JPC SYSTEMIC PATHOLOGY

INTEGUMENTARY SYSTEM

September 2025

I-N24B

SLIDE A

Signalment (JPC # 2785784): Miniature schnauzer

HISTORY: Firm, pedunculated dermal mass

HISTOPATHOLOGIC DESCRIPTION: Haired skin: Expanding the dermis and elevating the overlying hyperplastic and focally ulcerated epidermis is an unencapsulated, pedunculated, moderately cellular neoplasm composed of spindle cells arranged in short, interlacing streams and bundles separated by moderate amounts of collagenous matrix. Neoplastic cells have indistinct cell borders, moderate amounts of eosinophilic cytoplasm that occasionally contains brown, globular pigment (melanin) and an oval to elongate nucleus with finely stippled chromatin and 1 variably distinct nucleolus. Anisocytosis and anisokaryosis are mild and there are 1 per 2.37 mm². Multifocally, there are individual or small nests of neoplastic cells within the epidermis (junctional activity). Multifocally within the dermis there are scattered macrophages with intracytoplasmic melanin. The epidermis is focally ulcerated with an overlying serocellular crust composed of cellular debris, degenerate neutrophils, hemorrhage, fibrin, and colonies of basophilic cocci. Subjacent to the crust within the superficial dermis there are increased numbers of small caliber blood vessels lined by reactive endothelium that is oriented perpendicular to the ulcer and perpendicular to abundant surrounding hypertrophied fibroblasts (granulation tissue). Rare apocrine glands are ectatic and surrounded by moderate numbers of lymphocytes, plasma cells, and fewer transmigrating neutrophils and macrophages (hidradenitis) and there is multifocal hemorrhage, fibrin and edema. The epidermis is hyperplastic, characterized by acanthosis, spongiosis, and rete ridge formation.

MORPHOLOGIC DIAGNOSIS: Haired skin: Melanocytoma, miniature schnauzer, canine.

SLIDE B

Signalment (JPC # 2327682): Age and breed unspecified dog.

HISTORY: A mass on the digit

HISTOPATHOLOGIC DESCRIPTION: Haired skin and bone, digit: Expanding the dermis, elevating a focally extensively ulcerated epidermis, and infiltrating the bone of the third phalanx (P3) is an unencapsulated, poorly demarcated, moderately cellular, infiltrative neoplasm composed of polygonal to spindle cells arranged in lobules, nests, and packets supported on a moderate fibrovascular stroma. Neoplastic cells have variably distinct cell borders, a scant to moderate amount of eosinophilic, granular cytoplasm that often contains brown pigment globules (melanin), and a round to oval nucleus with finely stippled chromatin and 1 to 2 prominent nucleoli. Anisocytosis and anisokaryosis are moderate and there are 3 mitotic figures per 2.37 mm². Multifocally, there are individual or small nests of neoplastic cells within the follicular epithelium (junctional activity). Within the neoplasm there is frequent single cell necrosis, moderate numbers of melanin-laden macrophages, and multifocal areas of lytic necrosis with replacement by hemorrhage, fibrin, edema, moderate numbers of viable and degenerate neutrophils, and fewer hemosiderin-laden macrophages. There is multifocal bone loss (osteolysis) with replacement by neoplastic cells. There are often scalloped trabeculae of immature woven bone extending from the remaining lamellar mature bone, basophilic reversal lines, and osteoclasts within Howship’s lacunae/resorption bays (bony remodeling).

MORPHOLOGIC DIAGNOSIS: Haired skin and bone, digit: Melanoma, breed unspecified, canine.

GENERAL DISCUSSION:

• Melanocytes:
  • Originate from neuroectoderm, and migrate to the skin and hair bulbs during fetal development
  • Mature, dendritic, pigment-producing cells found between basal keratinocytes of the epidermis and hair bulb; contain E-cadherin cell surface markers which serve as adhesion mechanism between melanocytes and keratinocytes
  • Produce melanin, which is stored within melanosomes, transferred to keratinocytes, and serve to protect the skin from UV radiation
  • Melanoblasts which fail to reach the epidermis will reside in the dermis as intradermal melanocytes
• Melanocytic tumors are most common in dogs, horses, and some breeds of pig; reported in many wild and domestic species

PATHOGENESIS:

• Not completely understood; UV radiation plays a role in development of melanocytic tumors in humans; no demonstrated role of UV radiation in the development of melanomas in dogs and other domestic species
  • Angora goats prone to UV-induced melanomas
• Overexpression of microphthalmia transcription factor may promote melanocyte stem cell pool exhaustion and melanoma development in horses with grey phenotype; grey phenotype due to mutation in STX17 gene
• One recent study found that over 60% of canine oral malignant melanomas showed evidence of defective DNA mismatch repair proteins (Inanaga S et al., Vet Pathol 2021)
• Expression of checkpoint molecules (which suppress tumor-infiltrating lymphocytes [TILs] in tumors) in canine melanomas via quantification of mRNA. As in human melanomas, overexpression of three checkpoint molecules, PDCD1 (PD-1), CD274 (PD-L1), and PDCD1LG2 (PD-L2) is a common feature of canine melanoma. The study found that the expression of these checkpoint molecules is modulated by interactions between CD3+ T cells and cancer cells (Stevenson VB, Vet Pathol 2021)

TYPICAL CLINICAL FINDINGS:

• Mitotic index (MI) is a key prognostic indicator that predicts clinical behavior and should be determined in all melanocytic neoplasms; nuclear atypia, ulceration, and deep infiltration beyond the dermis are also associated with a poor outcome; see Smedley (2011) publication for detailed information
• Degree of pigmentation and histologic pattern are not correlated with prognosis according to several studies
• Oral and lip melanocytic neoplasms: Newer studies have demonstrated a subpopulation of oral and lip melanocytic neoplasms with a favorable diagnosis, though historically, these locations were considered to be “almost invariably malignant”; oral and lip neoplasms composed of heavily pigmented, well-differentiated melanocytes with a low mitotic index (<4/10HPF) have a favorable prognosis
• Lingual lesions: the most common canine neoplasms found in lingual biopsies in recent retrospective at the Athens VDL were melanocytic neoplasms; chow chows and Labrador retrievers accounted for 43% of cases (Riker, J Vet Diagn Invest 2025)
• Nailbed melanocytic neoplasms: often malignant
  • Recent report of first metastatic digital chondrogenic melanocytic tumor (da Silva, J Comp Pathol 2022)
• Cutaneous melanocytic neoplasms: often benign; canine melanocytic neoplasms with a mitotic index of > 3/10 HPF are expected to have shorter survival times
• Melanoma:
  • Often occur in older animals, though are reported in young animals of many species
  • Metastasis most often occurs via lymphatics to regional lymph nodes and lungs, though has been reported in unusual locations such as the brain, heart and spleen

TYPICAL GROSS FINDINGS:

• Melanocytoma (benign melanoma, melanotic nevus): Usually solitary, circumscribed, alopecic, gray to brown to black, cutaneous nodules that range from 1 to 4 cm in diameter; smooth or slightly papillated to pedunculated; ulceration is uncommon
• Melanoma: Sessile, variably circumscribed, unencapsulated; polypoid, dome-shape, or plaque-like; gray to brown to black; range from 1 to 10 cm in diameter; ulceration is common

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• General features:
  • Amount of pigmentation is variable in melanocytic neoplasms; a variety of cell morphologies (spindle cell, balloon cell (clear cell), epithelioid, and signet-ring cell) are possible
  • Junctional activity (proliferation of neoplastic melanocytes in small nests within the epidermis, at the epidermal/dermal, or follicular/dermal junction) is a helpful diagnostic feature; see differentials for others tumors with junctional activity
• Melanocytoma (benign melanocytic neoplasm, melanotic nevus):
  • Histological classifications: Junctional (confined to the epidermis and dermoepidermal junction), compound (involving both dermis and epidermis), or dermal; compound and dermal are the most common in domestic animals
  • Can be composed of any melanocytic cell type; most common are spindle cells (whorls or fingerprint patterns in the dermis), epithelioid cells (nests in the dermis or epidermis, and along the dermo-epidermal junction) or a combination
  • Degree of pigmentation can vary; epithelioid cells are often darkly pigmented, and spindle cells are often lightly pigmented to amelanotic
  • Mitotic figures are rare; MI <3 is reported to predict benign behavior
  • Balloon cell melanocytoma variant: dermal mass composed of large epithelioid to polygonal cells with abundant amphophilic to eosinophilic cytoplasm with a granular appearance; few neoplastic cells will contain fine melanin granules; nuclei are small, uniform and hyperchromatic
  • Melanocytoma-acanthoma (melanoacanthoma): Rare, reported in dogs; circumscribed, unencapsulated, solitary, pigmented nodule, < 1 cm in diameter, combination of junctional melanocytoma with a benign epithelial tumor; epithelial cells forms nests and cords +/- cystic structures containing keratin, and melanocytic cells forms nests in the epidermis and sometimes within the epithelial cell cords, or may have a spindle shape and form whorls between epithelial cords

• Melanoma:
• Can be composed of a variety of melanocytic cell morphologies; most common are epithelioid cells, spindle cells, or a combination
  • • Epithelioid cells form clusters and/or nests
    • Spindle cells form streams, bundles, and/or whorls
• Cells may be heavily pigmented or amelanotic; epithelioid and spindle cell form typically pigmented; balloon cell form and signet-ring cell form are usually poorly pigmented to amelanotic
• Cytoplasm is moderate to abundant
• Variable nuclear pleomorphism
• 3 or more mitotic figures per 2.37 mm² (for cutaneous location), +/- mitotic atypia
• Varying degrees of junctional activity
• Other variants:
  • Balloon cell melanoma: Dermal masses, sometimes multilobulated; junctional activity absent; large cells with large, vesicular nuclei, prominent nucleoli, low MI, abundant clear cytoplasm without visible melanin; rarely, few cells will contain pale, dust-like granules; rare multinucleated cells
  • Signet-ring melanoma: Round to polygonal cells with eccentric nuclei compressed by abundant pale eosinophilic or amphophilic cytoplasm without visible melanin; rarely, few cells contain pale granules; rare multinucleated cells
  • Angiomatoid melanomas reported rarely in humans; recent report documents cases in the skin and oral cavity of two dogs; composed of CD34 (-), SOX10 (+) neoplastic cells resembling endothelial cells, lining large blood vessels; “vasculogenic mimicry” (Ramirez-Hernandez C, J Comp Pathol 2022)

ADDITIONAL DIAGNOSTIC TESTS:

• Immunohistochemistry:
• Melanocyte specific markers:
  • Melan-A (currently the most specific marker – melanocyte-differentiating protein recognized by cytotoxic T cells) useful in many species
  • PNL2, TRP-1 and TRP-2 used alone or as a cocktail with Melan-A is JKP recommendation
  • HMB-45: Specific marker for melanoma cells
  • SOX-10 and TRP-1 cross reactive in feline non-neoplastic melanocytes; variable expression in ocular and nonocular melanomas (Orlandi, Vet Pathol 2024)
• Neural crest markers: S-100 and neuron specific enolase (NSE) are sensitive markers for melanocytes, but are not specific
• SOX-10: transcription factor associated with melanocytic, neural crest, PNS development; high sensitivity; may be useful screening marker for canine melanoma (King, Vet Pathol 2024)
  • SOX-10 is a promising diagnostic marker; may improve early detection of metastatic lesions (Sabattini, Vet Pathol 2025)
• Mesenchymal markers: Vimentin
• Prognostic markers:
  • Programmed cell death ligand (PDLI): membranous immunoreactivity in 17/17 melanomas in a recent study; part of immune checkpoint regulating antitumor adaptive immune response (Muscatello, Vet Pathol 2025)
  • FoxP3, CTLA-4, and IDO likely play a role in melanoma immunoescape. All show high gene and protein expression in oral melanomas and were differently expressed in cutaneous melanoma compared to benign counterparts; FoxP3 expression >6.9 cells/HPF is an independent predictor of death; CTLA-4 expression associated with a worse prognosis; IDO expression associated with increased death hazard (Porcellato, I, Vet Pathol 2021)
  • A recent study looked at tumor-infiltrating lymphocyte (TILs) presence and distribution in canine oral melanomas; patients with higher TIL scores and an increased frequency of CD8+ T lymphocytes had higher survival rates, suggesting that TIL evaluation in canine oral melanoma is relevant to predicting tumor aggression and patient prognosis (Yasumaru, Vet Pathol 2021)
  • Recent study found no apparent relationship between detected c-Kit mutations and KIT expression, indicating that, unlike in human oral melanoma, the use of tyrosine kinase inhibitor therapy to treat canine oral malignant melanoma is unlikely to be effective (Smedley, RC, Vet Pathol 2021)
• Other molecular diagnostics:
  • Multivariate analysis/Western blot/Immunofluorescence: Canine oral malignant melanomas expressing HIF-1α and VEGF-A and CXCR4 had shorter disease-free interval; markers of hypoxia may be prognostically useful (Gola, Vet Pathol 2024)
• Histochemical stains:
• Fontana-Masson silver stain: Highlights the small amounts of melanin in amelanotic melanomas
• Bleach: Can be utilized to determine cytomorphologic characteristics in heavily pigmented melanocytes
• Cytologic findings:
• Benign and malignant neoplasms contain pleomorphic cells, ranging from epithelioid to spindle, or less often are discrete and round; well-differentiated cells contain abundant, fine, black-green cytoplasmic granules which may obscure the nucleus; benign forms contain small, uniform nuclei; malignant melanomas contain increased anisocytosis and anisokaryosis, coarse nuclear chromatin and prominent nucleoli
• AI: Recent study found machine-learning algorithm had similar accuracy to pathologists in diagnosing canine skin melanomas, among other common canine skin neoplasms (Fragoso-Garcia, Vet Pathol 2023)

DIFFERENTIAL DIAGNOSIS:

• Other melanocytic lesions:
• Melanocytic hyperplasia: In dogs, found on nipple; in cats, found on lips, eyelid, pinna, frequently in orange, cream or silver coat colors; hyperplasia of non-neoplastic melanocytes within the basal layer of the epidermis, with melanomacrophages in the superficial dermis
• Spindle cell neoplasms:
• Spindle cell melanoma: Composed entirely of amelanotic spindle cells and impossible to distinguish from fibrosarcoma or neurofibrosarcoma without IHC stains
• Pigmented peripheral nerve sheath tumor (PNST): May require IHC stains in some cases; PNST is GFAP positive and melanomas are rarely positive
• Fibrosarcoma: May require IHC stains in some cases; fibrosarcomas stain negative with S100, melan-A, HMB-45, tyrosinase, and TRP-2
• Other neoplasms that display junctional activity: Epitheliotrophic lymphoma, rarely cutaneous histiocytoma and mast cell tumors

COMPARATIVE PATHOLOGY:

• Non-human primates: Malignant melanoma and melanocytoma have both been reported in macaques (cynomolgus and rhesus, respectively); malignant melanomas are rare, despite the heavy pigmentation of primate skin
• Canine oral melanomas may be a valuable model for human oral melanoma; more work needed to characterize mechanisms of tumorigenesis in both dogs and humans (Di Palma, Vet Pathol 2021)
  • Recent review describes shared features (spontaneous occurrence, some macroscopic/microscopic features, IHC markers, some histopath prognostic factors) and differences (apparent absence of BRAF mutations, less aggressive clinical behavior in dogs)
  • Dermal melanoma with plasmacytoid differentiation recently diagnosed in a dog; similar to rare variant of melanoma in humans (Mendes, J Vet Diagn Invest 2025)
• Cats: Melanomas are uncommon and are often amelanotic; greatest incidence in domestic shorthair cats; often occur on head
  • Recent study of 22 suspected oral malignant melanomas confirmed 2 cases by IHC; 12 did not express melan-A, PNL2, laminin, CD34, or pan-CK; some did express S100; IHC routinely required for diagnosis in suspect cases (Saverino, Vet Pathol 2021)
  • Recent study of immunohistochemistry of feline round cell tumors found KIT expression in one melanocytic neoplasm and E-cadherin labelling in some melanocytic tumors (Davidson, J Comp Pathol 2025)
• Horses: Common in older gray horses, often on perineum, genital area and distal limbs; behavior is difficult to predict based on histological features, can have slow growth for years and then a sudden onset of malignant behavior; equine melanocytic tumors do not express Melan A, use PNL2 and S-100 instead; recent report of a primary sinonasal malignant melanoma with systemic metastasis in a 27 year old Anglo-Arabian (non-grey) gelding (Hatai, H, J Vet Diagn Invest 2021)
• Pigs: Sinclair miniature swine and melanoblastoma-bearing Libechov minipig (Hormel crosses, MeLiM strain, used in research) develop congenital melanoma; high incidence of spontaneous malignant melanoma, with reports of spontaneous regression or malignant behavior with metastasis
• Guinea pigs: in recent retrospective, melanocytic neoplasms comprised 5 of 99 total neoplasms (Dobromylskyj J Comp Pathol 2023)
• Gerbil: One of the most common cutaneous tumors in gerbils (in addition to SCC)
• Cattle:
  • Most are benign; may occur as a congenital lesion or at any age; Angus breeds overrepresented
  • Melanomas are among the four most commonly reported congenital neoplasms in cattle, according to a recent literature review (Sosa, J Vet Diagn Invest 2025)
• Sheep and goats: Uncommon and are generally pigmented
  • Angora goats: UV radiation induces aggressive, locally invasive and often metastatic melanomas on the dorsal surface of the pinna (less commonly on coronary bands and at horn base)
  • Recent investigation of goats in Sicily, Italy found melanomas to be the second most frequently diagnosed malignant skin neoplasm (far behind SCC) (Mignacca, J Comp Pathol 2024)
• Avian species:
  • Penguins: Malignant melanoma is relatively common in macaroni, Humboldt, and rockhopper penguins. Skin of the foot and hock, and subcutis and muscle near the beak and oral cavity are common sites. Histologically, neoplastic cells tend to be pleomorphic and heavily pigmented with prominent junctional activity. Surface ulceration correlates with systemic spread to liver, lung, adrenal gland, brain, and bone. Amelanotic melanomas not reported. PNL-2 can be used for IHC confirmation; S-100, Melan-A, and Ki67 cannot
  • Recent multi-institutional retrospective on beak neoplasia in several avian species found melanoma to be the second most frequent neoplasm arising from the beak (Barantes Murillo, J Comp Pathol 2025)
    • these neoplasms may distort the beak and surrounding tissue and cause bone lysis
  • Melanomas also reported in the avian heart (often metastatic), nasal sinuses, syrinyx and trachea(grey parrot), lungs (metastatic), liver (primary or metastatic), kidney (metastatic), ovary (metastatic), adrenal glands (primary or metastatic), pancreatic islets (metastatic), bone marrow (metastatic), spleen (metastatic), muscle (primary, especially on face, feet, and legs of penguins), brain (metastatic), integument (primary), uveal tract (primary), pleura/peritoneum (metastatic)
    • Characteristic cytoplasmic granules may be seen on cytologic samples
    • PNL-2 and Melan-A are useful in diagnosis of avian melanomas
• Snakes: Chromatophoromas (I-N30) are neoplasms that arise from pigment-bearing cells (chromatophores) of the dermis; chromatophores include xanthophores, iridophores, and melanophores (containing melanosomes); melanocytic neoplasms are the most common
• Siberian Tiger: Recent report of an elevated, ulcerated cutaneous mass on the flank that was removed and determined to be an amelanotic signet-ring melanoma. Surgical excision was curative with no recurrence four years later, suggesting that this variant is not as malignant as its counterpart in domestic cats (Hensel ME, J Comp Pathol 2021)

 

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