Diagnostic Utility of Neural Stem and Progenitor Cell Markers Nestin and SOX2 in Distinguishing Nodal Melanocytic Nevi From Metastatic Melanomas

Pei-Ling Chen; Wei-Shen Chen; Jianping Li; Anne C Lind; Dongsi Lu


Mod Pathol. 2013;26(1):44-53. 

In This Article


One of the diagnostic pitfalls in melanoma sentinel lymph node evaluation is the presence of nodal melanocytic nevi.[8] Stewart and Copeland[28] initially described these intranodal nevocellular aggregates in 1931, yet the mechanism by which these nevus cells reach and reside within the lymph nodes remains poorly understood. Two theories have been proposed to explain the origin of nodal melanocytic nevi.[29] One theory invokes the hypothesis that nodal melanocytic nevi arise from aberrant or arrested migration of neural crest cells during embryogenesis, whereas the opposing theory, or the so-called 'benign metastasis theory' attributes nodal nevi to the mechanical transport of nevus cells from cutaneous melanocytic nevi to lymph nodes via lymphatic drainage.

Even though most investigators consider these nevocellular aggregates benign because of their bland cytology and lack of malignant behavior, the presence of these melanocytes, especially in patients with a history of melanoma, can make the evaluation of sentinel lymph node biopsies challenging for practicing pathologists.29 Unfortunately, immunohistochemical markers such as melan-A/MART1, S100 protein and SOX10 demonstrated limited utility in differentiating metastatic melanomas from melanocytic nevi in lymph nodes.[13,14,16]

In the present study, we showed that the neural stem/progenitor cell markers nestin and SOX2 exhibited high specificity in differentiating metastatic melanomas from nodal melanocytic nevi. In addition, nestin immunostain showed superior sensitivity compared with SOX2 and exhibited preferential staining in melanomas with spindle cell morphology and amelanotic tumor cells. As nestin is a stem/neural progenitor cell marker, the decreased expression of nestin in melanin-producing tumor cells may be related to the more 'differentiated' state of these cells.

When assessing benign nodal nevi and metastatic melanomas, the combined use of nestin and SOX2 immunostains further enhanced the sensitivity and specificity of these two markers in detecting and differentiating melanocytic lesions. In this study, all cases of nodal metastatic melanomas showed either strong nestin (diffusely or in rare cells) or SOX2 positivity, but no nodal melanocytic nevi were positive for both markers. Our experience also indicates that when encountering histologically ambiguous melanocytic lesions, a strong (3+) nestin staining alone is highly suggestive of metastatic melanoma rather than nodal melanocytic nevi.

We specifically selected metastatic melanomas and nodal melanocytic nevi with indisputable histomorphology for this study. In reality, diagnostic challenge often arises when single or rare melanocytes are detected by immunohistochemistry, and in these situations, the classification of such lesions as benign or malignant is not so clear cut. Our study included one case of 'subcapsular/intranodal melanocytic rest' that showed deceptively bland cytology and a benign diagnosis was favored originally. Correlation with strong cytoplasmic nestin staining and clinical follow-up suggested that the 'melanocytic rest' was more likely a histologically ambiguous melanoma micrometastasis rather than a benign melanocytic nevus. We propose that the diagnostic accuracy of sentinel lymph node evaluation, especially when confronted with melanocytes of non-classic histological features, could potentially benefit from nestin and SOX2 immunostains. Future studies involving a larger number of lymph node specimens are needed to address the value of nestin and SOX2 in borderline melanocytic lesions of uncertain malignant potential.

A limiting factor in this study was tissue loss, specifically the loss of melanocytic nevi, upon serial sectioning of tissue blocks. At the outset of this study, six additional cases of nodal melanocytic nevi were identified through a search of our institutional database. However, because of tissue exhaustion, those cases were excluded from this study. One case of a nodal melanocytic nevus had adequate tissue for only one immunostain (nestin) and was thus included in this study. When small nodal melanocytic lesions are encountered in the future, it may be advantageous that additional tissue sections be preserved in the event that further immunohistochemical analysis may be needed for the interpretation. A cocktail of anti-mouse nestin (cytoplasmic)/anti-goat SOX2 (nuclear) antibodies can also be considered for future studies to preserve tissue.

Lastly, one case of metastatic desmoplastic melanoma merits special mention. Unlike conventional melanomas, desmoplastic melanomas are typically positive for S100 protein and SOX10, but are negative, or at best focally positive for melan-A and HMB-45.[12,13] When pathologists encounter desmoplastic melanoma lymph node biopsies, S100 protein immunostain, with all of its limits, and SOX10 are the best options. Here we demonstrated that both nestin and SOX2 immunostains strongly highlighted nodal metastatic desmoplastic melanoma, whereas S100 protein was positive in both the tumor cells and the follicular dendritic cells. We believe nestin and SOX2 may be superior to S100 when evaluating desmoplastic melanomas in sentinel lymph nodes.

In summary, we have provided evidence that the neural stem/progenitor cell markers nestin and SOX2 can effectively differentiate metastatic melanomas from benign nodal melanocytic nevi and potentially serve as powerful diagnostic adjuncts in melanoma sentinel lymph node biopsies and staging.