Case 1 -

Clear Cell Sarcoma Rajiv M. Patel, University of Michigan Health System, Ann Arbor, MI

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Clinical History 29-year-old male with a 5-year history of a slow-growing nodule on the plantar aspect of the base of the first toe overlying the first metatarsal phalangeal joint. The lesion was excised by the patient's podiatrist. Case 1 - Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer Case 1 - Figure 1 Multinodular amelanotic poorly circumscribed tumor involving the dermis and infiltrating into deep soft tissue. Case 1 - Figure 2 Spindled to fusiform cells arrayed in nests and fascicles defined by fibrocollagenous septa. Case 1 - Figure 3 Focal myxoid change and microcystic growth pattern. Case 1 - Figure 4 Atypical multinucleated giant cells. Case 1 - Figure 5 Atypical multinucleated giant cells. Case 1 - Figure 6 Increased mitotic activity. Case 1 - Figure 7 Spindle cells are atypical and have vesicular nuclei, macronucleoli and variably clear to eosinophilic cytoplasm. Case 1 - Figure 8 Case 1 - Figure 9 Case 1 - Figure 10 Case 1 - Figure 11 Positive EWSR1 break-apart FISH. Split green and red signals (translocated EWSR1) with adjacent red/green signal (intact EWSR1). Pathological/Microscopic Findings and any Immunohistochemical or Other Studies: This is an amelanotic multinodular poorly-circumscribed neoplasm which involves the dermis and extends into underlying fibrocollagenous tissue (Figure 1). Tumor cells are spindled to fusiform and arrayed in nests and fascicles which, in areas, are defined by thin fibrocollagenous septa (Figure 2). Focally there is prominent myxoid change and the cells take on a microcystic growth pattern (figure 3). Scattered throughout the tumor there are occasional multinucleated tumor giant cells with a wreath of peripherally placed atypical nuclei of uniform size and shape (Figures 4 and 5). Mitotic figures are easily identified (Figure 6). Constituent cells have vesicular nuclei with prominent macronucleoli and the cytoplasm varies from clear to lightly eosinophilic (Figure 7). The neoplasm is strongly positive for S-100 protein, HMB45 and MITF (Figures 8 to 10) and negative for SMA and AE1/AE3. Break-apart FISH is positive for a translocation involving the EWSR1 gene locus (Figure 11). Differential Diagnoses: The differential includes a number of cutaneous neoplasms, benign and malignant, primary and metastatic. The most important are conventional melanoma and cellular blue nevus. Other considerations might include PECOMA, epithelioid MPNST, synovial sarcoma, spindle cell epithelioid sarcoma and fibrosarcoma. Final Diagnosis: Clear Cell Sarcoma Case Discussion: Clear cell sarcoma was first described by Enzinger in 1965. [1] It is a rare aggressive sarcoma of uncertain histiogenesis that typically originates in the tendons, aponeuroses, and fascial structures of the extremities of young adults of either sex, with a peak incidence in the third and fourth decade. [2] CCS usually presents as a slowly enlarging mass clinically, which may be painful. Tumors are infiltrative and when extremely large may extend into the dermis and present as a cutaneous lesion histopathologically, particularly in small and/or superficial biopsies. Recently, a series of primary cutaneous CCS have been reported. [3] As described by Enzinger, CCS is composed of nests and fascicles of pale fusiform to epithelioid cells, surrounded by a delicate framework of fibrocollagenous tissue contiguous with adjacent tendons and aponeurosis, forming a vaguely organoid ('neuroendocrine-like') pattern. [4] In addition CCS may grow in diffuse sheet-like, pseudoalveolar, microcystic, or seminoma-like patterns. Tumors cells are generally uniform with vesicular nuclei containing prominent macronucleoli similar to melanoma. Cellular pleomorphism is uncommon, although it has been suggested that recurrent or metastatic lesions tend to become more pleomorphic. [1] Rhabdoid cytomorphology may be seen is a subset of tumors. [5] A particularly characteristic and helpful diagnostic feature is the presence of multinucleated tumor giant cells with peripherally placed wreath-like nuclei. Melanin may be occasionally identified in scattered cells, but this is usually not a prominent feature. CCS has an immunophenotype indistinguishable from melanoma with near universal expression of S-100 protein, with a somewhat smaller percentage of cases expressing more specific melanocytic markers such as HMB45, Melan-A and microphthalmia transcription factor (MiTF). A recent study of 33 genetically confirmed cases of CCS by Hisaoka et al showed strong S-100 protein expression in 100% of cases and HMB45, Melan-A and MiTF in 97%, 71% and 81% of cases, respectively. [5] There may be neuroendocrine and/or nerve sheath differentiation as well, with Hisaoka et al demonstrating synaptophysin (43%), CD56 (21%) and CD57 (75%) expression in a significant percentage of cases. [5] Muscle markers are usually negative, but there may be anomalous expression of epithelial markers (cytokeratins and epithelial membrane antigen) . Unlike melanoma and other tumors in the differential diagnosis, CCS demonstrates a recurrent translocation involving the EWSR1 gene located on chromosome 22q12 in greater than 90% of cases. [6] The most common translocation partner is activating transcription factor-1 (ATF1) gene on chromosome 12q13. [7] Recently, CREB1 a translocation partner located on chromosome 2q34 has been preferentially reported in CCS of the gastrointestinal tract and rare cases of CCS of soft tissue [5, 7]a nd cutaneous CCS. [3] Translocations can be identified by classical cytogenetics, reverse-transcriptase (RT-PCR) and fluorescence in situ hybridization (FISH). [6] The latter has become the molecular test of choice at many institutions. [8] In contradistinction to melanoma, activating mutations in BRAF have not been described in CCS. [9] Dermatopathologists must have a high index of suspicion and good clinicopathologic correlation to make the correct diagnosis. In a patient presenting with a classic clinical history, namely, a young patient with a slowly enlarging deep-seated spindle cell lesion of the extremities involving deep soft tissue, CCS is the favored diagnosis. When CCS presents in the skin the diagnosis is more difficult, as dermatopathologists often do not appreciate that CCS may present as a cutaneous lesion. Melanoma (particularly dermal melanoma) is the most important differential diagnosis. Melanoma typically has at least focal epithelioid morphology and a greater degree of pleomorphism than CCS. Given the overlap in clinical, histopathological and immunophenotypic features, in difficult cases molecular studies may be the only way of distinguishing between the two. Cellular blue nevi arise in similar age groups and anatomic locations and commonly contain multinucleated cells and spindle cells with small nucleoli. CCS has more atypical (vesicular) nuclei and large macronucleoli resembling melanoma. The giant cells in CCS demonstrate atypical features in contradistinction to those seen in cellular blue nevi. PECOMA have a prominent vasculature with epithelioid cells arrayed in a perivascular location and surrounding spindle cells having (counterintuitively) more abundant clear cytoplasm than is found in CCS. PECOMA also generally shows less nuclear atypia than CCS. In addition to melanocytic markers PECOMA express markers of smooth muscle differentiation, such as smooth muscle actin and desmin and are usually negative for S-100 protein. Epithelioid MPNST is more uniformly epithelioid than CCS and does not express markers of melanocytic differentiation. Approximately half of epithelioid MPNST arise in patients with neurofibromatosis 1 (NF1). Epithelioid sarcoma (ES) also occurs in younger patients and preferentially arises in the extremities. The spindle cell variant may mimic CCS when more typical epithelioid features of ES are lacking (e.g., due to sampling error in small biopsies). Unlike CCS, ES strongly express markers of epithelial differentiation (cytokeratins and epithelial membrane antigen) and lacks melanocytic differentiation (Melan-A, HMB45, MITF). Monophasic synovial sarcoma (SS) does not have prominent macronucleoli and expresses markers of epithelial differentiation. The molecular alterations in SS differ in that this sarcoma demonstrates rearrangements of the SYT gene on chromosome 18, rather than EWS rearrangements on chromosome 22. Fibrosarcoma (FS), once one of the most commonly diagnosed sarcomas, is now a diagnosis of exclusion as most spindle cell sarcomas previously designated as FS are now classified as other spindle cell sarcomas. None of the tumors in the differential diagnosis of CCS demonstrate EWSR1 translocations and thus molecular testing for this abnormality provides confirmation of the diagnosis in the majority of cases. Review of the Literature/Treatment Options (if applicable): CCS has a poor prognosis with multiple local recurrences and late metastases. Up to 30% of patients may present with metastatic disease. [4] In Enzinger's original series local recurrence, metastases and death from disease were seen in 84%, 63% and 74%, respectively. [1] Subsequent large studies have reported 5-year, 10-year and 20 year survival of 47- 67%, approximately 33% and 10%, respectively. [4] Although large tumor size and presence of necrosis have been suggested as poor prognostic indicators , a recent study failed to identify any significant prognostic clinicopathologic features, but this may have been due to small sample size in this study. [5] In the recent series of 12 cases of cutaneous CCS, local recurrences and metastases developed in 2 and 3 patients, respectively, and 1 patient died of disease. [3] The mainstay of therapy for CCS is wide resection with or without adjuvant radiotherapy. Chemotherapy has not been shown to be effective. [10] Sentinel lymph node biopsy does not appear to be clinically useful, at least in patients with localized disease after complete radiologic evaluation. [11] Conclusion(s): CCS is a rare sarcoma with an aggressive clinical course that has a propensity to arise in the peripheral extremities of younger patients. Large tumors may extend into the dermis and present as a cutaneous lesion in superficial biopsies. Rare primary dermal CCS have recently been reported. A high index of suspicion and careful clinicopathologic correlation are required to make the correct diagnosis. Molecular confirmation of translocation of the EWSR1 gene allows confirmation of the diagnosis as this abnormality has not been described in tumors in the differential diagnosis of CCS. The mainstay of treatment is wide local excision with tumor free margins. Currently adjuvant chemotherapy and sentinel lymph node biopsy have an unproven role in the treatment and prognosis of CCS. References: Enzinger FM. Clear-Cell Sarcoma of Tendons and Aponeuroses. An Analysis of 21 Cases. Cancer 1965 Sep; 18: 1163-74. Sciot R, Speleman F. Clear cell sarcoma of soft tissue. In Fletcher CD, Unni KK, Mertens F, eds. World Health Organization classification of tumours. IARC Press: Lyon, 2002, 211-2. Hantschke M, Mentzel T, Rutten A, et al. Cutaneous clear cell sarcoma: a clinicopathologic, immunohistochemical, and molecular analysis of 12 cases emphasizing its distinction from dermal melanoma. Am J Surg Pathol 2010 Feb; 34(2): 216- 22. Kosemehmetoglu K, Folpe AL. Clear cell sarcoma of tendons and aponeuroses, and osteoclast-rich tumour of the gastrointestinal tract with features resembling clear cell sarcoma of soft parts: a review and update. J Clin Pathol 2010 May; 63(5): 416-23. Hisaoka M, Ishida T, Kuo TT, 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. Patel RM, Downs-Kelly E, Weiss SW, et al. Dual-color, break-apart fluorescence in situ hybridization for EWS gene rearrangement distinguishes clear cell sarcoma of soft tissue from malignant melanoma. Mod Pathol 2005 Dec; 18 (12): 1585-90. Wang WL, Mayordomo E, Zhang W, et al. Detection and characterization of EWSR1/ATF1 and EWSR1/CREB1 chimeric transcripts in clear cell sarcoma (melanoma of soft parts). Mod Pathol 2009 Sep; 22(9): 1201-9. Tanas MR, Rubin BP, Tubbs RR, et al. Utilization of fluorescence in situ hybridization in the diagnosis of 230 mesenchymal neoplasms: an institutional experience. Arch Pathol Lab Med 2010 Dec; 134(12): 1797-803. Panagopoulos I, Mertens F, Isaksson M, Mandahl N. Absence of mutations of the BRAF gene in malignant melanoma of soft parts (clear cell sarcoma of tendons and aponeuroses). Cancer Genet Cytogenet 2005 Jan 1; 156(1): 74- 6. Jones RL, Constantinidou A, Thway K, et al. Chemotherapy in clear cell sarcoma. Med Oncol Apr 14 (epub). Maduekwe UN, Hornicek FJ, Springfield DS, et al. Role of sentinel lymph node biopsy in the staging of synovial, epithelioid, and clear cell sarcomas. Ann Surg Oncol 2009 May; 16(5): 1356-63.