Actas Dermosifiliogr.

2019;110(1):4---11

REVIEW

Leiomyosarcoma and Pleomorphic Dermal Sarcoma:

Guidelines for Diagnosis and Treatment夽
B. Llombart,a,∗ C. Serra-Guillén,a C. Requena,a M. Alsina,b D. Morgado-Carrasco,b
I. Machado,c O. Sanmartína

a
Servicio de Dermatología, Instituto Valenciano de Oncología, Valencia, España
b
Servicio de Dermatología, Hospital Clínic de Barcelona, Universitat de Barcelona, Barcelona, España
c
Servicio de Anatomía Patológica, Instituto Valenciano de Oncología, Valencia, España

Received 11 February 2018; accepted 24 June 2018

KEYWORDS Abstract There are 3 types of leiomyosarcoma of the skin: dermal, subcutaneous, and
Sarcoma; metastatic cutaneous. Dermal leiomyosarcoma arises from smooth muscle fibers in arrector pili
Cutaneous; muscles, genital dartos muscles, and the nipple-areola complex. It is an intermediate-grade
Leiomyosarcoma; tumor associated with a tendency for local recurrence (24%) and low metastatic potential (4%).
Pleomorphic Subcutaneous leiomyosarcoma originates from smooth muscle in blood vessel walls and has
sarcoma; higher rates of local recurrence (37%) and metastasis (43%).
Atypical Plemorphic dermal sarcoma typically affects elderly patients and arises in sun-exposed areas
fibroxanthoma; (e.g., the scalp). Its histologic and immunohistochemical characteristics are similar to those of
Diagnosis; atypical fibroxanthoma, but it is more aggressive (metastasis rate of 1010%-20%). Histologically,
Treatment it can be distinguished from atypical fibroxanthoma by the observation of subcutaneous tissue
invasion, perineural invasion, and foci of necrosis.
© 2018 Elsevier España, S.L.U. and AEDV. Published by Elsevier España, S.L.U. All rights reserved.

PALABRAS CLAVE Leiomiosarcoma y sarcoma pleomórfico dérmico: directrices para el diagnóstico y

Sarcoma; tratamiento
Cutáneo;
Resumen El leiomiosarcoma de la piel se clasifica en tres grupos: dérmico, hipodérmico y
Leiomiosarcoma;
cutáneo metastásico. El dérmico se origina de las fibras musculares lisas del músculo erector del
Sarcoma pleomórfico;
pelo, dartos genital o de la areola mamaria. Se considera un tumor de malignidad intermedia,
Fibroxantoma
con tendencia a la recidiva local (24%) y un bajo riesgo de metástasis (4%). El leiomiosarcoma
atípico;
hipodérmico se origina de las paredes musculares de los vasos, y se caracteriza por presentar
una mayor tasa de recidiva local (37%) y metástasis (43%).

夽 Please cite this article as: Llombart B, Serra-Guillén C, Requena C, Alsina M, Morgado-Carrasco D, Machado I, et al. Leiomiosarcoma y

sarcoma pleomórfico dérmico: directrices para el diagnóstico y tratamiento. Actas Dermosifiliogr. 2019;110:4---11.
∗ Corresponding author.

E-mail address: [email protected] (B. Llombart).

1578-2190/© 2018 Elsevier España, S.L.U. and AEDV. Published by Elsevier España, S.L.U. All rights reserved.
Leiomyosarcoma and Pleomorphic Dermal Sarcoma 5

El sarcoma pelomórfico dérmico aparece habitualmente en pacientes ancianos y se localiza

Diagnóstico; característicamente en zonas de piel fotoexpuesta (cuero cabelludo). Comparte características
Tratamiento histológicas e inmunohistoquímicas con el fibroxantoma atípico, pero con un comportamiento
más agresivo (metástasis en el 10-20%). Los criterios histológicos que lo diferencian son la
infiltración del tejido celular subcutáneo, la infiltración perineural y la presencia de focos de
necrosis.
© 2018 Elsevier España, S.L.U. y AEDV. Publicado por Elsevier España, S.L.U. Todos los derechos
reservados.

Leiomyosarcoma

Leiomyosarcoma (LMS) is a tumor derived from smooth mus-

cle that arises in deep soft tissue, the uterus, and, more
rarely, the dermis. It accounts for approximately 5% to 10%
of all sarcomas, but just 2% to 3% of cutaneous sarcomas
(0.04% of all skin tumors).1,2 It is the third most common
cutaneous sarcoma, after dermatofibrosarcoma and Kaposi
sarcoma. LMSs located in the retroperitoneum and abdomi-
nal cavity form the most common subgroup of LMS and are
much more aggressive than other variants.
LMS of the skin has 11traditionally been classified into 3
major groups, each with different prognostic implications:
cutaneous (dermal) LMS, subcutaneous LMS, and metastatic Figure 1 Cutaneous leiomyosarcoma on the pubis.
LMS.3 The deeper the lesion, the worse the prognosis. Cuta-
neous LMS arises from the smooth muscle fibers of arrector It is more common in men (male to female ratio, 3:1) and
pili muscle, the genital dartos muscle, or the nipple-areola appears to be more common in whites.3 Most LMSs involving
complex, while subcutaneous LMS originates from smooth the skin develop de novo and are unrelated to a previ-
muscle in blood vessel walls.4 Both entities2 cause metas- ous piloleiomyoma-like lesion. A mutation in the fumarate
tases that can affect the skin. Most cutaneous metastases, hydratase gene was recently discovered in patients with
however, are from retroperitoneal LMS. hereditary leiomyomatosis and renal cell cancer syndrome.8
Cutaneous LMS is a tumor of intermediate malignancy LMS has also been described in areas previously treated with
that has a tendency to recur locally (24%) and low metastatic radiation therapy, and some patients have reported a history
potential (4%).5 In view12 of this, Kraft et al.6 proposed of trauma or scarring in the area. Most patients, however,
that cutaneous LMSs with minimal subcutaneous involve- have no known triggers.
ment should not be considered sarcomas and suggested Fifty percent of cutaneous LMSs are located on the exten-
instead naming them atypical intradermal smooth muscle sor surface of the lower limbs, and less frequently on the
neoplasms. This term, however, has not had much uptake. scalp and face,9 although there have been reports of tumors
Dermatofibrosarcoma protuberans, for instance, has a much involving the trunk, lip, genital region (scrotum, vulva, and
lower tendency to metastasize to the skin, yet is still con- penis), and buttocks.
sidered a sarcoma. Subcutaneous LMS is characterized by The clinical presentation of LMS is nonspecific. The most
higher rates of local recurrence (37%) and distant metastasis common presentation is a firm, solitary nodule with a
(43%). Finally, cutaneous metastases from LMS indicate pro- smooth, pinkish surface, or a more exophytic tumor that has
gression of a primary tumor, generally of visceral origin, and a reddish or brown color (Fig. 1). Clinically, subcutaneous
are associated with an approximate survival of 16 months lesions appear to be better circumscribed than their cuta-
from the time of detection.7 neous counterparts, and they are reminiscent of lipomas,
Before a definitive diagnosis of a primary LMS of the skin but with a more solid consistency. There have been reports
can be established, it is essential to rule out metastasis from of plaque-like LMS with multiple nodules that form clusters
an LMS in the deep tissues or organs, particularly if the tumor and are very indurated on palpation. Cutaneous lesions3
is subcutaneous. typically 13grow 14slowly and15 are larger than subcuta-
neous lesions, with a size of between 1 and 3.5 cm (range,
Clinical Characteristics 0.5-19 cm). They are frequently painful on palpation (63%).
Spontaneous pain is also reported but is less common (25%).9
LMS can occur at any age, but it mostly affects older Patients may experience pruritus, a burning sensation, and
adults, with a peak incidence between 50 and 70 years. paresthesia.3,9
6 B. Llombart et al.

Figure 2 Characteristic histologic features of leiomyosarcoma. A, Panoramic view of a poorly circumscribed dermal tumor invading
the subcutaneous tissue. B, Higher-magnification view showing interlacing fascicles of nonuniformly arranged spindle cells in the
dermis reminiscent of muscle fibers. C, Invasion of subcutaneous tissue. D, Fascicles of pleomorphic spindle cells intersecting each
other at a right angle; mitotic figures.

Histopathologic Characteristics LMSs show positive staining for vimentin, desmin, h-

caldesmon, muscle specific actin, ␣-smooth muscle actin,
The biopsy specimen must include subcutaneous tissue. and smooth muscle myosin.4 More poorly differentiated and
Histologic examination of cutaneous LMS generally subcutaneous lesions often test negative for desmin.18,19 At
reveals a poorly circumscribed lesion occupying the full least 2 smooth muscle markers must be included in the panel
thickness of the dermis and occasionally extending into the to confirm a diagnosis of LMS. Protein S-100 is sometimes
subcutaneous tissue (Fig. 2A and B). Subcutaneous LMSs are positive, as are cytokeratins. Other immunohistochemical
better circumscribed; they compress the adjacent tissue and stains used to rule out other spindle cell tumors (spindle cell
are located entirely in the subcutaneous layer, with spar- carcinoma, desmoplastic melanoma, dermatofibrosarcoma
ing of the dermis. In both cases, low magnification shows protuberans, malignant peripheral nerve sheath tumors,
interlacing fascicles of smooth muscle fibers. The cells are and vascular tumors) are EMA, CD34, CD117, CEA, HMB45,
spindle-shaped and have elongated nuclei with blunt ends, Mart-1, Melan A, and CK7. These are all negative in
an unremarkable nucleolus, and eosinophilic fibrillar cyto- LMS.
plasm (Fig. 2C and D). Several cells have a clear, perinuclear
halo characteristically seen in muscle cells.4,10,11 Staging
Two histologic growth patterns have been described:
nodular and diffuse.12 The nodular pattern is characterized There is no specific TNM staging system for LMS and tumors
by greater cellularity, atypia, and a higher number of mitotic are therefore staged using the classification system for soft
figures, while the diffuse pattern is characterized by less tissue sarcomas in the American Joint Committee on Cancer
cellularity and pleomorphism and fewer mitotic figures.13 Cancer Staging Manual.
Cutaneous LMS with a diffuse growth pattern has little Prognosis in LMS varies depending on whether the lesion
cellular atypia and can therefore be difficult to distinguish is cutaneous or subcutaneous. Cutaneous LMS has a ten-
from leiomyoma. Although a more invasive pattern and dency to recur locally (24%), but rarely metastasizes (4%),
greater cellularity point to the malignant variant, observa- while subcutaneous LMS is more like to recur locally (37%)
tion of mitosis is key for confirmation. and metastasize (43%). The respective staging and follow-up
Several histopathologic variants of LMS have been approaches are therefore different.
described, including epithelioid LMS,14 LMS with multinucle- Cutaneous LMS
ated giant cells,15 granular cell LMS,16 and sclerotic LMS.17 Magnetic resonance imaging (MRI) of the area surrounding
Considerable desmoplasia has also been described and can a cutaneous LMS is recommended prior to surgery, especially
complicate diagnosis. There have also been reports of myx- 16for large5, indurated5, 17or difficult-to-access 18lesions
oid and pleomorphic variants of subcutaneous LMS.4 (19eg, on the head). Ultrasound may well be a useful aid for
When there is histologic evidence of LMS, an immunohis- dermatologists and could even replace MRI (Fig. 3), but no
tochemical study must be performed to rule out spindle cell studies have yet compared the 2 options. A chest radiograph
tumors with similar histologic features. Well-differentiated should be also performed before surgery.
Leiomyosarcoma and Pleomorphic Dermal Sarcoma 7

Figure 3 Algorithm for managing cutaneous leiomyosarcoma. CT indicates computed tomography; MMS, Mohs micrographic
surgery; MRI, magnetic resonance imaging.

Subcutaneous LMS MMS would therefore appear to be a good surgical option for
An MRI of the area and computed tomography (CT) scan of superficial cutaneous LMS.
the chest and abdomen should always be performed before The role of radiation therapy in cutaneous LMS is still a
operating on a subcutaneous LMS to rule out metastasis from topic of debate. Adjuvant radiation therapy may be of par-
a tumor in the deeper tissues20 (Fig. 3). ticular value in patients with positive or borderline surgical
margins or who are not candidates for a second operation;
this is particularly the case for patients with deep-seated or
high-grade tumors. Factors associated with a worse progno-
Treatment and Prognosis sis are a subcutaneous or acral location, a size larger than
5 cm, aneuploidy, and vascular invasion.13 Radiation therapy
Considering the low incidence of cutaneous LMS, patients can also be used for local palliative control in patients with
should always be referred for treatment at a hospital spe- metastasis.
cialized in sarcoma. Chemotherapy is essential in patients with metastatic
Complete surgical excision is the treatment of choice for disease. The most widely used agents are doxorubicin and
LMS. The best results are obtained with wide local excision ifosfamide, gemcitabine and taxotere, dacarbazine, and tra-
or Mohs micrographic surgery (MMS), which offers a more bectedin. Chemotherapy is not curative, but it can delay
precise analysis of margins. disease progression.26
The main surgical dilemma in LMS is margin width, as
there are no clear guidelines on recommended widths in the
literature. Wide local excision with margins of 3 20cm to Follow-up
5 cm used to be the recommended approach, but nowadays,
similar results are achieved using more conservative mar- There are no standardized follow-up guidelines for LMS, but
gins of21 between 1 22cm 23and 3 cm30,21---24 (Fig. 3). Deep a clinical check-up every 4 months is recommended for the
margins should include the fascia and, in the case of more first 2 years to aid the early detection of local recurren-
invasive tumors, the muscle. ces. After that, 6-monthly visits are recommended for the
There is very little experience with the use of MMS in following 3 years (up to year 5 after surgery) and then
cutaneous LMS. The literature contains reports on approxi- once a year up to year 20, as very late recurrences have
mately 50 cases, and the recurrence rates described range been described.3,11 Standardized guidelines on radiologic
between 0% and 13%.3,22,23,25 These rates are much lower studies for postoperative follow-up are also lacking for cuta-
than those observed for conventional surgery, which is asso- neous sarcoma (Fig. 3). Nevertheless, a simple annual chest
ciated with recurrence rates of between 9% and 40%.3,21---23 radiograph for the first 5 years after surgery and clinical
8 B. Llombart et al.

Clinical Presentation

PDS typically affects elderly patients and is located in areas

of sun-exposed skin, typically the head (Fig. 4) and in partic-
ular the scalp. As indicated by Tardío et al.,33 other tumors
must be ruled out and a diagnosis of PDS should be treated
with suspicion if the tumor does not involve sun-damaged
skin in an elderly patient. PDS manifests as an exophytic,
asymmetric tumor that is fast growing and often ulcerated
and hemorrhagic. Mean tumor size is 2.2 24cm to 2.5 cm,33,34
although sizes ranging from just a few millimeters to sev-
eral centimeters have been reported. Clinically, the tumor
is indistinguishable from atypical fibroxanthoma, but it has
Figure 4 Pleomorphic dermal sarcoma on the scalp of an a larger subclinical extension. It does7 not25 therefore typ-
elderly patient. Poorly circumscribed tumor in the form of an ically raise clinical suspicion and tends to be diagnosed as
indurated plaque. squamous cell carcinoma.

Histopathologic Characteristics and Diagnosis

As PDS is of unknown origin and histogenesis, the diagnosis

evaluation of the surgical bed and locoregional lymph nodes is one of exclusion.
would appear to be a good strategy.26 MRI can occasionally PDS is confined to the dermis; there is no connection to
be of value, particularly in the case of recurrent or subcu- the epidermis or Grenz zone (area of normal collagen in the
taneous lesions or complicated surgery. dermis that separates the epidermis and the tumor).33,34
The metastasis rates for cutaneous and subcutaneous The tumor is formed by 2 populations of cells present in
LMS are 4% (range, 3%-14%) and 43% (range, 21%-62%), different proportions: atypical spindle cells and pleomor-
respectively.3 These tumors primarily spread through the phic epithelioid cells. Images of mitosis and multinucleated
bloodstream and affect the lungs, skin, and less frequently, giant cells are common. Cells typically display a fascicular
the regional lymph nodes. The ideal staging test for patients pattern and less frequently a storiform one, although non-
with confirmed or suspected disseminated disease is a spiral specific patterns may be observed (Fig. 5). Some degree
CT scan of the chest and abdomen.26 of inflammatory infiltration is often seen, as is evidence
of hemorrhaging with hemosiderin deposits. These histo-
logic features are also seen in atypical fibroxanthoma and
therefore the 2 tumors are normally indistinguishable.29 The
Pleomorphic Dermal Sarcoma histologic criteria that define PDS and set it apart from
atypical fibroxanthoma are subcutaneous tissue invasion,
Introduction perineural or perivascular invasion, and foci of necrosis. Any
of these findings in a cutaneous tumor with histologic fea-
Pleomorphic undifferentiated sarcoma, formerly known as tures of atypical fibroxanthoma are sufficient to establish a
malignant fibrous histiocytoma, is a malignant soft-tissue diagnosis of PDS.29,31,33---35
tumor (sarcoma) that is typically highly pleomorphic and has According to the 2 largest series of PDS to date,33,34 15% to
no characteristic immunohistochemical features that point 16% of tumors had invaded the subcutaneous tissue, while
to a specific line of differentiation.27---32 61% to 75% had invaded the fascia or underlying muscle,
Pleomorphic undifferentiated sarcoma that originates in clearly reflecting the aggressive nature of this tumor. Many
the skin is known as pleomorphic dermal sarcoma (PDS). cases of metastatic atypical fibroxanthoma described in the
It has very similar histologic features to atypical fibrox- literature were probably actually PDS.36 Perineural invasion
anthoma, but has a worse prognosis.33,34 Because of the was observed in 28% of the tumors described by Miller et al.34
confusion generated by the different names classically given and in none of those described by Tardío et al.33 Vascu-
to these tumors and the update published by the World lar invasion and necrosis, in turn, were observed in 17%
Health Organization in 2013,31 there are very few large to 26% and 17% to 53% of PDSs, respectively.33,34 There are
series of PDS to add to the body of knowledge and from no specific immunohistochemical markers for PDS, although
which to draw conclusions on adequate management. positive results are observed for vimentin, CD10, CD99, and
actin. These, however, are all nonspecific markers and serve
only to guide diagnosis.37 It is important, however, and more
useful to request the inclusion of markers that are negative
Definition in PDS and positive in other entities contemplated in the dif-
ferential diagnosis. A cytokeratin panel should be ordered to
PDS is a cutaneous tumor of uncertain histogenesis. Its rule out poorly differentiated squamous cell carcinoma. This
clinical characteristics are largely nonspecific and it is histo- panel should include high-molecular-weight cytokeratins, as
logically and immunohistochemically very similar to atypical certain sarcomatoid or spindle cell squamous cell carcino-
fibroxanthoma, although its behavior is more aggressive.29 mas may test negative to cytokeratins with a low molecular
Leiomyosarcoma and Pleomorphic Dermal Sarcoma 9

Figure 5 Histologic findings in a pleomorphic sarcoma. A, Panoramic view of a tumor invading the dermis and subcutaneous layer.
B, Tumor formed by spindle cells arranged in a storiform pattern. C, Cells immersed in a myxoid stroma. D, Detail of several more
pleomoprhic cells with a wide cytoplasm.

weight. The melanocytic markers protein S100, HMB-45, and be performed to investigate bone involvement and MRI to
Melan-A should be ordered to rule out spindle cell or desmo- investigate deep soft tissue involvement.
plastic melanoma.29 It should be noted, however, that foci Staging is not normally necessary in PDS. Imaging stud-
of S100-positive dendritic cells can be observed in PDS. ies should be ordered, following evaluation of the patients’
The presence of multinucleated giant cells may also cause history, for cases consisting of large tumors, long-standing
focal positivity for Melan-A. When faced with a differen- tumors, or multiple recurrences. In the series described by
tial diagnosis featuring PDS and angiosarcoma, note that Tardió et al.,33 recurrence was more common among larger
CD31 positivity may be seen in some cases of PDS.33,34 In tumors and size should therefore be considered one of the
this case, the vascular stains, CD31, ERG, and CD34, will main risk factors for metastasis.
be positive in angiosarcoma and negative in PDS. CD34 also Similarly to with other sarcomas, radiation therapy
helps to distinguish between PDS and dermatofibrosarcoma should be reserved for inoperable cases of PDS or for9 pal-
protuberans.34 liative treatment.
Classic chemotherapy with adriamycin or ifosfamide is
used in patients with metastasis.34

Management
Prognosis
As PDS is a recently defined tumor, there are no standardized
guidelines for its management. Based on the 2 series published to date, 20% to 28% of PDS
Treatment is surgical 26and is normally curative. The cases recur and 10% to 20% metastasize, mainly to the skin,
main risk factor for recurrence is the presence of positive lungs, or lymph nodes.33,34
or borderline surgical margins,33,34 hence the general rec-
ommendation for wide excision with margins of at least
1 cm.38 Because PDS invades the subcutaneous tissue and Follow-up
even the fascia or muscle in up to 75% of cases, metic-
ulous surgery with negative deep margins is crucial. The Follow-up visits consisting of clinical examination of the skin
slow Mohs technique, which allows more rigorous analysis and lymph node stations should be scheduled every 3 months
of margins, is recommended for recurrent tumors, tumors for the first year and every 6 months for the next 4 years.
in difficult-to-access locations, and tumors suspected to Thereafter, depending on the case, patients could be sched-
have unpredictable subclinical extension. The benefits of uled for annual check-ups up to year 10.
this technique, however, have not yet been studied in this Recommended follow-up tests are blood tests and chest
setting. radiography for patients with an increased risk of distant
Preoperative imaging studies are not normally necessary metastasis due to tumor size, time since onset, or deep
in PDS. If deep invasion is suspected, a CT study should invasion.
10 B. Llombart et al.

Conflicts of Interest 17. Karroum JE, Zappi EG, Cockerell CJ. Sclerotic primary cuta-
neous leiomyosarcoma. Am J Dermatopathol. 1995;17: 292---6.
The authors declare that they have no conflicts of interest. 18. Oliver GF, Reiman HM, Gonchoroff NJ, Muller SA, Umbert IJ.
Cutaneous and subcutaneous leiomyosarcoma: a clinicopatho-
logical review of 14 cases with reference to antidesmin staining
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