Metastatic
malignant melanoma is notorious for its phenotypic diversity and loss of
differentiation markers. We herein summarized our experience with 14 metastatic
melanomas showing complete loss of immunohistochemical melanocytic markers (with or without heterologous differentiation). Patients included 11 men and 3 women aged 24 to 78 years (median, 67 y). Thirteen patients had histologically confirmed primary skin
melanoma, and 1 had metastatic
melanoma of unknown primary. Undifferentiated
metastasis was diagnosed synchronous to primary
tumor (n=1), following skin
melanoma by 3 months to 9 years (n=11) and preceding it by 1 year (n=1). Sites of undifferentiated
metastases were axillary (3), inguinal (1), or submandibular (1) lymph nodes, digestive tract (2), bone/soft tissue (2), lung/pleura (2), and disseminated (n=3). Histology of
metastases mimicked undifferentiated pleomorphic or
spindle cell sarcoma with variable myxoid and giant cell areas (n=10) and
cytokeratin-positive undifferentiated
small cell sarcoma (n=1). Three cases showed heterologous dedifferentiation: pleomorphic
rhabdomyosarcoma (n=1), teratocarcinosarcoma-like with prominent rhabdomyoblasts (n=1), and
adenocarcinoma-like with metaplastic bone (n=1). All cases were negative for S100,
melanoma cocktail, HMB45,
Melan A, and SOX10. Other markers showed following results: smooth muscle actin (1/14), p16 (1/14), TP53 (2/12), pancytokeratin (4/14),
desmin (5/14), h-
caldesmon (0/9), and MDM2/CDK4 (0/5). SMARCB1 was intact in 8/8 cases. Genotyping showed BRAF(V600E) mutation (5/14), NRAS mutation (5/14), and BRAF/NRAS wild-type (4/14). In conclusion, undifferentiated/dedifferentiated metastatic
melanoma is likely underrecognized and frequently mistaken for undifferentiated
sarcoma or other
neoplasms. Diagnosis of undifferentiated
sarcoma at sites where
melanoma metastasis are frequent (eg, inguinal and axillary region) should be made with great caution and warrants exploration of the remote history. Genotyping is a helpful
surrogate marker in classifying such difficult cases. In the light of available targeted
therapies, recognition of undifferentiated/dedifferentiated metastatic
melanoma is mandatory for appropriate treatment.