title: Loss of the epigenetic mark, 5-Hydroxymethylcytosine, correlates with small cell/nevoid subpopulations and assists in microstaging of human melanoma.
abstract: 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.
authors.affiliation: Program in Dermatopathology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Lee
authors.affiliation: Department of Histopathology, Royal Surrey County Hospital, Guildford, United Kingdom.|Cancer Research UK, Manchester Institute, Manchester, United Kingdom.
authors.forename: Martin
authors.initials: M
authors.lastname: Cook
authors.affiliation: Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Martin C
authors.initials: MC
authors.lastname: Mihm
authors.affiliation: Program in Dermatopathology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Shuyun
authors.initials: S
authors.lastname: Xu
authors.affiliation: Program in Dermatopathology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhan
authors.affiliation: Program in Dermatopathology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Wang
authors.affiliation: Program in Dermatopathology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: George F
authors.initials: GF
authors.lastname: Murphy
authors.affiliation: Program in Dermatopathology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Christine G
authors.initials: CG
authors.lastname: Lian
mesh_terms: D044503:5-Methylcytosine / Q000031:analogs & derivatives; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism; D018288:Carcinoma, Small Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D003596:Cytosine / Q000031:analogs & derivatives* / Q000378:metabolism; D057890:Epigenomics; D005260:Female; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D008545:Melanoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008875:Middle Aged; D009367:Neoplasm Staging / Q000592:standards*; D009508:Nevus, Pigmented / Q000235:genetics / Q000473:pathology*; D011379:Prognosis; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D055815:Young Adult; D000096142:Cutaneous Malignant Melanoma
chemical_list: D014408:Biomarkers, Tumor; C011865:5-hydroxymethylcytosine; D044503:5-Methylcytosine; D003596:Cytosine
keywords: 5-hydroxymethylcytosine (5-hmC); maturation; melanoma; pre-existing nevus; small cell/nevoid subpopulation