MelanA-negative spindle-cell associated melanoma, a distinct inflammatory phenotype correlated with dense infiltration of CD163 macrophages and loss of E-cadherin

Abstract

MelanA is a known melanocyte marker and is important in melanoma diagnostics. Some tumours, however, show loss of MelanA expression and may therefore be difficult to distinguish from tumours of mesenchymal origin. Pure spindle-cell melanoma is a rare event, and little is known about its biological background and prognosis. However, morphological changes towards a more mesenchymal shape and cellular dedifferentiation may correlate with reactivation of important developmental programmes (epithelial-to-mesenchymal transition) and disseminative tumour cell properties. Inflammation and CD163+ macrophages have been shown to be important inducers of E-cadherin and cell-to-cell adhesion loss, a pivotal and final event of epithelial-to-mesenchymal transition. In a cohort of 385 patients with melanoma, we located nine tumours with a clonal MelanA expression, defined as a tumour section with a distinct MelanA-negative clone next to a MelanA-positive clone. Interestingly, MelanA-negative clones correlated significantly with an augmented inflammatory response of tumour-infiltrating macrophages (CD163+), complete loss of E-cadherin and a spindle-shaped morphology, irrespective of ulcerated status. These cases show the inflammatory heterogeneity of melanoma, which may have important diagnostic, prognostic and therapeutic implications for the patients. We show that melanomas harbour cell clones that bear strong resemblance to tumour-associated macrophages, a pivotal player in a tumour-supporting microenvironment. Interestingly, this distinct inflammatory phenotype is associated with loss of MelanA expression, the presence of spindle-shape morphology and complete loss of E-cadherin, considered as possible markers of poorly differentiated and more invasive tumour cells.

Melanoma subtypes demonstrate distinct PD-L1 expression profiles

“…Spindle cell morphology in melanomas is thought to represent a more immature, dedifferentiated, mesenchymal phenotype. 34,35 PD-L1 expression has previously been associated with an epithelial to mesenchymal transition (EMT) in other tumor types, 36,37 though the relationship between PD-L1, EMT, and the presence of a cytotoxic T-cell infiltrate was not assessed. Our findings comparing the pure desmoplastic type vs other CSD melanomas raise the possibility that it could be a combination of EMT (as exemplified here by a spindle cell morphology) and a diffusely-arrayed antitumor immune response that may contribute to increased levels of PD-L1 expression.…”

A Preclinical Model of Malignant Peripheral Nerve Sheath Tumor-like Melanoma Is Characterized by Infiltrating Mast Cells

“…Experimental mouse studies have shown that mast cells promote B16 melanoma growth and/or metastatic spread through mast cel-derived HIF-1a (45). Histomorphologic analyses of nine primary melanomas with a distinct MelanA-negative clone next to a MelanApositive clone discovered a significant correlation of the loss of MelanA expression with an increased infiltration of CD163 þ macrophages and a spindle-shaped tumor cell morphology in comparison with MelanA expression tumor areas (46). These observations as well as our results suggest that reciprocal tumor-immune cell interactions shape the microenvironment and the melanoma cell phenotype in mouse and man.…”

Inflammation markers in cutaneous melanoma - edgy biomarkers for prognosis

“…This inflammatory phenotype of macrophages is associated with loss of MelanA expression, possible marker of a more invasive tumor cells 27 . Classic inflammation players, like complement system elements, were also studied in relation to tumorigenesis.…”