title: 5-Hydroxymethylcytosine is a nuclear biomarker to assess biological potential in histologically ambiguous heavily pigmented melanocytic neoplasms.
abstract: BACKGROUND
  5-Hydroxymethylcytosine (5-hmC) is an epigenetic marker detectable through immunohistochemistry (IHC) that has been shown to distinguish benign nevi from melanoma with high sensitivity and specificity. The purpose of the study was to explore its diagnostic utility in a subset of histologically challenging, heavily pigmented cutaneous melanocytic neoplasms.
  
  
  METHODS
  5-hmC IHC was performed on 54 heavily pigmented melanocytic tumors. Semi-quantitative analysis of immunoreactivity was correlated with clinical, pathologic and follow-up data.
  
  
  RESULTS
  Benign melanocytic neoplasms (4 of 4 blue nevi with epithelioid change; 12 of 12 combined nevi; 5 of 5 deep penetrating nevi, DPN) exhibited strong 5-hmC nuclear reactivity. Eight heavily pigmented blue nevus-like melanomas and 7 of 8 pigmented epithelioid melanocytomas (PEM) showed significant 5-hmC loss. Five of 7 atypical DPN cases and 8 of 10 melanocytic tumors of uncertain malignant potential (MELTUMP) showed low to intermediate 5-hmC immunoreactivity. These differences were statistically significant (P-value <.0001).
  
  
  CONCLUSIONS
  Loss of 5-hmC may be helpful in differentiating benign, diagnostically challenging, heavily pigmented melanocytic tumors from those with malignant potential. The intermediate to low 5-hmC immunoreactivity in atypical DPNs, PEMs and so-called MELTUMP categories further underscores the need to consider these neoplasms as having some potential for lethal biological behavior.
authors.affiliation: Program in Dermatopathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Lee
authors.affiliation: Melanoma Institute Australia, North Sydney, Australia.|Sydney Medical School, The University of Sydney, Sydney, NSW, Australia.|Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, NSW, Australia.
authors.forename: Ricardo E
authors.initials: RE
authors.lastname: Vilain
authors.affiliation: Program in Dermatopathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Scott R
authors.initials: SR
authors.lastname: Granter
authors.affiliation: Program in Dermatopathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Nina R
authors.initials: NR
authors.lastname: Hu
authors.affiliation: Program in Dermatopathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Scott C
authors.initials: SC
authors.lastname: Bresler
authors.affiliation: Program in Dermatopathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Shuyun
authors.initials: S
authors.lastname: Xu
authors.affiliation: Program in Dermatopathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Alexander H
authors.initials: AH
authors.lastname: Frank
authors.affiliation: Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Martin C
authors.initials: MC
authors.lastname: Mihm
authors.affiliation: Melanoma Institute Australia, North Sydney, Australia.|Sydney Medical School, The University of Sydney, Sydney, NSW, Australia.|Discipline of Surgery, Royal Prince Alfred Hospital, Sydney, NSW, Australia.
authors.forename: Robyn P M
authors.initials: RP
authors.lastname: Saw
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Fletcher
authors.affiliation: Melanoma Institute Australia, North Sydney, Australia.|Sydney Medical School, The University of Sydney, Sydney, NSW, Australia.|Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, NSW, Australia.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Scolyer
authors.affiliation: Program in Dermatopathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: George F
authors.initials: GF
authors.lastname: Murphy
authors.affiliation: Program in Dermatopathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
authors.forename: Christine G
authors.initials: CG
authors.lastname: Lian
mesh_terms: D044503:5-Methylcytosine / Q000031:analogs & derivatives* / Q000032:analysis; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis*; D015331:Cohort Studies; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008545:Melanoma / Q000175:diagnosis*; D008875:Middle Aged; D009508:Nevus, Pigmented / Q000175:diagnosis; D012189:Retrospective Studies; D012878:Skin Neoplasms / Q000175:diagnosis*; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; C011865:5-hydroxymethylcytosine; D044503:5-Methylcytosine
keywords: 5-hydroxymethylcytosine; MELTUMP; epigenetics; melanoma; pigmented epithelioid melanocytoma