March 2019

Final Diagnosis and Discussion

A 64 year old man with an 8-year history of a slow-growing lower extremity soft tissue ma

Final diagnosis

Extraskeletal myxoid chondrosarcoma

Discussion

Extraskeletal myxoid chondrosarcoma (EMC) is categorized by the WHO as a tumor of uncertain differentiation since there is a paucity of convincing evidence of cartilaginous differentiation. Despite having often an indolent course, EMC has a propensity for late recurrence, metastasis, particularly to the lungs, and poor response rates to most conventional chemotherapeutic agents. Most patients present with a slowly growing deep-seated mass that causes pain and tenderness in approximately one-third of cases. The duration of symptoms varies considerably, ranging from a few weeks to several years. More than two-thirds of the tumors occur in the proximal extremities and limb girdles, especially the thigh and popliteal fossa, similar to myxoid liposarcoma. [1] Currently, the only curative option for EMC is early wide local resection with or without radiation for localized disease [3]

Macroscopically, the neoplasm is a soft to firm, ovoid, lobulated to nodular, circumscribed mass surrounded by a dense fibrous pseudocapsule. On cross-section, it has a gelatinous, gray to tan-brown surface, and its color largely depends on the extent of hemorrhage, a frequent feature of the tumor. The size varies from a few centimeters to 15cm or more; most, however, are 4-7cm in greatest dimension at the time of excision [1]

Microscopically, a characteristic multinodular pattern is evident. The individual tumor nodules consist of round or slightly elongated cells of uniform shape and size separated by variable amounts of myxoid stroma. The individual cells have small hyperchromatic nuclei and a narrow rim of deeply eosinophilic cytoplasm reminiscent of chondroblasts. Unlike chondrosarcoma of the bone, differentiated cartilage cells with distinct lacunae are rare. Mitotic figures are also rare. Characteristically, the individual cells are arranged in short anastomosing cords, strands, or pseudoacini, often creating a lace-like appearance. Less frequently, they are disposed in small loosely textured whorls or aggregates, reminiscent of an epithelial neoplasm. Rarely, cellular foci composed of fibroblastic/myofibroblastic spindle-shaped cells are present. A distinct subset are hypercellular with less myxoid stroma between the neoplastic cells; they are composed of sheets of large cells with vesicular nuclei and prominent nucleoli and are referred to as the cellular variant of extraskeletal myxoid chondrosarcoma. Even more rarely, typical extraskeletal myxoid chondrosarcomas are associated with or progress to a high-grade pleomorphic sarcoma, and still others may have rhabdoid features characterized by cells with large paranuclear hyaline inclusions [1]

Diagnosis of EMC can be challenging as a result of its various differential diagnoses, such as myoepithelial tumors, epithelioid sarcoma, epithelioid MPNST and myxoid/round cell liposarcoma. To some extent, immunohistochemically antibody markers are useful in differentiating an EMC from its diagnostic mimics. [3] The cells of myxoid chondrosarcoma stain strongly for vimentin, but this is the only marker that is consistently positive. [1] In a recent study by Bharat Rekhi et al [2], 16 cases of EMC were evaluated prospectively for immunohistochemically features. By IHC, tumor cells were positive for NSE(13/13)(100%), S100 protein(10/15)(66.6%), EMA(2/12)(16.6%),AE1/AE3(0/9), P63(0/2) and SMA(2/3), the latter antibody marker positive in tumors containing “rhabdoid” cells. INI1/SMARCB1 was diffusely retained in all 16 tumors (100%), including the 3 tumors that displayed rhabdoid features.

Infrequent expression of epithelial IHC markers and positive expression of neuroendocrine markers is useful in differentiating an EMC from myoepithelial tumors that invariably display epithelial antibody IHC markers, apart from S100 protein positivity, in most cases. Optimal IHC panel for differentiating an EMC from its diagnostic mimics according to this study may be composed of NSE, S100 protein, AE1/AE3, EMA and SMA [3]

Extraskeletal myxoid chondrosarcoma is distinguished from other sarcomas by its unique histology and a characteristic chromosomal translocation, typically t (9; 22) (q22; q12.2), fusing EWSR1 to NR4A3. A small proportion of EMC have a different translocation, t (9; 17) (q22; q11.2), which results in a RBP56-NR4A3 fusion gene and neuroendocrine differentiation in some cases.[2]. A third chromosomal variant, t (9; 15) (q22; q21) has also been more recently described [1]. These fusion products are postulated to modify transcriptional activity and regulate cellular differentiation and growth, leading to tumorigenesis.

Our case was consistent with the previously reported epidemiologic data including site (thigh), size (8cm) and slow-growing history (8 years). Histologically, the cells displayed the classic morphology of oval to spindle cells embedded in a myxoid stroma, and interestingly, some areas displayed the infrequent rhabdoid morphology. Although some sources claim that tumors with rhabdoid features variable loss the expression of SMARCB1/INI, the tumor cells in our case retained their positivity, similar to the data reported by Bharat Rekhy et al [2]

References

1. SHARON W. WEISS, JOHN R. GOLDBLUM. Enzinger and Weiss’s Soft Tissue Tumors. 5th ed. Mosby Elsevier, 2008

2. BHARAT R, MUKTA R, and JYOTI B, 2017: “Extraskeletal Myxoid Chondrosarcomas are not Characterized by Loss of INI1/SMARCB1: Immunohistochemical Analysis of 16 Cases”, Journal of Carcinogenesis and Mutagenesis.

3. DRILON A, POPAT S, BHUCHAR G, D’ADAMO D, KEOHAN M, FISHER C, ANTONESCU C, SINGER S, BRENNAN M, JUDSON I, MAKI R, 2008: “Extraskeletal myxoid chondrosarcoma: a retrospective review from 2 referral centers emphasizing long-term outcomes with surgery and chemotherapy”, Cancer