A Call for Help

A Call for Help

Clear Cell Sarcoma of the Orbit A N N A S TA G N E R , M D E A S T E R N O P H T H A L M I C PAT H O L O G Y S O C I E T Y A N N U A L M E E T I N G SEPTEMBER 13-15, 2018 NO FINANCIAL DISCLOSURES Initial Presentation 29-year-old woman with left eyelid swelling

and occasional diplopia History At least several months of eyelid swelling and intermittent double vision At initial presentation MRI with gadolinium showed a cystic/solid orbital floor mass Initial biopsy: skeletal muscle and fibrosis

Initial Examination: 1 year PTD Visual acuity 20/20-1 OU Normal pupils with no RAPD 1-2 mm of left proptosis with upward displacement of the globe 1-2 mm left upper eyelid ptosis Anterior segment and DFE unremarkable Past Medical and Social History Patient originally from Haiti

History of travel to multiple developing countries Treated for infectious diseases encountered in her travels: malaria, giardia, cholera and amebiasis Mild asthma (on albuterol/fluticasone inhalers)

Hypothyroidism on levothyroxine Referral Interval growth over two subsequent MR scans spanning 6 months time (from 19 to 24 mm) Patient now 19 weeks pregnant 20/40 OS with severely limited up- and downgaze Left relative afferent pupillary defect Repeat orbitotomy was preformed due to

progressive optic neuropathy. H&E x 10 H&E x100 Pathology Trichrome, x

H&E x400 H&E x 200 Sox10, x200 S100, x200 Ki67, x 400 Diagnosis

Orbital melanoma or is it? Molecular Diagnostics No BRAF or NRAS variants identified BUT: Solid Fusion Assay POSITIVE for EWSR1-ATF1 gene fusion Clear cell sarcoma

Clear Cell Sarcoma Clear cell sarcoma of tendon and aponeurosis Melanoma of soft parts (formerly) Translocation-associated sarcomas of soft tissues showing melanocytic differentiation Clinical Features Rare, occurs in young adults (3rd-4th decades)

with slight female predominance 90% in extremities (esp foot; head/neck/trunk rare) and often attached to tendon/aponeurosis Deep (subcutis or deeper); painful in half of cases Histopathology

Cells with characteristically uniform/monotonous appearance Spindled to ovoid/round cells in nests and fascicles Clear to pale eosinophilic cytoplasm Prominent central nucleoli Average 4 mits/10 HPF Intervening collagen bands IHC/Molecular Genetics Immunohistochemistry

Essentially identical to melanoma Positive: S100, SOX10, +/- MART-1/Melan-A, HMB-45, MITF Molecular Genetics

EWSR1-ATF1 fusion resulting from t(12;22) (>90% of cases) EWSR1-CREB1 alternate fusion resulting from t(2;22) No BRAF/NRAS variants Identical gene fusions have been found in variety of tumors, including angiomatoid fibrous histiocytoma CCS Versus Melanoma

Similar presentation: Dermal/subcutaneous/deep nodule Immunophenotype may be identical to CCS Metastatic melanoma usually more pleomorphic and mitotically active Melanoma often has BRAF or NRAS mutations and lacks EWSR1-ATF1 and EWSR1-CREB1 fusions Better prognosis than melanoma for size/depth

Treatment/Prognosis Usually treated with surgery only; usually chemotherapy resistant Poor prognosis but often prolonged clinical course

(70% 5- and 10% 20-year survival) Late metastases or recurrence (lymph nodes, unlike most sarcomas; lung) Local

recurrence, size >5cm, and necrosis most important poor prognostic factors Orbital tumor Chromosomal alteration Affected gene Prevalence

Alveolar rhabdomyosarcoma t(2;13)(q35;q14) or t(1;13) (p36;q14) PAX3-FKHR or PAX7-FKHR fusions (FKHR gene is now known as FOXO1) 60-70% t(2;13) and 20% t(1;13)

Desmoplastic small round cell tumor t(11;22)(p13;q12) EWS-WT1 gene fusion >95% Ewing sarcoma/ primitive neuroectodermal tumor (PNET)

t(11;22)(q24;q12) or t(21;22)(q22;q12) EWSR1-FLI1 fusion or EWSERG fusion 85% t(11;22) and 10% t(21;22) Inflammatory myofibroblastic tumor

Various rearrangements involving 2p23 ALK rearrangement About 50% Liposarcoma Myxoid: t(12;16)(q13;p11)

Myxoid: FUSDDIT3 fusion Myxoid: >90% Well-differentiated: amplification of 12q13-15 Well-differentiated: MDM2 amplification Well-differentiated:

~90% Mesenchymal chondrosarcoma10,45 Fusion of 8q21.13and 8q13.3 HEY1-NCOA2 gene fusion At least 66% Rhabdoid tumor13,20 Mutation or deletion at

22q11 Loss of SMARCB1/ hSNF5/INI1 gene >90% Solitary fibrous tumor17,42 inv12(q13q13)

NAB2-STAT6 >90% Synovial sarcoma16,18,29,43 t(X;18)(p11;q11) SYT-SSX1 (or SSX2) fusion >90%

Our Patient Patching for diplopia after surgery Staging MRI showed no evidence of regional or distant metastases (T2N0M0) Plan for definitive proton beam therapy (74 Gy in 31 fractions) Thank you!

G. Petur Nielsen, MD Rosalynn Nazarian, MD H&E, x 200 References Chung EB, Enzinger FM. Malignant melanoma of soft parts. A reassessment of clear cell sarcoma. Am J Surg Pathol. 1983 Jul;7(5):405-13. Gardner, JM. Clear Cell Sarcoma. Expertpath.com. Hisaoka M, et al. Clear cell sarcoma of soft tissue: a clinicopathologic,

immunohistochemical, and molecular analysis of 33 cases. Am J Surg Pathol. 2008 Mar;32(3):452-60. Hocar O, et al. Clear cell sarcoma (malignant melanoma) of soft parts: a clinicopathologic study of 52 cases. Dermatol Res Pract. 2012;2012:984096. Epub 2012 May 30. Thway K, Fisher C. Tumors with EWSR1-CREB1 and EWSR1-ATF1 fusions: the current status. Am J Surg Pathol. 2012 Jul;36(7):e1-e11.

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