Research Papers:

Loss of the epigenetic mark, 5-Hydroxymethylcytosine, correlates with small cell/nevoid subpopulations and assists in microstaging of human melanoma

Jonathan J. Lee, Martin Cook, Martin C. Mihm, Shuyun Xu, Qian Zhan, Thomas J. Wang, George F. Murphy and Christine G. Lian _

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Oncotarget. 2015; 6:37995-38004. https://doi.org/10.18632/oncotarget.6062

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Jonathan J. Lee1, Martin Cook2,3, Martin C. Mihm4, Shuyun Xu1, Qian Zhan1, Thomas J. Wang1, George F. Murphy1 and Christine G. Lian1

1 Program in Dermatopathology, Department of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

2 Department of Histopathology, Royal Surrey County Hospital, Guildford, United Kingdom

3 Cancer Research UK, Manchester Institute, Manchester, United Kingdom

4 Department of Dermatology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA

Correspondence to:

Christine G. Lian, email:

George F. Murphy, email:

Keywords: 5-hydroxymethylcytosine (5-hmC), melanoma, maturation, small cell/nevoid subpopulation, pre-existing nevus

Received: August 05, 2015 Accepted: September 24, 2015 Published: October 09, 2015


Melanomas in the vertical growth phase (VGP) not infrequently demonstrate cellular heterogeneity. One commonly encountered subpopulation displays small cell/nevoid morphology. Although its significance remains unknown, such subpopulations may pose diagnostic issues when faced with differentiating such changes from associated nevus or mistaking such regions for nevic maturation (pseudomaturation). That ‘loss’ of the epigenetic biomarker, 5-hydroxymethylcytosine (5-hmC), is a hallmark for melanoma and correlates with virulence prompted us to explore the diagnostic utility and biological implications of 5-hmC immunohistochemistry (IHC) in melanomas with small cell/nevoid subpopulations. Fifty-two cases were included in this study, including melanomas with small cell/nevoid subpopulations (MSCN) or melanomas with pre-existing nevus (MPEN). Semiquantitative and computer-validated immunohistochemical analyses revealed invariable, uniform loss of 5-hmC in the conventional melanoma component. By contrast, the nevic components in MPEN cases demonstrated strong nuclear immunopositivity. In MSCN cases, there was partial to complete loss of 5-hmC restricted to these nevoid areas. Based on recent data supporting tight correlation between 5-hmC loss and malignancy, our findings indicate a potential ‘intermediate’ biological nature for small cell/nevoid subpopulations. Because 5-hmC assisted in differentiating such regions from associated nevus, the use of 5-hmC as an adjunct to microstaging in difficult cases showing VGP heterogeneity should be further explored.

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