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Uncertain differentiation

Clear cell sarcoma


Editorial Board Member: Jose G. Mantilla, M.D.
Deputy Editor-in-Chief: Borislav A. Alexiev, M.D.
Kemal Kösemehmetoğlu, M.D.

Topic Completed: 30 July 2021

Minor changes: 30 July 2021

Copyright: 2002-2021, PathologyOutlines.com, Inc.

PubMed Search: Clear cell sarcoma[title] soft tissue[title]

Kemal Kösemehmetoğlu, M.D.
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Table of Contents
Definition / general | Essential features | Terminology | ICD coding | Epidemiology | Sites | Pathophysiology | Etiology | Clinical features | Diagnosis | Radiology description | Radiology images | Prognostic factors | Case reports | Treatment | Clinical images | Gross description | Gross images | Frozen section description | Microscopic (histologic) description | Microscopic (histologic) images | Cytology description | Cytology images | Positive stains | Negative stains | Electron microscopy description | Molecular / cytogenetics description | Molecular / cytogenetics images | Videos | Sample pathology report | Differential diagnosis | Additional references | Board review style question #1 | Board review style answer #1 | Board review style question #2 | Board review style answer #2
Cite this page: Kösemehmetoğlu K. Clear cell sarcoma. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/softtissueclearcellsarcoma.html. Accessed November 27th, 2021.
Definition / general
  • Clear cell sarcoma (CCS) is a malignant soft tissue sarcoma composed of monotonous epithelioid and spindle cells with clear to eosinophilic cytoplasm characterized by melanocytic differentiation and EWSR1-ATF1 / CREB1 rearrangement
Essential features
  • Young adult, M:F = 1, distal extremity, slow growing
  • Not related to epidermis (hence, tendon and aponeuroses)
  • Do not confuse with clear cell sarcoma of kidney
  • Sheets and nests of monotonous epithelioid spindle cells with clear to eosinophilic cytoplasm separated by a delicate framework of fibrocollageneous stroma
  • Scattered Touton type or wreath-like multinucleated giant cells are relatively common
  • S100 / SOX10+, Melan A+, HMB45+
  • EWSR1-ATF1 or EWSR1-CREB1
Terminology
  • Melanoma of soft parts (not recommended)
  • Clear cell sarcoma of tendon and aponeuroses
  • Clear cell sarcoma of soft parts
ICD coding
  • ICD-O: 9044/3 - clear cell sarcoma, NOS (except of kidney M-8964/3)
  • ICD-10: C49.9 - malignant neoplasm of connective and soft tissue, unspecified
  • ICD-11: 2B5K & XH77N6 - unspecified malignant soft tissue tumors or sarcomas of bone or articular cartilage of other or unspecified sites & clear cell sarcoma of soft tissue
Epidemiology
  • < 1% of all soft tissue tumors
  • Young adults (third decade)
  • No gender predilection
Sites
Pathophysiology
  • Microphthalmia associated transcription factor (MITF) seems to be critical oncogenic target of EWSR1-ATF1 in CCS leading to melanocytic phenotype but not in angiomatoid fibrous histiocytoma with the same EWSR1-ATF1 rearrangement (Cancer Cell 2006;9:473, Am J Surg Pathol 2012;36:e1)
  • Regarding gene expression profile, CCSs cluster with melanomas, not soft tissue sarcomas (J Clin Oncol 2003;21:1775)
  • Classified as tumor of uncertain differentiation in WHO 2020
Etiology
  • Unknown
Clinical features
  • Not uncommon to get a long history (prebiopsy duration)
  • Pain and mass are common presenting symptoms
Diagnosis
  • Magnetic resonance imaging (MRI)
  • Biopsy and molecular pathology
Radiology description
  • Well defined, homogeneous and benign looking mass
  • Magnetic resonance imaging
    • Homogeneous iso hyperintense on T1 and heterogeneous on T2 with variable contrast enhancement
  • Reference: Skeletal Radiol 2000;29:187
Radiology images

Contributed by Ustun Aydingoz, M.D.
Magnetic resonance imaging

Magnetic resonance imaging



Images hosted on other servers:
     

MRI of CCS

Prognostic factors
Case reports
Treatment
  • Complete surgical excision with or without radiotherapy
  • Chemotherapy / immunotherapy has no effect
Clinical images

Images hosted on other servers:

Clear cell sarcoma of large toe

Gross description
Gross images

Contributed by Kemal Kösemehmetoğlu, M.D. and Mark R. Wick, M.D.
Magnetic resonance imaging    

Clear cell sarcoma of soft tissue

Frozen section description
  • Sentinel lymph node can be encountered
  • Melanoma is the main differential diagnosis and may be impossible to separate in this setting
Microscopic (histologic) description
  • Essential: nests of epithelioid spindle cells with clear eosinophilic cytoplasm and prominent nucleoli plus melanocytic differentiation
  • Morphological patterns (Am J Surg Pathol 2008;32:452, J Clin Pathol 2010;63:416):
    • Vaguely organoid (neuroendocrine-like) pattern: nests and short fascicles of epithelioid or spindle cells, surrounded by a delicate framework of fibrocollagenous tissue contiguous with the adjacent tendons and aponeurosis
    • Diffuse pattern: solid sheets of epithelioid to spindle cells
    • Pseudoalveolar pattern: reminiscent of alveolar soft part sarcoma
    • Myxoid / microcystic pattern
    • Inflammatory pattern: reminiscent of seminoma
  • Cells:
    • Epithelioid to spindled
    • Monotonous round to oval nuclei with prominent nucleoli
    • Lightly eosinophilic to amphophilic cytoplasm
    • Clear cells typically comprise only a subset of the tumor
    • Scattered rhabdoid and pleomorphic cells
    • Scattered Touton type or wreath-like multinucleated giant cells are relatively common
    • Rare mitosis
  • Necrosis usually focally in 33%
  • Melanin pigment in scattered cells in half of the cases
  • No involvement of epidermis or no epidermal melanocytic proliferation but longstanding lesions (especially at fingers) may enlarge and therefore tumors may ulcerate
Microscopic (histologic) images

Contributed by Kemal Kösemehmetoğlu, M.D.
CCS attached to aponeurosis

CCS attached to aponeurosis

Tumor adjacent to tendon and aponeurosis

Tumor adjacent to tendon and aponeurosis

Classical (organoid / neuroendocrine-like) morphology

Classical (organoid / neuroendocrine-like) morphology

Short fascicles of spindle cells

Short fascicles of spindle cells

Mixed spindle and epithelioid cells

Mixed spindle and epithelioid cells


Intermixed spindle and epithelioid cells

Intermixed spindle and epithelioid cells

Solid sheets of epithelioid cells

Solid sheets of epithelioid cells

High power appearance of classical CCS

Classical CCS

Rare pleomorphic cells

Rare pleomorphic cells

Pseudoalveolar pattern in CCS

Pseudoalveolar pattern


Melanin pigment in CCS

Melanin pigment

Myxoid / microcystic pattern  

Myxoid / microcystic pattern

Lymph node metastasis

Lymph node metastasis

Fontana stain

Fontana stain


S100

S100

SOX10

SOX10

HMB45

HMB45

MelanA

MelanA

Cytology description
  • Hypercellular smears composed of monomorphic epithelioid / polygonal cells, including singly scattered or loosely clustered spindle cells, with prominent nucleoli
  • Granular to vacuolated, well defined cytoplasm
  • Binucleation / multinucleation (50%), abrupt anisonucleosis, racquet shaped cells (20%)
  • Tigroid background (10%)
  • Focal intracytoplasmic pigment (10%)
  • If available, immunohistochemical stains and molecular testing are crucial in reinforcing a diagnosis (Cytopathology 2020;31:280)
Cytology images

Contributed by Bharat Rekhi, M.D.
Cytology of CCS - Giemsa

Giemsa

Pap

Positive stains
Electron microscopy description
  • Resembles synovial sarcoma given the presence of basement membrane material, a biphasic pattern of cells and the presence of pseudoglandular structures with filopodia
  • Presence of melanosomes and interdigitating cellular processes wrapping around cells and extracellular structures are similar to melanoma and nerve sheath tumors
  • May contain aggregates of glycogen and inclusions composed of multilayered membrane structures forming myelin-like figures
  • References: Am J Pathol 1984;114:264, Virchows Arch A Pathol Anat Histopathol 1983;401:109
Molecular / cytogenetics description
  • t(12;22)(q13;q12) for EWSR1-ATF1 [4 splice variants including the most common EWSR1(ex8)-ATF1(ex4)] in 90 - 95%
  • t(2;22)(q32.3;q12) for EWSR1(ex7)-CREB1(ex7) in 5 - 10% (Mod Pathol 2009;22:1201)
  • Aberrations in chr 2, 3, 7, 8, 12, 13, 14, 15, 17, 21 and 22
  • Rare BRAF V599E and NRAS codon 61 mutations (Dermatol Res Pract 2012;2012:984096)
Molecular / cytogenetics images

Contributed by Kemal Kösemehmetoğlu, M.D.
EWSR1 break apart FISH

EWSR1 break apart FISH



Images hosted on other servers:

PCR showing EWSR1-ATF1 fusion product (81 bp)

Sequence of PCR product showing EWSR1-ATF1

Videos

Woman in 20s with gluteal mass

Sample pathology report
  • Right toe, incisional biopsy:
    • Clear cell sarcoma of soft tissue (see comment)
    • Comment: Tumor was composed of nests of clear cells with prominent nucleoli and melanocytic differentiation. FISH break apart study revealed the presence of an EWSR1 rearrangement, which excluded the diagnosis of melanoma. These tumors are definitionally regarded as high grade - grade 3 sarcomas. Wide excision is recommended.
Differential diagnosis
Board review style question #1


An 18 year old woman presented with a 1 cm mass in the right great toe. Morphological features are shown above. Which one of the following immunohistochemical panels is the most helpful for reaching the correct diagnosis?

  1. EMA, SMA, INI1
  2. HMB45, MelanA, desmin
  3. PanCK, INI1, S100
  4. PanCK, synaptophysin, CD31
  5. SMA, desmin, SOX10
Board review style answer #1
C. PanCK, INI1, S100. If you order just HMB45, MelanA, and desmin and all of them turn out to be positive you may end up with the diagnosis of PEComa. PEComa is in the differential, even desmin is negative. So IHC panel should include an S100 or Sox10 and not necessarily HMB45 and MelanA at first. HMB45 and MelanA are better requested after S100/Sox10 positivity. panCK and INI1 are to exclude epithelioid sarcoma. INI1 could be replaced by HMB45 if requested.

Comment Here

Reference: Clear cell sarcoma
Board review style question #2


An 18 year old woman presented with a 1 cm toe mass. There was diffuse S100 expression plus SOX10, HMB45 and MelanA positivity. What is the next step?

  1. Diagnose as melanoma
  2. Order PAX8 and TFE3
  3. Order whole genome sequencing
  4. Perform an EWSR1 break apart FISH
  5. Request PCR for EWSR1-CREB1
Board review style answer #2
D. Perform an EWSR1 break apart FISH. The differential diagnosis is between melanoma and CCS and EWSR1 FISH is less time consuming and cheaper than NGS to reach the correct diagnosis.

Comment Here

Reference: Clear cell sarcoma
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