Page 389 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

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Melanoma

PHILIP J. BERGMAN, LAURA E. SELMIC, AND MICHAEL S. KENT

Melanoma is a relatively common cancer of dogs, especially those Pathology and Molecular Biology
with significant amounts of skin pigmentation. Melanomas are rela-
tively rare in cats. The most common location for canine melanoma Melanomas can be difficult to diagnose pathologically in some
is the haired skin, where they grossly appear to be small brown to situations, especially anaplastic amelanotic melanomas, which
black masses, but they can also appear as large, flat, and/or wrinkled can masquerade as soft tissue sarcomas. 32–34 Numerous investiga-
1,2
masses. Primary melanomas can also occur in the oral cavity, tors have attempted to increase the precision of identifying mela-
nailbed, footpad, eye, gastrointestinal tract, nasal cavity, anal sac, or nomas, predominantly through immunohistochemical (IHC)
mucocutaneous junction. 3–6 Metastatic sites are numerous includ- means. 16,33,35–37 This has been accomplished through the use of
ing lymph nodes (LNs), lungs, liver, meninges, and adrenal glands. 3 multiple IHC assays or use of an IHC cocktail of antibodies. The
Melanoma arises from melanocytes, which are the cells that use of PNL2 and tyrosinase beyond the typical use of Melan A and
generate pigment through the melanosome by a number of mela- S-100 appears to hold particular promise. 38–40
nosomal glycoproteins. In humans, cutaneous melanoma can arise The molecular characterization of canine and feline melano-
as a result of mutations induced by repeated, intense exposure to mas is significantly limited compared with the more comprehen-
41
ultraviolet light (for example, frequent tanning or working out- sive evaluation of human melanomas. BRAF is a member of the
doors). Melanoma is currently the most rapidly increasing inci- MAPK signaling pathway that is commonly mutated in human
42
7,8
dent human cancer. Significant recent research into the etiology cutaneous melanoma, but not in human oral melanoma. Inter-
of human melanoma suggests multiple causes independent of the estingly, BRAF mutations are also uncommon in canine oral malig-
aforementioned UV-associated mutagenesis. 9,10 Because most nant melanomas (MMs). However, downstream constitutive
43
breeds of dogs have a significant hair coat that likely affords them activation of ERK has been identified in both human and canine
44
protection from sunlight, UV-associated melanoma is less likely to MMs, supporting the idea that certain canine and feline malig-
be a primary causative agent in the dog. However, risk factors for nancies can have molecular signatures similar to those of human
canine melanoma are not well established. malignancies in addition to their already well known clinical simi-
The most common oral malignancy in the dog is mela- larities in the context of resistance to chemotherapy and/or radia-
noma. 2,3,11,12 Oral melanoma is most commonly diagnosed in tion therapy (RT) and similar atypical sites of metastasis. A number
Scottish terriers, golden retrievers, Chow Chows, poodles, and of other investigators have reported a variety of molecular abnor-
dachshunds. 2,13–16 Oral melanoma is more commonly seen in malities and/or associations in canine and feline melanoma. 44-85
heavily pigmented breeds and is primarily a disease of older dogs Transcriptome analysis has recently uncovered a variety of pos-
without gender predilection, but may also be seen in younger sible new therapeutic targets in canine melanoma. The melanoma-
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dogs. 13,17,18 Differential diagnoses for oral tumors include squa- associated genes clustered in the areas of focal adhesion and PI3K-Akt
mous cell carcinoma, fibrosarcoma, osteosarcoma, acanthomatous (phosphoinositide 3-kinase/protein kinase B) signaling pathways,
ameloblastoma, and peripheral odontogenic fibroma. 2,3,12,19–21 extracellular matrix–receptor interactions, and protein digestion and
Canine oral melanomas are found in the following locations by absorption. A small subset of dogs with malignant melanoma have
order of decreasing frequency: gingiva, lips, tongue, and hard pal- exon 11 c-kit gene mutations, 62,87 and therefore the more routine
ate. 2,3,11,13,16 Feline melanoma is relatively rare, but appears to be use of c-kit mutation analysis by polymerase chain reaction (PCR)
malignant in most cases. 3,22–29 of canine MMs, and subsequent use of KIT small molecule inhibi-
Melanomas in dogs have extremely diverse biologic behaviors tors (particularly in dogs with advanced stage disease and/or lack
depending on a large variety of factors. A greater understanding of response to Oncept), should be considered. Furthermore, with
of these factors helps the clinician to determine the appropri- somatic mutations in NRAS and PTEN being found in canine
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ate staging, treatment options, and prognosis. The primary fac- MM, similar to human melanoma hotspot sites, these may repre-
tors that determine the biologic behavior of an oral melanoma sent logical therapeutic targets in the future.
in a dog are site, size, stage, and histologic parameters. 13,17,18,30,31
Unfortunately, even with a comprehensive understanding of all of Biologic Behavior and Prognostic Factors
these factors, there are melanomas that have an unreliable biologic
behavior, hence the need for additional research into this relatively The biologic behavior of canine oral melanoma is extremely vari-
common, heterogeneous, but frequently aggressive tumor. able and best characterized based on anatomic site, size, stage,

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