MALIGNANT GRANULAR-CELL TUMOR OF SOFT-TISSUE - DIAGNOSTIC-CRITERIA AND CLINICOPATHOLOGICAL CORRELATION

Seventy-three cases of malignant, atypical, and multicentric granular cell tumors of soft tissue were studied to clarify criteria for malign ancy and prognostic factors. Six histologic criteria were assessed: ne crosis, spindling, vesicular nuclei with large nucleoli, increased mit otic activity (> 2 mitoses/10 high-power fields at 200x magnification) , high nuclear to cytoplasmic (N:C) ratio, and pleomorphism. Neoplasms that met three or more of these criteria were classified as histologi cally malignant; those that met one or two criteria were classified as atypical; and those that displayed only focal pleomorphism but fulfil led none of the other criteria were classified as benign. Hence, 46 ca ses were classified as histologically malignant, 21 as atypical (3 wer e multicentric), and 6 as benign tall were multicentric). The patients with benign multicentric and atypical granular cell tumors had no met astases and there were no tumor deaths. In contrast, 11 of 28 patients (39%) with malignant granular cell tumor with follow-up information d ied of disease at a median interval of 3 years; 8 of 28 (29%) were ali ve with disease, and 9/28 (32%) were disease free (median intervals, 2 and 7 years, respectively). There were local recurrences in 9 of 28 m alignant cases (32%) and metastases in 14 of 28 (50%) (median interval s, each 2 years). Forty-eight cases were studied immunohistochemically ; 100% expressed vimentin, 98% S-100 protein, 98% neuron-specific enol ase, 69% CD57, and 65% CD68. Alpha-smooth muscle actin, desmin, epithe lial membrane antigen (EMA), cytokeratins (with CAM 5.2 and KL-1), chr omogranin, and HMB45 were not detected. The proliferative index with K i67 (MIB1) was 10-50% in 14 of 25 malignant tumors (56%), and immunost aining for p53 was detected in 50% or more of tumor cells in 17 of 25 (68%); both of these factors were statistically significant with regar d to the histologic classification as benign, atypical, or malignant. Ultrastructural examination of 13 benign, atypical, and malignant gran ular cell tumors showed engorgement of the cytoplasm with complex gran ules and lysosomes, as well as Schwannian features. By flow cytometric DNA analysis, two of six malignant tumors were aneuploid, two were hy perdiploid, and two were diploid. One atypical tumor was aneuploid and all 11 benign tumors were either diploid (9 cases) or hyperdiploid (2 cases). Statistically significant adverse prognostic factors with reg ard to survival included local recurrence, metastasis, larger tumor si ze, older patient age, histologic classification as malignant, presenc e of necrosis, increased mitotic activity, spindling of tumor cells, v esicular nuclei with large nucleoli, and Ki67 values less than 10%. Th is study defines clinical and morphologic criteria for malignancy in g ranular cell tumors and shows that malignant granular cell tumor is a high-grade sarcoma with a high rate of metastases and a short survival .