A case of S-100 negative melanoma: A diagnostic pitfall in the workup of a poorly differentiated metastatic tumor of unknown origin

Abstract

When confronted with a metastatic poorly differentiated tumor of unknown origin, the initial workup includes the standard panel of immunostains to rule out carcinoma, sarcoma, lymphoma, and the greatest mimicker in pathology – malignant melanoma. Although not specific, the S-100 protein is expressed in over 95% of malignant melanomas. Herein, we present a case of multiorgan metastatic malignancy with a dominant hilar and mediastinal mass in a current smoker; clinically, highly suggestive of widespread primary lung cancer. This case was eventually classified as malignant melanoma, despite a significant diagnostic challenge due to lack of prior history, unusual cytomorphology, and S-100 protein negativity. A battery of immunostains was performed and the addition of other melanocytic-associated markers confirmed the melanocytic lineage of the neoplasm. This case highlights the pitfalls in the differential diagnosis of a metastatic tumor of unknown origin by fine needle aspiration cytology due to the significant morphologic overlap of poorly differentiated malignancies. We emphasize that, albeit rare, malignant melanomas can be completely negative for S-100 protein and the use of additional melanocytic-associated markers in the differential workup maybe critical in arriving promptly at a proper diagnosis. We also briefly discuss other currently available immunohistochemical markers that can assist in the identification of the S-100 negative melanoma.

Current state of melanoma diagnosis and treatment

“…Other common melanocytic markers used for melanoma diagnosis include S100 protein, micropthlamia transcription factor (MITF), Tyrosinase and SOX10. 33,34,58,59,61,64,65 Melan-A/MART-1, and HMB-45 have some of the highest specificity, their expression being limited to melanocytic tumors and only a few other, rarely encountered entities. 26,52,56 The choice of the melanocytic marker used in the evaluation of a melanocytic lesion depends on the goal of the outcome: sensitive markers such as S100 protein and Sox10 are useful when pathologists wish to detect a possible melanocytic neoplasm (although non-melanocytic neoplasms may also be detected with these stains), while specific markers are useful to establish unequivocal melanocytic derivation (although some melanocytic tumors may be missed using only these markers).…”

S-100-negative, GNA11 mutation-positive intramedullary meningeal melanocytoma of the thoracic spine: A radiographic challenge and histologic anomaly

“…[ 19 ] This may indicate loss of antigenicity/dedifferentiation. [ 1 , 3 ] Although S-100 loss of antigenicity has been reported in metastatic melanoma, its loss in primary melanoma is rare. [ 2 , 25 ] Aisner et al .…”

Immunohistochemical Markers in the Differential Diagnosis of Melanoma and Nevus in Humans

“…Correct identification, differentiating it from other benign and malignant entities, is of primordial importance; histological examination of surgical biopsies plays an important role in the diagnosis of primary cutaneous melanomas. IHC permits broad typification of tumors like carcinoma, melanoma, lymphoma or sarcoma, particularly in cases of barely differentiated malignant neoplasias in which the lineage of the cancerous cells is hard to establish by morphology alone (Biernacka et al, 2016).…”