Detection of Occult Invasion in Melanoma In Situ

JAMA Dermatol. 2016 Nov 1;152(11):1201-1208. doi: 10.1001/jamadermatol.2016.2668.


Importance: It is unclear why some patients with in situ melanoma develop metastases. Few reports demonstrate occult invasion with immunohistochemistry staining, which were discordant with reports interpreting such staining as false-positive.

Objective: To investigate the occurrence of occult invasive disease within in situ melanoma by using methods to circumvent potential limitations in prior study designs.

Design, setting, and participants: Unequivocal in situ melanoma without associated nevi or regression was identified using a consecutive sample of 33 cases plus 1 index case in an academic medical center. After cutting deeper into the most representative tissue block, 3 sequential slides were stained with hematoxylin-eosin (H-E), melanoma antigen (melan-A), and again with H-E. Melan-A-stained slides showing definitive invasion were double-stained with Sry-related HMg-Box gene 10 (SOX10) to confirm the melanocytic nature of the cells of interest. The study evaluated the possibilities of occult invasion detected by immunohistochemistry, sectioning deeper into the tissue block, or both. Slides were independently scored by 3 dermatopathologists with interrater reliability assessed. The study was conducted from January 1, 2012, to July 31, 2014.

Main outcomes and measures: Assessment of the occurrence of occult invasion, diagnosis of invasion by immunohistochemistry alone vs cutting deeper into the tissue block, and occurrence of false-positive results using immunohistochemistry alone.

Results: Occult invasive melanoma was detected in 11 of 33 consecutive cases (33%) of previously diagnosed unequivocal in situ melanoma. Six of 11 melanomas (55%) were diagnosable only by immunohistochemistry. The remaining 5 tumors (45%) were diagnosable by both melan-A and H-E staining, likely as a result of simply cutting deeper into the tissue block. Four cases (12%) showed a few melan-A-positive cells in the dermis, which was insufficient for a diagnosis of invasive melanoma and most consistent on a cytomorphologic basis with occult nevi.

Conclusions and relevance: Although rare, in situ melanoma may metastasize. Occult microinvasion was demonstrated in up to one-third of the specimens in the present study, which provides a plausible explanation for this adverse event. Thus, history and physical examination including regional lymph nodes, education, and surveillance recommendations should be based on a very low, but not zero, risk of metastasis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Biomarkers, Tumor / metabolism*
  • Female
  • Hospitals, University
  • Humans
  • MART-1 Antigen / metabolism*
  • Male
  • Melanocytes / metabolism
  • Melanoma / metabolism*
  • Melanoma / pathology*
  • Neoplasm Invasiveness
  • Predictive Value of Tests
  • Retrospective Studies
  • SOXE Transcription Factors / metabolism*
  • Sensitivity and Specificity
  • Skin Neoplasms / metabolism*
  • Skin Neoplasms / pathology*


  • Biomarkers, Tumor
  • MART-1 Antigen
  • SOX10 protein, human
  • SOXE Transcription Factors