Sporadic naturally occurring melanoma in dogs as a preclinical model for human melanoma

Abstract

Melanoma represents a significant malignancy in humans and dogs. Different from genetically engineered models, sporadic canine melanocytic neoplasms share several characteristics with human disease that could make dogs a more relevant preclinical model. Canine melanomas rarely arise in sun-exposed sites. Most occur in the oral cavity, with a subset having intra-epithelial malignant melanocytes mimicking the in situ component of human mucosal melanoma. The spectrum of canine melanocytic neoplasia includes benign lesions with some analogy to nevi, as well as invasive primary melanoma, and widespread metastasis. Growing evidence of distinct subtypes in humans, differing in somatic and predisposing germ-line genetic alterations, cell of origin, epidemiology, relationship to ultraviolet radiation and progression from benign to malignant tumors, may also exist in dogs. Canine and human mucosal melanomas appear to harbor BRAF, NRAS, and c-kit mutations uncommonly, compared with human cutaneous melanomas, although both species share AKT and MAPK signaling activation. We conclude that there is significant overlap in the clinical and histopathological features of canine and human mucosal melanomas. This represents opportunity to explore canine oral cavity melanoma as a preclinical model.

Keywords: animal model; clinical trial design; comparative study; digital telepathology; image analysis; melanoma; signal transduction.

Figure 1

Similarities between histopathological features of mucosal melanomas in dogs and humans. Photomicrographs of representative human (left side column A, C, E, G) and dog (right side column B, D, F, H) melanomas are shown. (A, B) Ulceration in amelanotic melanomas. (C, D, E, F) Extensive vertical growth phase with malignant melanocytes infiltrating the proprial/submucosal muscle and/or collagen bundles. (G, H) Extensive invasion of lymph node (LN) parenchyma by metastatic melanoma (*). Hematoxylin and eosin stain. (A, B, E, F, Bar = 50 μm; C, D, G, H, Bar = 500 μm).

Figure 2

Lentiginous-like in situ involvement in mucosal melanomas by malignant melanocytes in the mucosal epithelium. Clusters of malignant melanocytes occur in the epithelial stratum basale and ascend into superficial strata. Photomicrographs of hematoxylin–eosin-stained (A) human mucosal melanoma and (B) canine mucosal melanoma. (C) Radial extension of malignant melanocytes is evident in the intact mucosal epithelium lateral to the vertical tumor component in some canine melanomas; (same canine patient as in B). Antimelan-A immunohistochemistry, red chromogen label, hematoxylin counter stain. Bar = 50 μm.

Figure 3

Analysis of quantitative expression intensity for p-AKT, PTEN, p-ERK1/2, and KIT, and disease-specific survival within a subset of 27 canine melanoma patients with clinical follow-up. Kaplan–Meier survival curves were generated using patient groups defined as above or below the median expression for each marker (determined by color deconvolution image analysis as immunolabeling scores of brightfield chromogenic IHC from TMA tissue cores; see also Table S4). Expression of these proteins in this cohort was not significantly correlated with survival, as assessed using Mantel–Cox test (p-AKT, P = 0.90; PTEN, P = 0.14; p-ERK, P = 0.86, and KIT, P = 0.68). Primary melanoma tissue specimens were surgically collected from dogs at the time of initial diagnosis prior to further treatment.