The clinicopathological and gene expression patterns associated with ulceration of primary melanoma

Abstract

Summary Ulceration of primary melanomas is associated with poor prognosis yet is reported to predict benefit from adjuvant interferon. To better understand the biological processes involved, clinico-pathological factors associated with ulceration were determined in 1804 patients. From this cohort, 348 primary tumor blocks were sampled to generate gene expression data using a 502-gene cancer panel and 195 blocks were used for immunohistochemistry to detect macrophage infiltration and vessel density. Gene expression results were validated using a whole genome array in two independent sample sets. Ulceration of primary melanomas was associated with more proliferative tumors, tumor vessel invasion and increased microvessel density. Infiltration of tumors with greater number of macrophages and gene expression pathways associated with wound healing and up-regulation of pro-inflammatory cytokines suggest that ulceration is associated with tumor related inflammation. The relative benefit from interferon reported in patients with ulcerated tumors may reflect modification of signalling pathways involved in inflammation.

Immune biomarkers are more accurate in prediction of survival in ulcerated than in non-ulcerated primary melanomas

“…Inflammatory cytokines can promote tumorigenesis and tumor growth. A recent study by the Newton-Bishop group defined a gene panel that correlating with ulceration in melanoma, and some of them, including IL-6 pro-inflammatory cytokine and certain chemokines (data not shown), plays distinctive roles in angiogenesis and tumor growth [12]. However, these genes may serve paradoxical functions among different tumor types and may act as adjuvants in the context of vaccination or immunotherapy, triggering anti-tumor responses [39].…”

“…Several groups have proposed that ulcerated melanomas have distinct gene profiles, increased vascularity, increased lymphovascular invasion, increased sentinel node positivity, and immunosuppression in primary lymph nodes even in the absence of tumor cells [2, 12]. In addition, it has been advanced that ulcerated melanomas show greater response rates to interferon therapy [3, 5, 13].…”

Increased tumour cell PD‐L1 expression, macrophage and dendritic cell infiltration characterise the tumour microenvironment of ulcerated primary melanomas

“…2,3 Second, melanoma ulceration is histologically characterised by a full-thickness loss of the epidermis and an associated host response surrounding the tumour. 4 These immunological alterations in the tumour microenvironment (TME) are partially explained by distinct gene-expression profiles associated with tumour ulceration 5,6 and may contribute to increased invasiveness. Immunohistochemical studies demonstrate an increase in microvessel density and lymphovascular invasion in ulcerated tumours, which are both markers of metastatic potential and poor prognosis.…”

Vitamin D, vitamin A, the primary melanoma transcriptome and survival

“…We therefore looked at the gene expression patterns associated with ulceration in a Leeds test set and in two validation sets from Leeds and Lund. 20 We saw that ulceration was associated with upregulation of the pro-inflammatory cytokines IL-6 and IL-8. A pathway analysis was suggestive of a wound healing response, bolstering our hypothesis that inflammation is a key driver of ulcerated tumours.…”

“…We had reported previously that ulcerated tumours have a more vascular stroma, rich in macrophages, suggesting the possibility that the ulcerated milieu is protumourigenic, predisposing to inflamed tumours. We therefore looked at the gene expression patterns associated with ulceration in a Leeds test set and in two validation sets from Leeds and Lund . We saw that ulceration was associated with upregulation of the pro‐inflammatory cytokines IL‐6 and IL‐8 .…”