Cases Of Extraskeletal Myxoid Chondrosarcoma Research Articles

CHRNA6 RNA In Situ Hybridization Is a Useful Tool for the Diagnosis of Extraskeletal Myxoid Chondrosarcoma

Extraskeletal myxoid chondrosarcoma (EMC) is an uncommon mesenchymal neoplasm characteristically composed of uniform-appearing round to spindle-shaped cells with eosinophilic cytoplasm and abundant myxoid extracellular matrix. Although the majority of cases harbor a pathognomonic t(9;22) translocation that fuses EWSR1 with the orphan nuclear receptor NR4A3, there are less common variants that partner NR4A3 with TAF15, TCF12, or TFG. By immunohistochemistry, EMC has features of both cartilaginous and neuroendocrine differentiation, as evidenced by inconsistent expression of S100 protein and synaptophysin or INSM1, respectively, in a subset of cases. Given the limitations of available immunohistochemical stains for the diagnosis of EMC, we analyzed genome-wide gene expression microarray data to identify candidate biomarkers based on differential expression in EMC in comparison with other mesenchymal neoplasms. This analysis pointed to CHRNA6 as the gene with the highest relative expression in EMC (96-fold; P = 8.2 × 10−26) and the only gene with >50-fold increased expression in EMC compared with other tumors. Using RNA chromogenic in situ hybridization, we observed strong and diffuse expression of CHRNA6 in 25 cases of EMC, including both EWSR1-rearranged and TAF15-rearranged variants. All examined cases of histologic mimics were negative for CHRNA6 overexpression; however, limited CHRNA6 expression, not reaching a threshold of >5 puncta or 1 aggregate of chromogen in >25% of cells, was observed in 69 of 685 mimics (10.1%), spanning an array of mesenchymal tumors. Taken together, these findings suggest that, with careful interpretation and the use of appropriate thresholds, CHRNA6 RNA chromogenic in situ hybridization is a potentially useful ancillary histologic tool for the diagnosis of EMC.

TAF15::NR4A3 gene fusion identifies a morphologically distinct subset of extraskeletal myxoid chondrosarcoma mimicking myoepithelial tumors.

Extraskeletal myxoid chondrosarcoma (EMC) is a rare sarcoma of uncertain differentiation predominantly arising in deep soft tissue. Its conventional morphologic appearance manifests as a relatively well-circumscribed, multilobular tumor composed of uniform short spindle-to-ovoid primitive mesenchymal cells with deeply eosinophilic cytoplasm arranged in anastomosing cords within abundant myxoid matrix. The genetic hallmark of EMC has long been considered to be pathognomonic gene rearrangements involving NR4A3, which when fused to TAF15, often have high-grade morphology with increased cellularity, moderate to severe cytologic atypia, and rhabdoid cytomorphology. Herein, we describe two cases of EMC with TAF15::NR4A3 fusion that appear morphologically distinct from both conventional and high-grade EMC. Both cases had an unusual biphasic appearance and showed diffuse positivity for p63, mimicking myoepithelial tumors. DNA methylation profiling demonstrated that both cases clearly cluster with EMC, indicating that they most likely represent morphologically distinct variants of EMC. The clinical significance and prognostic impact of this morphologic variance remains to be determined. Molecular testing, including DNA methylation profiling, can help to confirm the diagnosis and avoid confusion with mimics; it adds another layer of data to support expanding the morphologic spectrum of EMC.

Extraskeletal myxoid chondrosarcoma: Clinical features and overall survival

Introduction: Extraskeletal myxoid chondrosarcoma is a rare form of soft tissue sarcoma characterized by a unique chromosomal translocation involving the NR4A3 gene on chromosome 9. It is most frequently diagnosed in the proximal extremities of older adult males and is notable for its insidious growth with predilection for local recurrence and metastasis. Currently, extraskeletal myxoid chondrosarcoma is managed with wide resection, with recent investigations supporting the utility of adjuvant radiation and novel chemotherapeutic strategies. Methodology: A retrospective study was performed with the Surveillance, Epidemiology, and End-Results (SEER) database, which was searched for cases of extraskeletal myxoid chondrosarcoma diagnosed between years 2004 and 2015. Demographic variables were assessed, as well as Collaborative Staging variables including tumor size, metastatic disease, grade, and lymph node involvement. Cases were stratified according to the anatomic site of the primary tumor and were described by therapeutic intervention. A multivariate Cox proportional hazards model evaluated predictive factors for poor survival, and Kaplan-Meier analyses assessed effects of various staging, demographic, and therapeutic variables on overall survival. Results: There were 270 cases of extraskeletal myxoid chondrosarcoma reviewed in this study, which were diagnosed most frequently in the lower limb or hip of older adult males. The 5-year overall survival was 76.5% and was worse on univariate assessment for patients with age > 60, high histologic grade, pelvic location, tumor size > 8.0 cm, metastatic or nodal spread, and in patients without surgical intervention. The Cox regression predicted significantly worse survival for older age, larger tumor size, non-surgical status, and high tumor grade. Metastasis did not significantly predict worse survival on multivariate assessment, and neither chemotherapy nor radiotherapy provided a discernable improvement in survival in this cohort. Discussion and Conclusion: As a rare soft tissue sarcoma, many of the presenting features and survival outcomes of extraskeletal myxoid chondrosarcoma remain poorly defined due to the limited prevalence of this disease. The findings of this study suggest the overall survival may be worse than previously reported, and poor prognostic factors are those associated with worse survival in other soft tissue sarcomas, including high histologic grade, older age, larger tumor size, and lack of wide resection. Radiation and chemotherapy did not demonstrably improve survival for patients with localized or metastatic disease.

Recurrent Myxoid Chondrosarcoma of Mandible: A Case Report

Myxoid chondrosarcoma is a rare malignant neoplasm of bone or soft tissue origin, characterised by the presence of chondroid and myxoid matrix. These are traditionally radio resistant tumours, so wide surgical resection remains the mainstay of treatment. However, radiotherapy is generally advised for high-grade lesions with poor prognostic factors with adjuvant chemotherapy. The treatment decisions are primarily guided by the histological grade, extent of surgical resection, and site of the neoplasm. A case of a 28-year-old male who presented with recurrent painful swelling in the mandibular region is discussed here. To date, very few cases of Extraskeletal Myxoid Chondrosarcoma (EMC) occurring in the mandible region have been reported. So, due to the paucity of available literature, controversies still exist regarding effective treatment approaches in newly diagnosed and recurrent cases. This case reports the clinical presentation, histopathology, radiological characteristics, immune profile, and treatment modalities used in EMC with a comprehensive and relevant review of the literature.

Extraskeletal myxoid chondrosarcoma: combining cytopathology with molecular testing to achieve diagnostic accuracy

Advances in the genetics of soft tissue neoplasia have allowed for the diagnostic recognition of specific tumor types from small biopsy specimens, including those procured using the fine needle aspiration (FNA) biopsy technique. Extraskeletal myxoid chondrosarcoma (EMC) is a malignant mesenchymal neoplasm characterized by NR4A3 and, less specifically, by EWSR1 gene rearrangements. A series of EMC cytologic specimens was examined to demonstrate the diagnostic value of incorporating fluorescence in situ hybridization (FISH) testing in cytologic cases of suspected EMC. A search was made of our cytopathology and surgical pathology databases for cases diagnosed as EMC. FNA biopsy cytology, exfoliative cytology, imprint cytology, and FISH analysis were performed and examined using standard techniques. A total of 16 cases of EMC were retrieved from 15 patients (male/female ratio, 2.8:1; mean age, 62 years). Of the 15 patients, 10 were new patients with primary tumors, 2 had locally recurrent tumors, and 4 had metastases. The sites included the extremities in 10 cases, the trunk in 4, serous effusion in 1, and a mediastinal lymph node in 1 case. The specific cytologic diagnoses were EMC (14 cases; 88%), suspicious for EMC (n = 1), and malignant cells (n = 1). All cases for which FISH testing was successfully used were specifically recognized as EMC. Aspirates and imprint smears consisted of uniformly rounded cells set in an opaque myxoid/chondromyxoid stroma (less abundant and more diaphanous in the effusion sample), sometimes arranged in short anastomosing cords. FNA of 1 case of an EMC cellular variant mimicked a malignant small rounded cell tumor. EMC can be added to the growing list of soft tissue neoplasms that are specifically recognizable using cytopathology, coupled with judicious application of ancillary molecular testing.

Benefit of Radiotherapy in Extraskeletal Myxoid Chondrosarcoma: A Propensity Score Weighted Population-based Analysis of the SEER Database.

Extraskeletal myxoid chondrosarcoma (EMC) is a rare malignancy for which the role of radiotherapy is not well-defined. We examine the effect of external beam radiotherapy (EBRT) on cancer-specific survival (CSS) for patients with localized EMC, in a propensity score weighted, population-based analysis. The Surveillance, Epidemiology, and End Results database (1973 to 2012) was queried for cases of localized EMC arising from soft connective tissues of the trunk and extremities treated with surgery and/or EBRT. Inverse probability treatment weighting was utilized, with survival analysis by weighted Cox regression and Kaplan-Meier analysis with log-rank testing. The primary endpoint was CSS. One hundred seventy-two patients were identified, diagnosed from 2004 to 2012. Ninety-four percent and 32% of 156 assessable patients underwent surgery and EBRT, respectively. By inverse probability treatment weighting, balancing covariates of age group, sex, race, grade, T stage, N stage, receipt of surgery, and anatomic site, we observed CSS of 97% versus 85% and 94% versus 85% in patients receiving EBRT versus no EBRT, at 3 and 5 years, respectively, at median follow-up of 33 months, P=0.01. A trend toward an overall survival benefit associated with EBRT was noted, P=0.06. Further adjusting for type of resection performed, CSS benefit persisted, 97% versus 85% at 3 years and 94% versus 85% at 5 years, P=0.02, with trend toward an overall survival benefit, P=0.08. The receipt of EBRT is associated with a CSS benefit in localized EMC. Aggressive local therapy, including EBRT, should be considered in these patients.

Extraskeletal Myxoid Chondrosarcoma: A Comparative Study of Imaging and Pathology.

The purpose of this study was to achieve better understanding of extraskeletal myxoid chondrosarcoma (EMC). 13 cases of EMC confirmed by surgery biopsy were retrospectively studied. All patients underwent preoperative CT or/and MRI examinations. Among six patients who underwent preoperative CT examinations, six cases of lesions exhibited hypodensity on unenhanced image, three cases of tumor showed funicular spots or patchy calcification, and four cases of tumor did not show any obvious enhancement after enhanced CT scan. Among ten patients who underwent preoperative MRI examination, 8 cases of tumor revealed uniform or slight hyposignal intensity on T1WI, 10 cases of tumor demonstrated lobulated hypersignal intensity with multiple low signal intensity of interval septa on T2WI, and 5 cases of lesions indicated characteristic appearance: septa enhancement with tumor stroma between interval septa being unenhanced. EMC usually occurred at older men and at certain location such as limbs, trunk, and subcutaneous tissues. EMC usually exhibited low density mass (mostly 20-40HU) with calcification and in a portion of the cases showed light or no enhancement on CT. On MRI, EMC showed lobulated hypersignal intensity on T2WI with characteristic arc, septa, or interval septa enhancement.

Extraskeletal Myxoid Chondrosarcomas are not Characterized by Loss of INI1/SMARCB1: Immunohistochemical Analysis of 16 Cases

Background: Extraskeletal myxoid chondrosarcoma (EMC) is a rare soft tissue sarcoma, characterized by t (9; 22) translocation, including EWSR1 and NR4A3 gene rearrangements, observed in most cases. On histopathologic examination, an EMC has certain diagnostic mimics, such as myoepithelial tumors, epithelioid malignant peripheral nerve sheath tumor and epithelioid sarcomas. All these tumors are included in the category of INI1/SMARCB1- deficient tumors. Lately, few studies have shown loss of INI1 in certain EMCs. Considering there is preclinical data regarding role of EZH2 inhibitor in “INI1 deficient” tumors, it is crucial to recognize such tumors. Objectives: To evaluate immunohistochemical features, including INI1/SMARCB1 immunostaining results in 16 prospectively diagnosed cases of EMC. Methods: Immunohistochemical staining was performed on formalin-fixed paraffin embedded tissue sections by immunoperoxidase method using a MACH 2 Universal HRP-Polymer detection kit. Two cases were tested for EWSR1 rearrangement by fluorescent in-situ hybridization (FISH) technique. Results: Sixteen EMCs occurred in 13 males and 3 females, most commonly in lower extremities; followed by chest wall, pelvis, including iliac fossa, shoulder and parasapinal region; in patients within age-range of 17-72 years (median=47.5). On histopathologic examination, most tumors displayed round to polygonal cells arranged in cords, trabeculae and pseudoglandular pattern in an abundant myxoid stroma. Three tumors revealed “rhabdoid” cells. By immunohistochemistry, 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 in tumors containing rhabdoid-like cells. INI1/SMARCB1 was diffusely retained in all 16 tumors (100%). Two cases tested for EWSR1 rearrangement, were found to be positive for the same. Conclusion: An optimal immunohistochemical panel for differentiating an EMC from its diagnostic mimics may include antibody markers, such as NSE, S100 protein, AE1/AE3, EMA and SMA. EMCs, including those containing rhabdoid cells do not seem to be in the category of INI1-deficient tumors.

Clinicopathologic and radiologic features of extraskeletal myxoid chondrosarcoma: a retrospective study of 40 Chinese cases with literature review.

The aim of this study is to describe the clinicopathologic and radiologic features of 40 cases of extraskeletal myxoid chondrosarcoma (EMC) from China. There were 25 males and 15 females (sex ratio, 1.7:1). Apart from an adolescent, all patients were adults with a median age of 49years. Twenty-four tumors (60%) occurred in the lower limb and limb girdles, especially the thigh, followed by the upper limb and limb girdles (20%) and trunk (10%). Other less commonly involved locations included the head and neck, sacrococcygeal region, and perineum. Tumors ranged in size from 1.5 to 19cm (mean, 7cm). By radiology, they appeared as hypoattenuated or isoattenuated masses on computed tomography with hyperintense signal on T2-weighted magnetic resonance imaging. Intralesional hypointense septa were present in most cases. Of the 40 tumors, 30 belonged to the classic subtype, whereas 9 cases were cellular, and 1 case had a rhabdoid phenotype. Tumor cells showed variable expression of synaptophysin (36%), S-100 protein (29%), epithelial membrane antigen (11%), and neuron-specific enolase (7%). Ki-67 index was remarkably higher in the cellular variant (mean, 30%). EWSR1-related rearrangement was detected in 12 of 14 cases tested by fluorescence in situ hybridization using break-apart probes. The overall 5- and 7-year survival was 71% and 60%, respectively. Awareness of the imaging features may help pathologists in the diagnosis of EMC. Fluorescence in situ hybridization also serves as a useful diagnostic tool for EMC, especially in the distinction from its mimics.

Extraskeletal myxoid chondrosarcoma: a clinicopathologic analysis of seven cases

To study the clinicopathologic features, diagnosis and differential diagnosis of extraskeletal myxoid chondrosarcoma (EMC). The clinical and pathologic features of 7 cases of EMC encountered in Fujian Provincal Hospital and Fuzhou General Hospital of Nanjing Military Command during the period of 2005 to 2015 were analyzed. Immunohistochemical study and PAS staining were carried out. Relevant literature was reviewed. The male-to-female ratio was 6 to 1. The age of patients ranged from 21 to 50 years (median = 36 years). The maximum tumor dimension ranged from 2.5 to 15.0 cm (mean = 8.4 cm). The sites of involvement included left neck, right shoulder, left thigh, right thigh, right upper arm and abdomen. Most patients presented with painless lumps. Histologically, all cases showed similar features. Low-power examination showed a nodular or lobulated architecture, with intervening fibrous septa and myxoid matrix in the background. The tumor cells were arranged in cords or tufted clusters. They were spindly to epithelioid / rhabdoid (plasmacytoid) in shape, with eosinophilic to sometimes vacuolated cytoplasm. Intracytoplasmic eosinophilic inclusion bodies and coagulative necrosis were focally seen. Mitotic figures were rare (less than 2 per 10 high-power fields). Immunohistochemical study showed that the tumor cells were positive for vimentin (7/7) and INI1 (7/7). They were focally positive for CKpan (2/7), p63 (3/7), CD99 (3/7), S-100 protein (1/7) and synaptophysin (2/7). Ki-67 proliferation index ranged from 10% to 40%. The tumor cells were negative for α-smooth muscle actin, desmin, myoD1, CD34 and CD117. The cytoplasm of the tumor cells was positive for PAS. EWSR1 gene signal was detected in 5 cases. EMC is a rare malignant mesenchymal tumor. Arrival at correct diagnosis relies on morphologic examination and immunohistochemistry. Molecular pathology is helpful when necessary. The primary treatment modality for EMC is complete surgical excision and the prognosis is satisfactory.

Chromosomal translocation‐negative cellular extraskeletal myxoid chondrosarcoma in an adolescent female

Extraskeletal myxoid chondrosarcoma (EMC) is a relatively uncommon soft tissue sarcoma that typically presents in adults of middle age and affects the proximal thigh and limb girdles. Initially believed to be a low-grade malignancy, long-term patient follow-up has shown a high incidence of local recurrence and metastatic spread. EMC is uniformly resistant to chemotherapy and radiation therapy. These tumors characteristically display fibrous septae with large aggregates of mucin populated by clusters and strands of oval cells exhibiting minimal mitotic activity. A more aggressive cellular subtype has also been defined and exhibits basaloid cells showing the immunohistochemical staining features of neuroendocrine differentiation calling into question their proposed cartilaginous lineage. Most, although not all, examples of EMC possess a unique balanced chromosomal translocation [t(9;22)(q22;q12)] between the EWSR1 and NR4A3 (previously termed TEC) genes. Pediatric and adolescent cases of EMC are rare, as only 15 have been reported and appear to follow a more aggressive clinical course. Reported herein is a case of an EMC arising in the thigh of a 15-year-old female and the first to undergo evaluation of chromosomal translocation.

Myxoid Chondrosarcoma of the Phalanx with an EWS Translocation

Myxoid chondrosarcoma is a histologically and genetically distinct tumor that predominantly originates in soft tissue, unlike conventional chondrosarcoma, which arises primarily in bone1-3. Several hundred cases of extraskeletal myxoid chondrosarcoma have been reported, but true intraosseous myxoid chondrosarcoma tumors have rarely been reported. Several nonrandom chromosomal translocations, most commonly t(9;22) EWS-CHN, have been identified in extraskeletal myxoid chondrosarcoma4,5. These translocations can help with diagnosis; however, to date, no such translocation has been identified in an unequivocal skeletal myxoid chondrosarcoma tumor, leading previous authors to conclude that skeletal and extraskeletal myxoid chondrosarcoma tumors are separate and distinct entities6,7. We present the case of a patient with myxoid chondrosarcoma with both a clear skeletal origin and an EWS-containing chromosomal translocation, thus providing evidence that the skeletal and extraskeletal forms of myxoid chondrosarcoma represent the same pathologic entity. The patient was informed that data concerning the case would be submitted for publication, and she consented. A nineteen-year-old woman presented with a nine-month history of a progressively enlarging, painful mass of the right long finger. There was no history of trauma or foreign-body penetration. She had no constitutional symptoms, and the medical history was remarkable only for asthma. On examination, there was a 2 × 1.5 × 1.5-cm mass involving the middle phalanx (Fig. 1). There was decreased active digital flexion, mild ulnar deviation of the finger, and normal sensation. The patient had no antecubital or axillary lymphadenopathy. Fig. 1 Photograph demonstrating a mass in the middle phalanx of the long finger. Radiographs demonstrated a lytic expansile lesion of the middle phalanx of the long finger (Figs. 2-A and 2-B). No full-thickness cortical destruction was evident, although the extensive endosteal scalloping made this difficult to confirm. The lesion extended to the proximal articular surface, …

Fluorescence in situ hybridization is a useful ancillary diagnostic tool for extraskeletal myxoid chondrosarcoma

Extraskeletal myxoid chondrosarcoma is a rare soft tissue tumor characterized by a nodular growth pattern with eosinophilic cells usually in a reticular pattern and abundant myxoid stroma. In contrast to other myxoid sarcomas, the majority of extraskeletal myxoid chondrosarcomas harbor a balanced translocation, t(9;22)(q22;q12), that fuses EWSR1 with NR4A3 (also known as CHN). Other less common translocations involving NR4A3 have also been described. We examined the diagnostic utility of fluorescence in situ hybridization for extraskeletal myxoid chondrosarcoma using the LSI EWSR1 break-apart probe (Abbott Molecular/Vysis, Des Plaines, IL, USA). Sixteen cases of extraskeletal myxoid chondrosarcoma with formalin-fixed paraffin-embedded tissue available were retrieved (1991–2007). The mean age at time of presentation was 57 years (range, 30–78). The male to female ratio was 7:1. All cases where either consistent with or highly suggestive of the diagnosis, with most of the primary tumors occurring in the thigh, inguinal or gluteal region. Fifteen of 16 cases were analyzable, of which 14 (93%) were positive for the rearrangement of the EWSR1 locus. In this study, the vast majority of extraskeletal myxoid chondrosarcomas are associated with a rearrangement at the EWSR1 locus (22q12). Fluorescence in situ hybridization is useful to support the diagnosis of extraskeletal myxoid chondrosarcomas and may help to differentiate it from mimics such as other myxoid sarcomas, particularly in limited biopsies.

Cytopathology of extraskeletal myxoid chondrosarcoma

Extraskeletal myxoid chondrosarcoma (EMC) is a rare soft-tissue sarcoma rarely subjected to cytologic analysis. With the exception of a few small series, the cytology literature of EMC is largely limited to single-case reports. The purpose was to evaluate the cytomorphology of 8 EMC cases as obtained by imprint/scrape cytology and fine-needle aspiration (FNA) biopsy, to review the literature, and to demonstrate the utility of cytogenetic analysis in the diagnosis of EMC. The cytology files were reviewed for all soft-tissue lesions signed out as chondrosarcoma, myxoid sarcoma, and EMC, and the tissue files for any cases of EMC that had corresponding cytopathology. FNA was performed using a standard technique. Scrape preparations were performed from tissue sent fresh to the laboratory for either frozen section or for special studies such as electron microscopy or tissue banking. Eight cases of EMC were retrieved from 4 men and 3 women (median age = 62 years). One patient had 2 separate cytologic specimens 4.5 years apart. All patients had subsequent tissue confirmation of the diagnosis of EMC. Five individuals presented as new patients, and 2 had a prior diagnosis of EMC. Sites included 4 masses from the foot/ankle, 2 from the calf, 1 wrist mass, and 1 buttock mass. Five patients were diagnosed from FNA biopsy, whereas 3 were diagnosed using scrape slides. Five cases were correctly and categorically diagnosed by the cytologic method as EMC, 1 as chondrosarcoma favor EMC, 1 as sarcoma favor EMC, and 1 as myxoid spindle/epithelial neoplasm. Cytologic features ranged from hypocellular to highly cellular smears composed primarily of rounded cells set in an abundant myxoid stroma that varied from opaque to semitransparent and lacked vascularity or necrosis. Smears showed cells in short, sometimes anastomosing cords, but also as single cells and nondescript cell clusters. Cells displayed a monotonous uniformity in nuclear diameter and cell size. Bland nuclei with evenly dispersed chromatin displayed variably sized nucleoli, and a moderate amount of infrequently vacuolated cytoplasm. Tissue fragments of variable size were found in 5 of 5 FNA cell blocks. Fluorescence in situ hybridization (FISH) analysis using the EWSR1 probe showed a positive 22q12 translocation in 2 of 3 FNA cases that were tested. One case with negative FISH results on the cytologic preparation showed a positive translocation using the same technique in the subsequent resection specimen. A confident cytologic diagnosis of EMC depends on the presence of a uniform, round to oval cell population often arranged in cords and set in an abundant myxoid/chondromyxoid background and arising in the appropriate clinical context. If positive, FISH testing (of paraffin cell blocks or cytospin preparations) is confirmatory when coupled with this cytomorphology.

Extraskeletal Myxoid Chondrosarcoma Of Oropharynx

Extraskeletal myxoid chondrosarcoma is a rare soft tissue neoplasm. We report such a tumor in an 80-year-old man, who presented with a 10-cm right tonsillar mass. Histologic examination of the tumor revealed an infiltrative growth pattern, focal hypercellularity, frequent mitosis, and areas of necrosis, in addition to features commonly seen in typical cases of extraskeletal myxoid chondrosarcoma.

Extraskeletal and Skeletal Myxoid Chondrosarcoma: A Multiparameter Analysis of Three Cases Including Cytogenetic Analysis and Fluorescence In Situ Hybridization.

Background: Myxoid chondrosarcoma (MCS) is a rare, low-grade, indolent tumor that can occur in soft tissue and bone. It is, however, capable of distant metastases. Previous cytogenetic data include a translocation, t(9;22)(q22-31;q12), occurring in 6 of 14 cases of the extraskeletal variant of the disease. Recently, rearrangement of the EWS gene has been reported in MCS. Methods and Results: Three cases of MCS, two skeletal and one extraskeletal, were examined to identify primary cytogenetic changes and correlate these with immunohistochemical, ultrastructural, and flow-cytometric analysis. The extraskeletal variant of MCS revealed a clonal translocation, t(9;22)(q22;q12), and trisomy for chromosomes 5, 7, 8, 12, 18, and 19. Our two cases of skeletal MCS showed complex karyotypes. In one skeletal tumor, a cryptic translocation involving chromosome 6p21.3 was identified by fluorescence in situ hybridization analysis, using chromosome-specific libraries. Conclusions: Thus far, 50% of cases of extraskeletal MCS, including our cases, have demonstrated a specific translocation, t(9;22)(q22-31;q12). Identifying this translocation is useful in confirming the diagnosis of MCS. Additional cytogenetic and molecular analysis is useful for detecting this translocation, and is also essential to determine other regions of possible diagnostic importance, such as the 6p21.3 breakpoint demonstrated in the present study. These techniques may be most useful for the skeletal lesions, in light of their heterogeneous cell populations and karyotypic variability.

The gene expression profile of extraskeletal myxoid chondrosarcoma

Extraskeletal myxoid chondrosarcoma (EMC) is a soft tissue tumour that occurs primarily in the extremities and is characterized by a balanced translocation most commonly involving t(9;22) (q22;q12). The morphological spectrum of EMC is broad and thus a diagnosis based on histology alone can be difficult. Currently, no systemic therapy exists that improves survival in patients with EMC. In the present study, gene expression profiling has been performed to discover new diagnostic markers and potential therapeutic targets for this tumour type. Global gene expression profiling of ten EMCs and 26 other sarcomas using 42,000 spot cDNA microarrays revealed that the cases of EMC were closely related to each other and distinct from the other tumours profiled. Significance analysis of microarrays (SAM) identified 86 genes that distinguished EMC from the other sarcomas with 0.25% likelihood of false significance. NMB, DKK1, DNER, CLCN3, and DEF6 were the top five genes in this analysis. In situ hybridization for NMB gene expression on tissue microarrays (TMAs) containing a total of 1164 specimens representing 62 different sarcoma types and 15 different carcinoma types showed that NMB was highly expressed in 17 of 22 EMC cases and very rarely expressed in other tumours and thus could function as a novel diagnostic marker. High levels of expression of PPARG and the gene encoding its interacting protein, PPARGC1A, in most EMCs suggest activation of lipid metabolism pathways in this tumour. Small molecule inhibitors for PPARG exist and PPARG could be a potential therapeutic target for EMC.

Extraskeletal Myxoid Chondrosarcoma with Neuroendocrine Differentiation: A Case Report with Fine-Needle Aspiration Biopsy, Histopathology, Electron Microscopy, and Cytogenetics

Although extraskeletal myxoid chondrosarcoma (EMC) is a rare soft tissue sarcoma, its morphological, ultrastructural, and cytogenetical features have been well investigated. The authors describe a very rare variant of EMC with neuroendocrine differentiation. A 49-year-old woman presented with an 11-cm, deep-seated, lobulated soft tissue mass in the left thigh and a lymph node metastasis in the left groin. Analysis of fine-needle aspiration biopsy (FNAB) smears and a cellblock prepared from FNAB material, as well as histological sections of the excised tumor, showed a neoplasm composed of rounded and elongated cells arranged in strands and cords in a myxoid background matrix. The nuclei were rounded and often eccentric. The immunohistochemical phenotype was S-100 protein m, neuron specific enolase +, and chromogranin A+. Electron microscopy showed tumor cells harboring numerous mitochondria, partial basal lamina, and unequivocal neuroendocrine granules. Molecular genetic analysis revealed a TAF15/NR4A3 fusion, a characteristic rearrangement occurring in about 25% of cytogenetically investigated EMC. A few cases of EMC with neuroendocrine differentiation have been reported. However, the only previously described case with genetic information also displayed the t(9;17) instead of the more common t(9;22), suggesting an association between type of primary chromosome abnormality and neuroendocrine differentiation.

Extraskeletal myxoid chondrosarcoma: A clinicopathologic, immunohistochemical, and molecular analysis of 18 cases

Extraskeletal myxoid chondrosarcoma (EMCS) is an uncommon clinicopathologically well-defined tumor, but its pathogenesis and biologic behavior are poorly understood. We reviewed 18 cases of EMCS to verify clinicopathologic features and immunohistochemical profiles together with molecular detection of the tumor-specific fusion genes. The tumors were located mainly in the proximal extremities and limb girdles (72%). Two tumors arose at unusual anatomic sites: the finger and the hip joint. Nine of the 17 followed-up patients were alive and disease free, 4 were alive with recurrences and/or metastases, and 4 died of the tumor. Fifteen tumors showed typical features of EMCS, and 3 had hypercellular areas in addition to conventional EMCS areas. The tumors were variably immunoreactive for S-100 protein (50%), NSE (89%), peripherin (60%), and synaptophysin (22%). Chromogranin A and some epithelial markers (AE1/AE3, CAM5.2, and epithelial membrane antigen) were entirely negative. Frequent expressions of the neural/neuroendocrine markers suggest possible neural/neuroendocrine differentiation in at least some EMCSs, in addition to chondroid differentiation. In a reverse-transcription polymerase chain reaction (RT-PCR) assay using paraffin-embedded specimens, EWS-CHN or TAF2N-CHN fusion gene transcripts characteristic of EMCS could be detected in 15 (83%) of the 18 cases: EWS-CHN type 1 in 11 cases, EWS-CHN type 2 in 1, and TAF2N-CHN in 3. Three fusion-negative cases included 2 conventional EMCSs and 1 considered a “cellular” variant of the tumor. None of 30 other soft tissue and bone tumors with myxoid or chondroid morphology that we examined contained these fusion genes. Thus, RT-PCR detection of EWS-CHN or TAF2N-CHN fusion gene using archival paraffin-embedded tissue is a feasible and useful ancillary technique for the diagnosis of EMCS. HUM PATHOL 32:1116-1124. Copyright © 2001 by W.B. Saunders Company

Extraskeletal Myxoid Chondrosarcoma: A Clinicopathologic, Immunohistochemical, and Ploidy Analysis of 23 Cases

Twenty-three cases of extraskeletal myxoid chondrosarcoma, evaluated at the Mayo Clinic between 1968 and 1996, were studied for clinicopathologic features, immunohistochemical profile, Ki-67 activity, and ploidy status to identify adverse prognostic factors. Females and males were equally affected, and the median age at diagnosis was 50 years. The tumors were located mainly in the lower extremities (83%), and the median tumor size was 9.5 cm. Sixteen tumors showed low cellularity (70%), and eight tumors had high mitotic activity (more than two per 10 high-power fields). The tumors were immunoreactive for vimentin (89%), synaptophysin (72%), epithelial membrane antigen (28%), and S-100 protein (17%). Nine tumors were diploid, three aneuploid, and one tetraploid. Mean Ki-67 activity was 11% (range, 1 to 45%). The 10-year overall survival rate was 78%. On univariate analysis, tumor size ≥ 10 cm, high cellularity, presence of anaplasia or rhabdoid features, mitotic activity more than two per 10 high-power fields, Ki-67 ≥ 10%, and Ki-67 “hot spot” ≥ 25% were associated with decreased metastasis-free or overall survival. Ploidy status was not associated with any adverse outcome. The presence of any of these adverse prognostic factors can indicate the possibility of a more aggressive behavior in extraskeletal myxoid chondrosarcoma, and a closer follow-up is suggested.