lesion (LSIL)
Vulvar Intraepithelial Neoplasia grade 1 (VIN1)
Can be due to High or Low-risk HPV. Most common during
reproductive age. Low risk of progression to cancer.
Proliferation of hyperchromatic basal-like cells that extends no
more than 1/3 of the way up the epithelium
Cells differentiate (gain cytoplasm) in upper epithelium
Mitoses confined to lower zone. Epithelium often thickened.
Many nuclei are hyperchromatic with irregular nuclear contours
(at all levels)

Koilocytes = large superficial cells

with perinuclear halos and large,
irregular, “Rasinoid” nuclei.
Sometimes binucleated.

Often spontaneously regresses, so

just observed clinically with repeat
cytology

Condyloma acuminatum→ grossly evident variant of LSIL. Often composed of papillary fronds.
 Squamous Intraepithelial Lesion (SIL) (Continued…)
High-grade Squamous Intraepithelial Lesion (HSIL)
Associated with High-risk HPV (usually type 16). Higher risk
of progression to invasive carcinoma if left untreated
compared to LSIL, but not super high absolute risk.
Proliferation of hyperchromatic basal-like cells that extend
2/3 of the way up (VIN2) or full-thickness (VIN3/CIS) of the
epithelium
Cells have enlarged, hyperchromatic nuclei with irregular
nuclear contours and increased N:C ratios.
Little to no superficial maturation.
Mitoses common at all levels, including atypical mitoses
Nucleoli are unusual→ raise the possibility of inadequately
sampled invasive carcinoma (p16+) or metaplasia (p16-)

Can colonize skin appendages→ mimicking invasion!

Treatment includes: excision, laser ablation, topical

chemotherapy
When to use P16 Immunohistochemistry
Used as surrogate marker of High-risk HPV infection
• When the morphologic DDX is between HSIL (P16 +) and a mimic (P16 -)
• When you are considering a Dx of VIN2, which should be P16+ (vs. LSIL,
which should be P16 -)
• When there is disagreement between pathologists
• When there is a high-risk for missed HSIL disease (e.g., HPV +)

P16 Positive P16 Negative

Strong, diffuse, nuclear and cytoplasmic, Weak/Patchy
block staining along the basal layer going i.e., Anything but “Block” positive
at least 1/3 of the way up
When P16 Immunohistochemistry will NOT help
• When the biopsy is unequivocally LSIL, HSIL, or Negative morphologically
• When the DDX is between LSIL and Negative, as both processes are P16
negative.
 Differentiated-type Vulvar Intraepithelial Neoplasia
HPV-negative squamous dysplasia.
Predominantly in elderly women, associated with
lichen planus and lichen sclerosus.
Basal cell atypia with nuclear hyperchromasia.
Anastomosing of rete ridges.
Atypical basal mitoses. Prominent nucleoli.
Superficial terminal differentiation
(cornification) with hyperkeratosis and
dyskeratosis
IHC: p16 negative (non-block positive), p53
mutant with strong staining of all basal cells (see
example), Ki67 profoundly increased.
Higher risk/quicker progression to invasive SCC
than normal VIN3, so treat with excision.
p53 IHC→

(Extramammary) Paget Disease

Intraepithelial proliferation of apocrine-like cells.
Often old Caucasian women. Often red, pruritic lesion.
Large, round “Paget” cells with prominent pale
cytoplasm and nucleoli spreading throughout
epithelium. Can be single cells or in groups/glands.
Can extend down adnexal structures.
Important to rule out cutaneous pagetoid spread of
urothelial or GI cancer with IHC (see below)

Treatment: Resection, but high rates of recurrence.

Can progress to invasive adenocarcinoma.

CK7 CK20 GCDFP-15 CDX2 CEA S100, MelanA, UPK III HER2 GATA-3
etc…
Primary
Paget Disease + - + - + - - + +
Urothelial
carcinoma + + - - - - + - +
Anorectal
carcinoma +/- + - + + - - - -
Melanoma - - - - - + - - -
Squamous Cell Carcinoma
An invasive epithelial tumor composed of squamous cells with varying degrees of differentiation.
Derived from HSIL (HPV-related) or Differentiated VIN (not HPV-related)
Most common vulvar malignancy. Most common in elderly.
Most important factor determining outcome→ Lymph node status
Most important factor determining Lymph node metastases→ depth of invasion
Femoral and inguinal lymph nodes are the sites of regional spread
Sheet-like growth with infiltrating bands and single cells
Often desmoplastic/inflammatory stroma
Two main morphologic types:
Keratinizing Basaloid
Squamous Squamous
Carcinoma Carcinoma
High-risk HPV No Yes (Type 16>18)
association

Associated Differentiated-type VIN Classic VIN

precursor lesion
Basaloid SCC Keratinizing SCC
Association with Common. Often Lichen Rare
inflammatory sclerosus
condition

Morphology Keratinizing Warty, Basaloid

Age Older females Younger females

Distribution Usually unifocal Often multifocal

Verrucous Carcinoma: Highly-differentiated,
Prevalence More common Less common exophytic SCC variant with prominent acanthosis,
(approximately 80%) (approximately 20%) minimal nuclear atypia, superficial cells with
IHC p53: Some cases positive p53: Negative abundant eosinophilic cytoplasm, and broad
p16: Negative p16: Positive “pushing” invasion (non-infiltrative) with an
associated inflammatory infiltrate. Lymph node
Modified from: CAP Cancer Protocol Template: Vulva. 2020. metastases are very rare.

Other Tumors
Melanocytic nevi—Like nevi elsewhere on the skin, but remember the vulva is a “special site.” As
such, there can be concerning (but benign) changes including Pagetoid spread, moderate cytologic
atypia, an adnexal spread. There should be dermal maturation and no dermal mitoses.
Melanoma—Malignant. Variable appearances (epithelioid to spindled). Large nuclei, prominent
nucleoli. Absence of maturation. Lots of mitoses. Extensive pagetoid spread.
Basal Cell Carcinoma—Like elsewhere on the skin. Basaloid cells with peripheral palisading.
Bartholin Gland Carcinomas—can be SCC, adenocarcinomas, transitional cell, etc…
Mammary-type Adenocarcinoma—like breast cancers in the breast, thought to arise from anogenital
mammary-like glands. Notably, you can get phyllodes tumors too!
Adenocarcinoma of Skene glands—resembles prostate cancer. Stains with PSA
 Unique Vulvar Mesenchymal Lesions
Fibroepithelial Stromal Polyp
Benign.
Polypoid growth with variably cellular central
fibrovascular core covered in squamous epithelium.
Stroma contains predominantly bland spindled cells. Can
see multinucleated stroma cells with degenerative-type
atypia including significant pleomorphism.
Most common in reproductive age women.
Can grow during pregnancy.

Massive Vulvar Edema

Also called “Vulvar hypertrophy with lymphedema”
(or other, similar, names)
Reactive (non-neoplastic), likely due to lymphatic
obstruction.
Associated with obesity and immobilization.
May present with generalized vulvar enlargement,
papillomatous plaques, polyps, or pedunculated
masses.

Dermal edema with uniformly distributed cells.

Dilated lymphatics (arrows).
Perivascular inflammation.

Aggressive Angiomyxoma
Benign (despite name!), but with a tendency to
recur after incomplete recurrence.
Often presents as a “cyst” in reproductive age
Large (>5 cm), poorly-circumscribed, infiltrative.
Gelatinous consistency.
Low-grade, hypocellular. Composed of small,
bland spindled cells with scant cytoplasm.
Numerous blood vessels of varying sizes,
including thin-walled capillary-like and thick-
walled arteries with radiating perivascular
smooth muscle.
Invades fat and muscle. Extravasated RBCs.
No mitotic activity of atypia.
IHC: (+)ER, PR, desmin. (+/-)CD34
Molecular: HMGA2 rearrangements
Treatment: Complete surgical resection. Most
people treated with first surgery.
 Superficial Angiomyxoma
Benign with localized recurrences.
Small (<5 cm), exophytic polypoid mass centered in skin
and subcutaneous tissue (“Superficial”!!). Multilobulated.
Well-dermarcated, but unencapsulated.
Hypocellular myxoid nodules in dermis.
Bland stellate and spindled cells and inflammatory cells
(classically neutrophils) and numerous delicate vessels.
Can envelope skin adnexal structures/epithelium
Cellular Angiofibroma
Benign. Usually painless superficial mass or polyp.
Small (<5 cm). Rare.
Circumscribed, but unencapsulated. Often traps fat at edges.
Composed of uniform bland spindled cells in fibrous stroma.
Small to medium-sized blood vessels with thick hyalinized
walls.
Sort of resembles a spindle-cell lipoma, but with wispy
collagen.

Superficial Myofibroblastoma
Benign.
Discrete, unencapsulated. Usually small (< 5 cm)
Oval to spindled cells with wavy nuclei and scant
cytoplasm
Fine collagenous stroma. Varied architecture.
Thin-walled vessels, which might be dilated and
“Stag-horn”
IHC: (+) Desmin, ER/PR; (+/-) CD34

Angiomyofibroblastoma
Benign. Non-recurring.
Small (<5 cm), circumscribed.
Alternating hypocellular and
hypercellular areas
Spindle and plump epithelioid or
plasmacytoid cells

IHC: (+) Desmin, ER/PR; (-) CD34