A Review of Key Biological and Molecular Events Underpinning Transformation of Melanocytes to Primary and Metastatic Melanoma

Abstract

Melanoma is a major public health concern that is responsible for significant morbidity and mortality, particularly in countries such as New Zealand and Australia where it is the commonest cause of cancer death in young adults. Until recently, there were no effective drug therapies for patients with advanced melanoma however significant advances in our understanding of the biological and molecular basis of melanoma in recent decades have led to the development of revolutionary treatments, including targeted molecular therapy and immunotherapy. This review summarizes our current understanding of the key events in the pathway of melanomagenesis and discusses the role of genomic analysis as a potential tool for improved diagnostic evaluation, prognostication and treatment strategies. Ultimately, it is hoped that a continued deeper understanding of the mechanisms of melanomagenesis will lead to the development of even more effective treatments that continue to provide better outcomes for patients with melanoma.

Keywords: diagnosis; melanoma; melanomagenesis; metastasis; pathology; progression; treatment.

Figure 1

Key phenotypic and molecular events in melanoma pathogenesis and progression. Readers are referred to the text for in depth discussion of each event.

Figure 2

Background skin adjacent to melanomas (haematoxylin and eosin (H&E) images). (A) Melanocytic hyperplasia (arrows) in chronically sun damaged skin adjacent to lentigo maligna is a manifestation of a dysregulated single cell microenvironment. Various mutations have been identified in this background skin, many of which are attributed to keratinocytes, but native melanocytes are also postulated to acquire a high mutational burden. (B) CyclinD1 amplifications have been detected in melanocytes in epidermis adjacent to acral melanomas (open arrow).

Figure 3

Subtypes of nevi (H&E images). (A) The common acquired nevus is a stable lesion resting in a state of senescence and the vast majority possess a low mutational burden. (B) Blue nevus. (C) Spitz nevus. Both blue nevi and Spitz nevi lack significant chromosomal aberrations by comparative genomic hybridization. (D) Some Spitz nevi are associated with isolated gain of chromosome 11p and HRAS mutations, and harbor translocations involving kinase gene fusions.

Figure 4

Dysplastic nevi have an overall mutational burden between that of nevi and melanoma (H&E images). (A) Multiple dysplastic nevi, such as this example, are clinical markers of increased risk for cutaneous melanoma and diagnosis of lesions with mild to moderate degrees of cytological and architectural atypia (solid arrows) is relatively reproducible. (B) Lesions with histological features between severely dysplastic nevus and melanoma in situ, such as this case with focal pagetoid spread and lentiginous architecture (open arrows) among an otherwise nested junctional component, are subject to interobserver and intraobserver variability, even among experts. Identification of differing mutational profiles between dysplastic nevi and melanomas has the potential to assist in diagnosis of these challenging lesions.

Figure 5

Blue nevi and atypical variants are characterized by GNAQ and GNA11 mutations (H&E images). (A,B) Blue nevus. The pigmented spindle cells show minimal cytological atypia in benign lesions. (C,D) This atypical blue nevus shows nuclear atypia, raising suspicion for malignancy but other histological features fall short of melanoma. Recent investigations suggest that BAP1 mutation is a late event on the pathway to malignancy among blue nevus-like lesions so BAP1 loss may be a useful ancillary test to support a diagnosis of malignancy in ambiguous cases.

Figure 6

BAP1 inactivated Spitz tumor (A–C: H&E images, D: BAP1 immunohistochemistry). (A) Low power silhouette of a BAP1 inactivated Spitz tumor (H&E × 12.5). (B,C) These lesions often have a characteristic voluminous cytoplasm and a prominent lymphocytic reaction, suggesting a peculiar. (D) Lesional melanocytes show loss of nuclear expression of BAP1. Lymphocytes serve as a positive internal control.

Figure 7

Deep penetrating nevus (A–C: H&E images, D: HMB45 immunohistochemistry). (A) Deep penetrating nevi are often seen in conjunction with a conventional nevus (combined nevus). (B) Both components harbor MAPK pathway mutations but activated WNT signaling appears to drive transformation to the deep penetrating nevus phenotype with its distinctive large cells, pigment synthesis and lack of maturation. (C,D) In addition to the distinct genetic differences, the components are delineated by morphology and differing HMB45 expression, with stronger labelling in the DPN component (solid arrows) compared to the conventional nevus component (open arrows).

Figure 8

Melanoma (A–D: H&E images, C: inset Sox 10 immunohistochemistry). (A) Melanoma in situ is conceptualised as an early melanoma confined by the basement membrane. Loss of contact inhibition is a biological event that is thought to allow the radial growth of melanocytes through the epidermis. TERT promoter mutations are identified in melanoma in situ. (B) Nodular melanoma. The vertical growth phase of melanoma requires the accumulation of mutations that promote tissue invasion, tumor cell survival, mesenchymal interactions and host immune system evasion. (C and inset) Desmoplastic melanomas, shown here with Sox 10 immunohistochemistry, frequently harbor NF1 mutations. (D) Melanomas at sun protected sites, such as this acral melanoma, are biologically distinct from their sun exposed counterparts due to higher frequencies of KIT mutations and multiple gene amplifications, commonly cyclinD1.

Figure 9

Metastatic melanoma. (A) H&E × 12.5. In transit metastasis. Tumor metastasis is dependent on critical factors that drive tumor cell motility, dissemination into angiolymphatics, and tumor cell proliferation away from the primary site. (B) H&E × 40. Targeted therapy and immunotherapy have heralded a revolutionary era in melanoma management. Pathological response manifests variably as tumor cell necrosis, melanosis, lymphocytic infiltration and fibrosis, as seen in this lymph node metastasis of melanoma after neoadjuvant therapy. Mechanisms of resistance and primary non-response are the focus of active research.