title: Proliferative nodules arising within congenital melanocytic nevi: a histologic, immunohistochemical, and molecular analyses of 43 cases.
abstract: The histopathologic interpretation of proliferative nodules (PNs) in congenital melanocytic nevi can present significant challenges as some PNs may exhibit atypical features that make the distinction from melanoma difficult. We compared histologic features, Ki-67%, PHH3, and CD117% expression levels by immunohistochemistry in 18 benign and 25 atypical PNs (from 41 patients) with that of background congenital nevi (of these 43 cases), 10 congenital nevi, and 3 dermal melanomas arising in congenital melanocytic lesions. In addition, we evaluated the presence of BRAF, GNAQ, HRAS, KRAS, and NRAS mutations in all groups using the SNaPshot Multiplex System. Follow-up was available on 19 patients (9 benign and 10 atypical PNs) (range, 2 to 20 y; median, 8 y) and all were alive with no evidence of disease. The specific histologic features of atypical PNs, such as sharp demarcation (P<0.001), expansile growth (P<0.001), epidermal effacement (P<0.001), nuclear pleomorphism (P<0.001), and increased mitoses (P<0.001), differed significantly from those of benign PNs. Immunohistochemical results showed that Ki-67% and PHH3 scores, but not CD117% expression, were significantly higher (P<0.05) in atypical PNs. Molecular analyses showed that the PNs and background congenital melanocytic nevi of the giant congenital nevi possess more frequent NRAS mutations and infrequent BRAF mutations when compared with those of the remaining cases. These findings suggest that histologic features and Ki-67 and PHH3 expression levels are the strongest parameters to distinguish between benign versus atypical PNs. The immunohistochemical results suggest that atypical PNs are distinct borderline lesions residing between benign PNs and dermal melanomas. Although numerous mutations are detected in the samples, the diagnostic use of molecular analysis in this regard is limited.
authors: Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
authors: Pushkar A
authors: PA
authors: Phadke
authors: Dinesh
authors: D
authors: Rakheja
authors: Long P
authors: LP
authors: Le
authors: Maria Angelica
authors: MA
authors: Selim
authors: Payal
authors: P
authors: Kapur
authors: Amy
authors: A
authors: Davis
authors: Martin C
authors: MC
authors: Mihm
authors: Mai P
authors: MP
authors: Hoang
mesh_terms: D000293:Adolescent; D000328:Adult; D014408:Biomarkers, Tumor / Q000032:analysis*; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D003937:Diagnosis, Differential; D005260:Female; D044385:GTP-Binding Protein alpha Subunits / Q000235:genetics; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D011905:Genes, ras; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D008545:Melanoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008875:Middle Aged; D009508:Nevus, Pigmented / Q000151:congenital / Q000235:genetics / Q000473:pathology*; D011518:Proto-Oncogene Proteins / Q000235:genetics; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D055815:Young Adult; D018631:ras Proteins / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; C554061:GNAQ protein, human; D044385:GTP-Binding Protein alpha Subunits; C117307:KRAS protein, human; D019394:Ki-67 Antigen; D011518:Proto-Oncogene Proteins; D019009:Proto-Oncogene Proteins c-kit; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins