JPC SYSTEMIC PATHOLOGY
Signalment (Slide A - 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 pigment globules (melanin), an oval to elongate nucleus with finely stippled chromatin and one variably distinct nucleolus. There is mild anisocytosis and anisokaryosis and mitotic rate is 1 per 10 HPF. 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 (melanomacrophages). The epidermis is focally ulcerated with an overlying serocellular crust composed of cellular debris, degenerate neutrophils, hemorrhage, fibrin, and colonies of basophilic cocci. Subadjacent to the crust within the superficial dermis there are increased numbers of small caliber blood vessels lined by reactive endothelium that are perpendicular to the ulcer, surrounded by abundant hypertrophied fibroblasts (granulation tissue). Rare apocrine glands are ectatic and surrounded by moderate numbers of lymphocytes, plasma cells and fewer transmigrating neutrophils and macrophages (hydradenitis). The remaining epidermis is moderately hyperplastic, with acanthosis, spongiosis, and rete ridge formation.
MORPHOLOGIC DIAGNOSIS: Haired skin: Melanocytoma, miniature schnauzer, canine.
Signalment (Slide B - 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 P3 is a moderately cellular infiltrative neoplasm composed of polygonal to spindle cells arranged in lobules, nests, and packets supported by moderate amounts of fibrovascular stroma. Neoplastic cells have variably distinct cell borders, scant to moderate amount of eosinophilic granular cytoplasm that often contains brown pigment globules (melanin), a round to oval nucleus with finely stippled chromatin and one to two prominent nucleoli. There is moderate anisocytosis and anisokaryosis. Mitotic rate averages 2-3 per HPF. Multifocally, there are individual or small nests of neoplastic cells within the hair follicular epithelium (junctional activity). There is single cell necrosis within the neoplasm moderate numbers of melanomacrophages as well as large multifocal areas of necrosis with hemorrhage, fibrin, edema, moderate numbers of viable and degenerate neutrophils, and fewer hemosiderin-laden macrophages. There is multifocal bone loss and replacement by neoplastic cells (osteolysis). There are often scalloped trabeculae of woven bone extending from the remaining mature bone and osteoclasts within Howship’s lacunae (bony remodeling).
MORPHOLOGIC DIAGNOSIS: Haired skin and bone, digit: Melanoma, breed unspecified, canine.
- Neoplasm originating from melanocytes or melanoblasts are of neuroectodermal in origin
- Melanocytoma - Common neoplasm in dogs; average age in dogs is nine years with no sex predilection; the neoplasm can be single or multiple, occurs most often on the head, eyelid, muzzle, trunk, or interdigital
- More common in Scottish terrier, airedale, Boston terrier, cocker spaniel, springer spaniel, boxer, golden retriever, Irish terrier, Chihuahua, chow chow
- Multiple melanocytomas are more common in the Irish setter, Doberman pinscher
- Malignant melanoma – Average age in dogs is nine years with no sex predilection; most frequently on the head, limbs, digits, eyelid, nail bed, scrotum, lip/oral cavity (more frequent in dogs with pigmented oral mucosa), or trunk
- Most common oral tumor in dogs
- Balloon-cell and signet ring melanomas are frequently amelanotic
- Breed predilection same as melanocytoma
- Scottish terrier, Irish setter, miniature and standard schnauzer more frequently develop subungual malignant melanomas
- Lesions in the nailbed or oral mucosa are frequently malignant; however, a recent report demonstrates that up to 30% of melanomas that are histologically malignant based upon some scoring systems do not metastasize
- Recent case report of a dog with disseminated melanoma with involvement of leptomeninges and bone marrow; leptomeningeal melanomatosis, a rare human melanoma variant
- Canine oral malignant melanoma does not have an active canonical Wnt signaling pathway; targeted suppression of B-catenin is not relevant
TYPICAL GROSS FINDINGS:
- Melanocytoma - usually solitary, circumscribed, alopecic, gray to brown to black, cutaneous nodule less than 1 cm in diameter, range up to 4 cm; smooth or slightly papillated to pedunculated; ulceration is uncommon
- Malignant 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:
- Melanocytic tumors:
- Amount of pigmentation is variable
- Variety of cell shapes from spindle cell, balloon cell (clear cell), epitheloid cell and signet ring cell
- Junctional activity can aid in diagnosis
- Mitotic index is a key prognostic indicator in the clinical behavior, ulcerated areas should be avoided
- Dogs with cutaneous melanocytic neoplasms with a MI >3/10 HPFs have a shorter survival time
- Oral and lip tumors that are heavily pigmented and composed of well differentiated melanocytes with a low MI (<4/10 HPFs) have a favorable prognosis
- Nuclear atypia, presence of ulceration and deep infiltration beyond the dermis are associated with a poor outcome
- Histological classification:
- Junctional – confined to the epidermis and dermoepidermal junction)
- Compound – involving both dermis and epidermis
- Compound and dermal are the most common in domestic animals
- Histological classification:
- Can be composed of any melanocytic cell type; most common are spindle cells (whorls or fingerprint patterns), epitheloid cells (nests) or a combination
- Degree of pigmentation can vary, dark pigmentation is common
- Mitotic figures are rare
- Malignant melanoma
- Can be composed of a variety of melanocytic cell morphologies; most common are epitheloid cells, spindle cells or a combination
- Cells may be heavily pigmented or amelanotic
- Rarely there may be areas of chondroid or osseous metaplasia
- Variable nuclear pleomorphism
- 3 or more mitotic figures per 10 HPFs with mitotic atypia
- Varying degrees of junctional activity
ADDITIONAL DIAGNOSTIC TESTS:
- Melan-A (currently the most specific marker – melanocyte-differentiating protein recognized by cytotoxic T cells), PNL2, TRP-1 and TRP-2 as single antibodies or as a cocktail
- S-100 sensitive marker for melanocytes but not specific (can also label nerve sheath cells, Langerhans cells, adipocytes, myoepithelial cells and leukocytes)
- HMB-45 is a specific marker for melanoma cells
- Fontana-Masson silver stain: Highlights the small amounts of melanin in amelanotic melanomas
- Bleach: To determine cytomorphologic characteristics of heavily pigmented melanocytes
- Immunohistochemical marker Ki67 (which assesses tumor growth fraction), but not PCNA, is a useful prognostic factor in melanomas of dogs and cats; however, Ki67 is not useful in predicting clinical behavior in equine melanomas
- COX-2 highly expressed in canine oral melanocytic neoplasms and low in cutaneous ones
- C-kit receptor (responsible for transmission of promigration signals to melanocytes)
- expressed in all canine benign dermal melanocytomas
- c-kit (KIT) expression anywhere within malignant mucosal melanocytic tumors correlated with significantly longer survivial times
- Higher levels of ctnnb1 (encodes β-catenin) expression in canine oral melanoma tissues compared to normal melanocytes
- Nuclear survivin expression is associated with histological features of malignancy, metastasis and death
- Melanoacanthoma: Rare, circumscribed, unencapsulated, solitary, pigmented nodule, < 1 cm in diameter, composed of both melanocytic and epithelial cells; combination of junctional melanocytoma with a benign epithelial tumor
- Melanocytic hyperplasia: In dogs, found on nipple; in cats 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
- Pigmented peripheral nerve sheath tumor; may require immunohistochemical stains in some cases; PNST is GFAP positive; melanomas are rarely positive
- Fibrosarcoma: May require immunohistochemical stains in some cases; fibrosarcomas have negative staining for S100, melan-A, HMB-45, tyrosinase, and TRP-2
- Other neoplasms that display junctional activity include: epitheliotrophic lymphoma and rarely cutaneous histiocytoma and mast cell tumors
- Cats: melanomas are uncommon and are often amelanotic
- 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/S-100
- Pigs: Sinclair and melanoblastoma-bearing Libechov Minipig (useful human melanoma models); high incidence of spontaneous malignant melanoma, spontaneous regression of benign and malignant melanomas with an infiltration of macrophages; metastases similar in distribution to humans; in slaughter pigs melanocytic tumors occur mainly in Duroc and Duroc crossbreeds and are bengin and spontaneously regress
- Cattle: may occur as a congenital lesion or at any age, most are benign
- Sheep and goats: uncommon and are generally pigmented
- Snakes: Chromatophoromas are neoplasms that arise from pigment-bearing cells (chromatophores) of the dermis, due to their dermal origin there is neither junctional activity nor lentiginous spread; moderate to marked nuclear atypia appears consistently in neoplasms with a high risk of metastasis; San Francisco garter snake is overrepresented; S-100 + more reliable than PNL-2; sensitivity of melan A and HMB45 is extremely low in reptile melanocytic tumors
- South American opossum (Monodelphis domestica) is a species exhibiting photoreactivity, and so are used to study ultraviolet radiation as a carcinogen in inducing melanomas
- Platyfish (Xiphophorus maculatus) and Swordtail fish (Xiphophorus helleri) hybrid crosses are used to study spontaneously developing melanomas
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