Malignant granular cell tumors are similar in epidemiology to their benign counterparts. Both are found twice as often in females as in males and occur most commonly between the age of 40 and 69 (2
). Initially, granular cell tumors were considered to arise from histiocytes, fibroblasts, myocytes or intestinal mesenchymal cells. On the basis of ultrastructural observations and histochemical evidence, the tumors are now widely accepted to originate from Schwann cells (7
). Larger tumor size, advanced age and local recurrence at presentation correlate with a worse prognosis (8
). MGCT is an extremely rare type of cancer and at present no more than 100 cases have been described in the English language literature. Among them, many cases lack adequate follow-up. Consequently, diagnostic criteria and management strategy for MGCTs remain controversial (9
It is difficult to distinguish between malignant and benign GCTs. Although metastasis remains one of the most important criteria for defining malignancy, there is general recognition that not all malignant tumors, even those of high grade, actually metastasize. Clinically, it is of great significance to define malignancy before metastasis occurs. Six histological criteria have been established to predict malignant behavior according to the retrospective analysis of previous case reports of malignant GCTs. These are spindling of the tumor cells, the presence of vesicular nuclei with large nucleoli, increased mitotic rate (2 mitoses per 10 high-power fields at ×200 magnification), a high nuclear to cytoplasmic ratio, pleomorphism and necrosis (10
). Neoplasms that meet three or more of these criteria are classified as malignant, those that meet one or two criteria are classified as atypical, and those that exhibit only focal pleomorphism are classified as benign (11
). In the reported case study, the two initial lesions were consistent with benign histological performance according to the stated criteria. The later lesions were classified as malignant due to the observation of spindling of the tumor cells, vesicular nuclei with large nucleoli and increased mitotic rate. The benign lesion existed for several years and recurred twice following local resection. Ultimately, multiple subcutaneous and lymph node metastases occurred. Therefore, we presume that MGCT results from the malignant transformation of benign GCT. Although the possibility that there were multiple primary GCTs (multifocality) cannot be excluded, metastasis is a logical explanation for the simultaneous appearance of MGCT in the right breast and right groin. In contrast to the common sites for distant metastases, which include bone, peripheral nerves, the peritoneal cavity and the lung (5
), the present case involved metastases in the breast. To the best of our knowledge, this is the first case of MGCT with breast metastasis that has adequate follow-up. The right breast GCT closely resembled breast carcinoma in the ultrasound and X-ray examination; however, microscopic examination revealed significant differences between them. Since S100 is positive in one third of breast carcinomas and cytokeratin is only positive in breast carcinomas, cytokeratin immunohistochemical staining was performed to differentiate GCT from common malignant breast tumors.
Although there is considerable overlap in the Ki-67 proliferative index between histologically benign, atypical and malignant GCTs (11
), statistical analysis reveals a correlation between the Ki-67 proliferative index and malignant classification. A score of >10% for the Ki-67 index was significantly correlated with malignancy and unfavorable prognosis. In the reported case, the previous two tumors of the abdominal wall had a Ki-67 proliferative index of <1%, which increased to 10% in the second recurrence and was associated with increased nuclear pleomorphism, vesicular nuclei with prominent nucleoli and increased mitotic rate. Similarly, Le et al
reported that a clinical recurrence exhibited progressively more marked nuclear pleomorphism and vesicular nuclei with prominent nucleoli, as well as an increased Ki-67 proliferative index (1–10%). Due to the absence of demonstrable metastases, the tumor was classified as atypical GCT of unknown malignancy (12
). We believe that in GCT clinical recurrences, an increased Ki-67 proliferative index predicts clinical behavior and should be one of the criteria for defining malignancy.
Wide local excision with regional lymph node dissection is the first choice of treatment for MGCT. In metastatic patients, there is no evidence that resection of the metastatic lesions improves prognosis. In this case, considering the axillary lymph node metastases of the right breast metastatic lesion, regional lymph node dissection of the metastatic lesion was advised. Whether regional lymph node dissection improves prognosis may be determined by the follow-up. Although certain cases of successful treatment have been reported, the effectiveness of chemotherapy and radiotherapy remains controversial.