Dedifferentiated Extraskeletal Myxoid Chondrosarcoma of the Masticator Space - a Case Report

The Korean Journal of Pathology 2011; 45(S1): S101-105 DOI: 10.4132/KoreanJPathol.2011.45.S1.S101

Dedifferentiated Extraskeletal Myxoid Chondrosarcoma of the Masticator Space - A Case Report -

Geunyoung Jung · Kyung-Ja Cho We describe a 69-year-old woman who presented with a dedifferentiated extraskeletal myxoid Seung-Ho Choi1 · Mi-Jung Kim chondrosarcoma arising in the left masticator space. Computed tomography and magnetic resonance imaging revealed a 5 cm sized mass in the left masticator space. Histologically, the tumor Departments of Pathology and consisted of two distinct areas. The less cellular area was a low-grade extraskeletal myxoid chon- 1Otorhinolaryngology, Asan Medical Center, drosarcoma, composed of strands or cords of uniform spindle cells and abundant myxoid stro- University of Ulsan College of Medicine, Seoul, ma. The more cellular, dedifferentiated area corresponded to a high grade myxofibrosarcoma, Korea consisting of anaplastic tumor cells in myxoid stroma and geographic necrosis. The tumor cells of the former area were positive for S-100 protein, microtubule-associated protein-2 (MAP-2) and Received: October 25, 2010 class III β-tubulin, but negative for cytokeratin, smooth muscle actin, and desmin. The tumor cells November 23, 2010 Accepted: in the latter, pleomorphic area showed MAP-2 and β-tubulin immunoreactivity with a high Ki-67 Corresponding Author labeling index. Based on its histologic and immunohistochemical features, the tumor was consid- Mi-Jung Kim, M.D. ered a dedifferentiated extraskeletal myxoid chondrosarcoma. Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, 388-1 Pungnap 2-dong, Songpa-gu, Seoul 138-736, Korea Tel: +82-2-3010-4557 Fax: +82-2-472-7898 E-mail: [email protected] Key Words: Extraskeletal myxoid chondrosarcoma; Cell dedifferentiation; Masticator space

Extraskeletal myxoid chondrosarcoma (EMC) is a rare malig- CASE REPORT nant soft tissue sarcoma, distinguished from its skeletal coun- terpart by cytogenetic and histologic features. EMC was first A 69-year-old woman presented with an 8-month history of described as a distinct pathologic entity in 1953,1 although its a painful firm mass palpable on the left buccal area. She had a clinicopathologic features, defined in 1972, showed that it was previous history of tuberculosis and leg fracture but was other- a distinctive type of soft tissue sarcoma characterized by a pro- wise healthy. Her laboratory findings were unremarkable. Both tracted clinical course despite high local recurrence and metas- computed tomography and magnetic resonance imaging reveal tasis rates.2 EMC usually develops in the deep soft tissues of the ed a 5-cm sized mass in the left masticator space, compressing extremities in middle-aged adults.2,3 Conventional EMC is char- the maxillary sinus, mandibular ramus, and medial pterygoid acterized by uniform round to oval cells forming cords or clus- plate (Fig. 1), but not infiltrating adjacent structures. Subse- ters and abundant myxoid stroma. In up to 30% of patients, quent biopsy revealed a spindle cell sarcoma, for which the pa- however, EMC may contain cellular foci reminiscent of chon- tient underwent wide excision and segmental mandibulectomy. droblastoma, Ewing’s sarcoma, synovial sarcoma, and fibrosar- Gross examination showed that the resected specimen was a coma, and may have rhabdoid features.4 Dedifferentiated EMC 4.9×3.9×3.8 cm sized well-encapsulated ovoid mass. Its cut is rare; to our knowledge, only three patients have been describ surface was heterogeneous, grayish yellow and gelatinous, with ed in the English language literature.5-7 We describe here a de- areas of geographic necrosis and hemorrhage (Fig. 2). Micro- differentiated EMC that arose in the left masticator space of a scopically, the tumor was lobulated and consisted of two dis- 69-year-old woman. tinct areas. The less cellular area was a low-grade EMC, composed of strands or cords of oval and spindle cells embedded in abundant myxoid stroma. These tumor cells had relatively uni-

S101 S102 Geunyoung Jung·Kyung-Ja Cho·Seung-Ho Choi, et al.

Fig. 1. T2-weighted magnetic resonance imaging demonstrating a Fig. 2. Gross features of the lesion, showing a well-demarcated, well demarcated 5-cm sized ovoid mass (arrows) in the left masti- ovoid 4.9× 3.9× 3.8 cm sized mass (arrows) adjacent to the man- cator space of our patient. dibular bone. The cut surface of the mass is heterogeneous, grayish yellow and gelatinous, with some areas showing geographic necrosis.

A B

C D

Fig. 3. Histologic features of the tumor. (A) The less cellular area consists of strands or cords of oval and spindle cells embedded in abundant myxoid stroma. (B) The tumor cells in the less cellular area have relatively uniform, spindle and oval nuclei and a moderate amount of cytoplasm. (C) The cellular, dedifferentiated area is pleomorphic sarcoma with myxoid stroma, corresponding to high-grade myxofibrosarcoma. (D) The tumor cells in the more cellular area have pleomorphic oval to spindle shaped nuclei and moderate to ample amounts of eosinophilic cytoplasm. Dedifferentiated Extraskeletal Myxoid Chondrosarcoma S103 form, spindle and oval nuclei, with dense, evenly dispersed chro- ly positive for MAP-2 and class III β-tubulin with a high Ki- matin, and a moderate amount of eosinophilic cytoplasm that 67 labeling index (40-50%) (Fig. 4), but the remaining mark- was often finely vacuolated. Mitotic figures were rare (Fig. 3A, ers were all negative. Based on its histologic and immunohisto- B). The more cellular area was a pleomorphic myxoid sarcoma chemical features, the tumor was diagnosed as a dedifferentiated consisting of pleomorphic tumor cells with occasional rhabdoid EMC. Fluorescence in situ hybridization (FISH) on formalin- features and geographic necrosis (Fig. 3C, D). In the less cellu- fixed, paraffin-embedded tissue samples using dual-color, break- lar area, the tumor was positive for S-100 protein (1:1,000, apart rearrangement probes (Vysis) to assess Ewing’s sarcoma Zymed, San Francisco, CA, USA), microtubule-associated pro- (EWS) gene breakage showed no evidence of EWS rearrange- tein-2 (MAP-2; 1 :200, clone AP18, Neomarkers, Fremont, ments. The patient underwent adjuvant radiotherapy. Her post- CA, USA), class III β-tubulin (1:200, clone TU-20, Genetex, operative course was unremarkable, with no evidence of recur- Irvine, CA, USA), focally positive for epithelial membrane anti- rence at 3 months. gen (1:25, Dako, Glostrup, Denmark) and negative for cytokeratin (CK; 1:250, Zymed), smooth muscle actin (1:200, Dako), synaptophysin (1:100, clone sp11, Neomarkers) and DISCUSSION desmin (1:200, Dako), supporting the conclusion that there had been neural-neuroendocrine differentiation. The Ki-67 EMC is a rare but clinicopathologically well-characterized (1:100, clone 7B11, Zymed) labeling index was very low (less soft tissue sarcoma. However, the line of differentiation of EMC than 1%). The tumor cells in the pleomorphic area were strong- cells remains unclear. EMCs consist of primitive mesenchymal

A B

C D

Fig. 4. Immunohistochemical findings of the tumor. The tumor cells in the less cellular, differentiated area are positive for S-100 protein (A) and class III β-tubulin (B). The tumor cells in the dedifferentiated area are negative for S-100 protein (C) and positive for class III-β-tubulin (D). S104 Geunyoung Jung·Kyung-Ja Cho·Seung-Ho Choi, et al. cells with the potential for multidirectional differentiation. De- sidered less aggressive, patient prognosis is not as good as previ- spite being described as a chondrosarcoma, discernible chondro- ously thought. Multivariate analysis has shown that older pa- cytic differentiation is unusual. Therefore, the 2002 World Heal tient age, larger tumor size, and tumor location in the proximal th Organization (WHO) classification has provisionally catego- extremity or limb girdle were significant, independent adverse rized EMCs as tumors of uncertain differentiation.8,9 Indeed, prognostic factors. In contrast, the prognostic significance of high percentages of cellular foci of these tumors have been found tumor histologic features, such as tumor grade and high-grade to show diverse histologic features, resembling the features of morphology, has not yet been established.4,12 Patients with an other tumors such as chondroblastoma, EWS, synovial sarcoma, EMC eventually die of this disease because of the high rates of and fibrosarcoma, as well as having rhabdoid features.4 Some recurrence and metastasis. Therefore, long-term follow-up is EMCs, so-called ‘cellular’ variants, consist of diffusely cellular mandatory in patients with EMC. The estimated 10 year sur- areas with minimal to absent myxoid stroma.4 In addition, EMCs vival rate is 70%.4 Chemotherapeutic agents currently in use have been found to show ultrastructural and immunohistochem- have not shown satisfactory results in these patients, making ical characteristics of neuroendocrine differentiation, including early wide local resection with or without radiation for localized neurosecretory granules and positivity for neuroendocrine mark- disease the only curative option for patients with EMC.13 ers such as synaptophysin, S-100 protein, and PGP9.5.10 Re- Besides their distinct histologic features and biologic behav- cently, expression of microtubule-related proteins, class III β- ior, EMCs harbor characteristic cytogenetic changes. Approxi- tubulin, and MAP-2 has been demonstrated in EMCs, support- mately 75% of tumors have the t(9;22)(q22;q12) translocation, ing neural-neuroendocrine differentiation of the tumor cells.11 resulting in a fusion of the 5´ part of the EWS gene at 22q12 to Most EMCs have a bland-looking or low-grade morphology, the NR4A3 gene at 9q22. Although the function of EWS/NR with dedifferentiated EMCs rarely being described. To our know 4A3 has not yet been determined, this fusion protein may con- ledge, only three such cases have been reported in the English tribute to tumorigenesis by transcriptional activation or influ- language literature.5-7 Dedifferentiated EMCs have been ob- encing pre-mRNA splicing.14,15 The t(9;17)(q22;q11) translo- served in older individuals, aged 65 to 85 years (mean, 72.7 cation occurs less frequently (~15%), generating the RBP56/ years). The affected site appears to vary, although the number of NR4A3 fusion transcript.16 Importantly, this fusion protein is patients is too small to be conclusive. Tumor diameters have detected exclusively in EMCs, and, theoretically, its presence ranged from 4.9 to 15 cm. Follow-up information is available may be diagnostic of EMC. Although we performed dual-color for three of the four patients, including the one described in break apart FISH analysis for EWS, the result was negative. The this report, with two of these patients showing tumor recur- rates of cytogenetic abnormalities, however, suggest that at least rence within 1 year postoperatively. Although our patient did 25% of EMCs are negative for EWS rearrangement. EWS is in- not show evidence of disease recurrence, the postoperative fol- volved in a broad variety of mesenchymal lesions, including low-up time was too short (3 months) to draw firm conclusions. EWS/peripheral neuroectodermal tumor, desmoplastic small The clinicopathologic findings of these 4 patients are summa- round cell tumor, clear cell sarcoma, angiomatoid fibrous his- rized in Table 1. EMCs have been reported in unusual sites such tiocytoma, EMC, and a subset of myxoid liposarcomas.17 There- as the retroperitoneum, mediastinum, fingers, and intracranial fore, analysis of the NR4A3 rearrangement would be helpful in cavity, as well as the head and neck area.12,13 the diagnosis of EMCs with atypical features. Evaluation of NR Although the biologic behavior of EMCs was initially con- 4A3 rearrangements in EMCs showed that these rearrangements

Table 1. Clinicopathologic summary of the 4 dedifferentiated extraskeletal myxoid chondrosarcomas described to date Case Age Size Reference Gender Location Histology Treatment Outcome No. (yr) (cm) 1 Ramesh et al.5 65 F Gluteal region 15 Fibrosarcomatous differentiation Surgery only Recurrence after 8 mo 2 Antonescu et al.6 NS NS NS NS High grade spindle cell sarcoma NS NS 3 Reid et al.7 85 M Upper arm 7 High grade spindle cell sarcoma with rhabdoid, Surgery followed Two recurrences epithelioid, and pleomorphic areas by radiation after 10 and 13 mo 4 Present case 68 F Masticator space 4.9 High grade myxofibrosarcoma Surgery followed NED during 3 mo by radiation follow-up

F, female; NS, not specified; M, male; NED, no evidence of disease. Dedifferentiated Extraskeletal Myxoid Chondrosarcoma S105

were present in two tumors not carrying any EWS breakpoint 8. Fletcher CD, Unni KK, Mertens F. World Health Organization clas- region 1 (EWSR1) rearrangements.18 sification of tumours: pathology and genetics of tumours of soft tis- In summary, dedifferentiated EMCs are extremely rare and sue and bone. Lyon: IARC Press, 2002; 234-57. may be confused with other benign or malignant tumors due to 9. Aigner T, Oliveira AM, Nascimento AG. Extraskeletal myxoid chon- their rarity and diversity of histologic features. Diagnosis of con- drosarcomas do not show a chondrocytic phenotype. Mod Pathol ventional EMCs may help in the diagnosis of dedifferentiated 2004; 17: 214-21. EMCs. Moreover, ancillary immunohistochemical studies, such 10. Goh YW, Spagnolo DV, Platten M, et al. Extraskeletal myxoid chon- as staining for the S-100 protein and microtubule-related pro- drosarcoma: a light microscopic, immunohistochemical, ultrastruc- teins, and cytogenetic analysis are recommended to confirm the tural and immuno-ultrastructural study indicating neuroendocrine diagnosis. differentiation. Histopathology 2001; 39: 514-24. 11. Hisaoka M, Okamoto S, Koyama S, et al. Microtubule-associated protein-2 and class III beta-tubulin are expressed in extraskeletal REFERENCES myxoid chondrosarcoma. Mod Pathol 2003; 16: 453-9. 12. Hisaoka M, Hashimoto H. Extraskeletal myxoid chondrosarcoma: 1. Stout AP, Verner EW. Chondrosarcoma of the extraskeletal soft tis- updated clinicopathological and molecular genetic characteristics. sues. Cancer 1953; 6: 581-90. Pathol Int 2005; 55: 453-63. 2. Enzinger FM, Shiraki M. Extraskeletal myxoid chondrosarcoma: an 13. Drilon AD, Popat S, Bhuchar G, et al. Extraskeletal myxoid chon- analysis of 34 cases. Hum Pathol 1972; 3: 421-35. drosarcoma: a retrospective review from 2 referral centers empha- 3. Rubin BP, Fletcher JA. Skeletal and extraskeletal myxoid chondro- sizing long-term outcomes with surgery and chemotherapy. Cancer sarcoma: related or distinct tumors? Adv Anat Pathol 1999; 6: 204- 2008; 113: 3364-71. 12. 14. Ohkura N, Yaguchi H, Tsukada T, Yamaguchi K. The EWS/NOR1 4. Meis-Kindblom JM, Bergh P, Gunterberg B, Kindblom LG. Extras fusion gene product gains a novel activity affecting pre-mRNA splic- keletal myxoid chondrosarcoma: a reappraisal of its morphologic ing. J Biol Chem 2002; 277: 535-43. spectrum and prognostic factors based on 117 cases. Am J Surg Pa 15. Hinrichs SH, Jaramillo MA, Gumerlock PH, Gardner MB, Lewis JP, thol 1999; 23: 636-50. Freeman AE. Myxoid chondrosarcoma with a translocation involv- 5. Ramesh K, Gahukamble L, Sarma NH, al Fituri OM. Extraskeletal ing chromosomes 9 and 22. Cancer Genet Cytogenet 1985; 14: 219- myxoid chondrosarcoma with dedifferentiation. Histopathology 26. 1995; 27: 381-2. 16. Panagopoulos I, Mencinger M, Dietrich CU, et al. Fusion of the RBP 6. Antonescu CR, Argani P, Erlandson RA, Healey JH, Ladanyi M, 56 and CHN genes in extraskeletal myxoid chondrosarcomas with Huvos AG. Skeletal and extraskeletal myxoid chondrosarcoma: a translocation t(9;17)(q22;q11). Oncogene 1999; 18: 7594-8. comparative clinicopathologic, ultrastructural, and molecular study. 17. Romeo S, Dei Tos AP. Soft tissue tumors associated with EWSR1 Cancer 1998; 83: 1504-21. translocation. Virchows Arch 2010; 456: 219-34. 7. Reid R, de Silva MV, Paterson L. Poorly differentiated extraskeletal 18. Noguchi H, Mitsuhashi T, Seki K, et al. Fluorescence in situ hybrid- myxoid chondrosarcoma with t(9;22)(q22;q11) translocation pre- ization analysis of extraskeletal myxoid chondrosarcomas using senting initially as a solid variant devoid of myxoid areas. Int J Surg EWSR1 and NR4A3 probes. Hum Pathol 2010; 41: 336-42. Pathol 2003; 11: 137-41.