Morphogenesis and Fibrogenesis Pathways for the Distinction of Slerosing Melanocytic Nevus and Desmoplastic Malignant Melanoma

Background: Fibroblastic reaction can be observed in benign and malignant melanocytic lesions and cause serious diagnostic problems. The mechanism of fibrogenesis and the diagnostic utility of fibrogenesis markers have not been investigated in this context.

Design: We analyzed symmetry, maturation, growth patterns (nested-trabecular, nodular-solid, diffuse), nuclear grade (including chromatin, nucleolus, pleomorphism and anisokaryosis), stromal reaction, and confluent necrosis in desmoplastic (sclerosing) melanocytic nevi (DMN, 18) and desmoplastic malignant melanoma (DMM, 24), classified according to the WHO criteria. Cases with history of previous excision, trauma or histological scarring were excluded. Representative samples were evaluated by quantitative RT-PCR and standard in situ techniques for morphogenesis and fibrogenesis pathways (fibrinogen, CD34, CTNNB1, FOXC2, JAG1, RAC1, SMAD2, SNAI1, SOX10, TGFB1, TGFB2, TGFB3, TWIST1, WNT11, WNT5A, PDGFA, SPARC, PDGFRA, HSPG2). Appropriate controls were run. Fisher’s exact tests and analysis of variance (significant if P<0.05) were used for comparison; significant variables were then selected for discriminant analysis with cross-validation for diagnostic groups (DMN vs. DMM).

Results: Fibrinogen expression was found in both DMN and DMM but with different pattern: perivascular stroma in DMN and in tumour cells and blood vessels with a heterogeneous pattern in MM. CD34 was revealed positive in dermal dendritic cells of the sclerosed interstitium of DMN, and in the peritumoural stroma of DMM. PDGFRA was expressed in DMN, but not in DMM and HSPG2 (perlecan protein) revealed significantly higher expression in DMM. The remaining markers revealed no statistically significant differences in the expression by DMN and DMM.

Conclusions: The sclerosis seen in DMN is directly correlated with fibrinogen leaking from blood vessels and it is not a destructive process (preserved intratumour CD34 positive cells), whereas the fibrogenesis in MM is secondary to tissue destruction (loss of intratumour CD34 positive cells and increased turnover of HSPG2) and is enhanced by PDGFRA-independent tumour cell expression of fibrinogen.