Clinical aggressiveness of myxofibrosarcomas associates with down-regulation of p12CDK2AP1: prognostic implication of a putative tumor suppressor that induces cell cycle arrest and apoptosis via mitochondrial pathway.

BACKGROUND: Attenuated endogenous protein levels of cyclin-dependent kinase 2 associated protein 1 (p12(CDK2AP1)) and its active homodimer p25(CDK2AP1) were found in myxofibrosarcoma-derived cell lines. Clinical and biological significances of this putative tumor suppressor in myxofibrosarcoma were studied. METHODS: Plasmids carrying the CDK2AP1 gene and small hairpin RNA interference (shRNAi) targeting CDK2AP1 were transfected into NMFH-1 and/or OH931 cells to evaluate the effects on the CDK2, active caspase 3 (CASP3), cleaved-CASP8 and -CASP9 levels, cell cycle regulation, and/or apoptotic responses. Immunostaining of p12(CDK2AP1) was interpretable in 102 primary myxofibrosarcomas and correlated with clinicopathological variables, CDK2, Ki-67 and active CASP3 protein levels, and disease-specific survival. RESULTS: Exogenous expression of p12(CDK2AP1) in NMFH-1 and OH931 cells significantly induced G0/G1 cell cycle arrest and down-regulated CDK2 protein level. In NMFH-1 cells, these aspects were reversed by shRNAi targeting CDK2AP1 gene. Increased active CASP3 and cleaved-CASP9, but not -CASP8, were detected after CDK2AP1 overexpression, suggesting the cellular apoptosis were induced through the mitochondrial pathway. Immunostains of p12(CDK2AP1) were aberrantly decreased in 56.9 % of cases; positively and negatively correlated with protein levels of CDK2 (p = 0.023), Ki-67 (p = 0.001) and active CASP3 (p < 0.001), respectively. Following by high histological grades, p12(CDK2AP1) down-regulation was predictive of worse disease-specific survival in univariate (p = 0.003) and multivariate (p = 0.004) analyses. CONCLUSIONS: Through down-regulation of CDK2, high p12(CDK2AP1) level induced cell cycle arrest and the mitochondrial-dependent apoptotic pathway. Low p12(CDK2AP1) level represents a poor prognostic factor in patients with myxofibrosarcoma.

Myxoinflammatory fibroblastic sarcoma in an unreported area (groin).

BACKGROUND: Myxoinflammatory fibroblastic sarcoma (MIFS) is a rare tumor presenting as a painless subcutaneous mass in the extremities first reported in 1998. We report the first case of a MIFS tumor in the groin. METHODS: We have performed seven immunohistochemical stains that were not applied before on MIFS. RESULTS: The first case of a MIFS tumor in the groin. CONCLUSIONS: MIFS must be considered in the differential diagnosis of a painless mass not only in the distal extremities but also in the groin. The diagnosis of this tumor is difficult and can be missed if not considered because of the unusual location. Due to high recurrence rates and one case of documented metastases, the recommended treatment is wide excision.

Myxoid clear cell sarcoma.

Clear cell sarcoma is a rare soft-tissue tumor presenting typically in the extremities of young adults. It has been also known as malignant melanoma of the soft parts because of the presence of melanin and cytoplasmic melanosomes. However, clear cell sarcoma is, at present, usually considered as a unique lesion because the t(12;22)(q13;q12) translocation is present only in clear cell sarcoma. Myxoid malignant melanoma is now a well-recognized morphologic variant of malignant melanoma. However, a myxoid variant of clear cell sarcoma has not been well described yet. We report a case of myxoid clear cell sarcoma occurring on the heel in a 22-year-old man. The tumor was composed of nests and fascicles of oval to fusiform cells with clear to pale eosinophilic cytoplasm, often separated by fibrous septa. The tumor cells were reactive for S-100 protein, HMB-45, and MART-1. Variably sized cysts lined by one or several layers of tumor cells were observed. Alcian blue and mucicarmine stains demonstrated prominent mucin deposition in the tumor stroma and especially in the lumen of the cysts. Fluorescence in situ hybridization for the Ewing sarcoma gene showed rearrangement in nearly all of the neoplastic cells.

Low-grade pulmonary myxoid sarcoma of uncertain histogenesis.

The present report describes an unusual case of low-grade pulmonary sarcoma with extensive myxoid change in a 60-year-old man. During 30 months, the tumor enlarged gradually and thereafter rapidly to 9 cm. Preoperative biopsy and cytology gave negative results. The resected mass, located at the periphery of the right upper lobe, was well circumscribed and showed gelatinous without necrosis or hemorrhage. Histologically, the tumor was composed of slightly atypical, spindle-shaped or stellate cells, which were loosely distributed within a prominent myxoid stroma. Epithelial differentiation was not seen. Lacunar structures were occasionally evident, but no cartilaginous matrix was seen. Mitotic figures were infrequent. Immunohistochemistry failed to clarify the nature of the neoplastic cells except vimentin positivity. Histochemically, the myxoid ground substance was composed of hyaluronic acid and acid mucopolysaccharide. Electron microscopy revealed no specific differentiation other than aggregates of filaments, which were seen in a number of neoplastic cells. Flow cytometric analysis of the neoplastic cells revealed a diploid pattern. These findings indicated that the neoplasm was a low-grade myxoid sarcoma; however, a definite diagnosis could not be made. The tumor might have been a variant of extraskeletal myxoid chondrosarcoma, especially considering the histochemical results.

Low-grade myxofibrosarcoma: progression in recurrence.

A case of low-grade myxofibrosarcoma with histologic progression in recurrence occurring in a 51-year-old male is described. The patient had a well-circumscribed encapsulated myxoid mass, which measured 2.5 cm at its greatest diameter, in the subcutis of the left forearm. Microscopically, the tumor was characterized by a proliferation of sparsely distributed spindle or stellate cells, curvilinear small vessels and myxoid stroma. It demonstrated mild pleomorphism without mitotic figures. The patient had the first recurrence at 3 years, which was histologically identical to the primary tumor. The patient had a second recurrence at 11 years, which was predominantly composed of sheets of anaplastic, rounded or oval cells with focal osteoid formation. Immunohistochemically, the tumor cells in the primary and the first recurrent lesions were focally positive for vimentin. In the second recurrence, the tumor cells contained vimentin, alpha-smooth muscle actin and muscle specific actin (HHF35). The primary lesion had a diploid DNA content with low S-phase fractions. The second recurrence showed a polyploidy. The patient was well with no evidence of disease 18 months after the second recurrence. These findings suggest that this neoplasm showed histological progression with an increasing risk of metastasis. Low-grade myxofibrosarcoma, which commonly is misinterpreted as benign, has a tendency for histological and biological progression in local recurrences, underlining the importance of accurate diagnosis and wide surgical excision of the primary lesion.

Myxofibrosarcoma. Clinicopathologic analysis of 75 cases with emphasis on the low-grade variant.

Myxofibrosarcoma is one of the most common sarcomas in the extremities of elderly patients. We analysed the clinicopathologic features in a series of 75 patients. All patients were adults (range, 22-91 years; median, 66 years) with an approximately equal incidence in men and women. Thirty-five tumors arose in the lower and 25 in the upper extremities, nine on the trunk, two each in the retroperitoneum and the head and neck region, and one each in the pelvis and penis. Forty-eight cases (69.5%) were located in dermal or subcutaneous tissues. Distinctive histologic features included the following: a commonly nodular growth pattern; a myxoid matrix containing elongated, curvilinear capillaries; and fusiform, round or stellate tumor cells with indistinct cell margins, slightly eosinophilic cytoplasm, and hyperchromatic atypical nuclei. These lesions varied from a hypocellular, mainly myxoid, and purely spindle-cell appearance (low-grade neoplasms) to high-grade, pleomorphic (malignant fibrous histiocytoma-like) lesions with multinucleated giant cells, high mitotic activity, and areas of necrosis. Immunohistochemistry in 44 cases revealed only vimentin and occasional actin positivity. Ultrastructurally, tumor cells had a fibroblastic phenotype. DNA flow cytometry and proliferation analysis showed an association between aneuploidy and histologic grade. An average follow-up of 45 months (range, 5-300 months) in 60 cases has revealed local recurrence in 33 cases (54%). Thirteen patients developed metastases, and 13 tumor-related deaths occurred. A short interval to first local recurrence was associated with poor clinical outcome. The rate of local recurrence was independent of histologic grade, but only intermediate and high-grade neoplasms metastasized. The depth of the primary lesion did not influence the incidence of local recurrence. However, in deep-seated neoplasms, the incidence of metastases was higher and the percentage of tumor-related deaths was twice as high as in superficially located lesions, reflecting the fact that deep-seated lesions tended to be higher-grade, larger tumors. Myxofibrosarcoma tends to become progressively higher grade in recurrences, as demonstrated in five cases in our series. The poorly recognized low-grade myxofibrosarcoma is emphasized, as proper diagnosis and treatment and scrupulous follow-up are mandatory to avoid local recurrence and gradual tumor progression to a higher-grade neoplasm that may then metastasize.