Elsevier

Human Pathology

Volume 36, Issue 9, September 2005, Pages 1016-1019
Human Pathology

Original contribution
Loss of S100 antigenicity in metastatic melanoma

https://doi.org/10.1016/j.humpath.2005.07.010Get rights and content

Summary

Melanoma is a highly malignant disease that may initially present as a poorly differentiated metastatic tumor. Therefore, the S100 immunostain, immunoreactive in 96% to 99% of melanoma, is used to evaluate poorly differentiated malignant tumors. To develop criteria for correctly diagnosing S100-negative melanomas, we studied the immunohistochemical profile of 1553 patients enrolled in ongoing National Cancer Institute clinical trials for melanoma. Seventeen patients (1%) had metastatic melanoma specimens that were negative for S100. Of the 17 S100-negative lesions, 10 (59%) were immunoreactive for both GP100 and MART-1. Of the 17 S100-negative cases, 13 had a documented primary melanoma. Twenty-four percent of the S100-negative cases had an ocular primary, whereas only 6% of all melanomas had an ocular origin. In 11 of the 17 cases with previous surgical specimens, a prior documented S100-immunoreactive specimen was identified in 9 cases (82%). The time interval for loss of S100 immunoreactivity ranged from 3 weeks to 3 years (average, 13.5 months). There was no association between S100-negative status and histological appearance or site of metastasis. We conclude that all S100-negative melanomas could be correctly identified by negative workup for carcinoma, lymphoma, and sarcoma plus (1) GP100/MART-1 immunoreactivity and/or (2) prior documentation of melanoma.

Introduction

Metastatic melanoma is one of the great mimickers in pathology. The diagnosis of metastatic melanoma is complicated by its ability to metastasize to any site and manifest variable histological patterns. In the absence of a known primary melanoma, accurate diagnosis requires a battery of immunostains. Although not specific, the S100 protein is expressed in all melanocytic cells and in 96% to 100% of malignant melanomas [1], [2], [3], [4]. Adjunct, but less sensitive, markers of melanoma include GP100 (86%), MART-1 (86%), tyrosinase (90%), and KBA-62 (87%) [3], [5], [6].

In up to 4% of metastatic melanomas, the S100 immunostain is negative [7], [8], [9]. One study that evaluated the immunoreactivity for S100 in 124 cases of metastatic melanoma showed a negative staining pattern in 2.4% of cases [6], whereas another study indicated a possible link between tumor metastasis and progression or atypical morphology with loss of immunoreactivity for S100 [8]. To develop criteria for accurately diagnosing S100-negative melanoma, we studied the evolution of S100 immunoreactivity in 1553 patients enrolled in ongoing clinical trials for metastatic melanoma in which multiple specimens were immunophenotyped during the course of their disease. We report on the primary site, histology, and immunophenotype of 17 cases that were negative for S100.

Section snippets

Selection of cases and immunohistochemistry

Melanoma cases in which S100 immunostaining was performed were identified with a keyword search performed on the National Cancer Institute (NCI) computerized database (1999-2004). Immunohistochemical studies were performed on formalin-fixed, paraffin-embedded tissue sections using heat-induced antigen retrieval. In brief, after deparaffinization, the slides were placed in a microwavable pressure cooker with 1.5 L of a 10 mmol/L concentration of citrate buffer (pH 6.0) containing 0.1% Tween 20

Results

A search of the NCI computerized database revealed that 2464 cases of melanoma representing 1553 patients were evaluated by immunohistochemical staining for S100 (Table 1). Of these, 19 metastatic lesions representing 17 unique patients were negative for S100. Of these 17 patients, 9 (53%) had a documented primary cutaneous melanoma. Four had a documented primary ocular melanoma (24%), whereas ocular melanoma represented only 6% of all patients reviewed. In the remaining 4 patients (24%) with

Discussion

The S100 family of proteins is a member of the calcium-binding EF-hand superfamily. Although the exact function of S100 proteins is not clear, they are involved in the regulation of a diverse host of cellular functions, including contraction, motility, growth, differentiation, cell cycle progression, transcription, and secretion [10], [11]. Certain S100 proteins are highly expressed in non–small cell lung cancer, breast cancer, gastric cancer, and lymphoma, whereas reduced levels of other

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