JPC SYSTEMIC PATHOLOGY
INTEGUMENTARY SYSTEM
September 2022
I-N04

 

Slide A:  Signalment (JPC #1869901) Age and breed unspecified dog

 

HISTORY:  Mass from the toe.

 

HISTOPATHOLOGIC DESCRIPTION:  Digit (per contributor):  Arising from the hyperplastic and ulcerated epidermis, extending to deep margins, and infiltrating preexisting bone is a densely cellular, unencapsulated, infiltrative neoplasm composed of anastomosing cords, trabeculae, and islands of polygonal cells supported by a moderate collagenous to desmoplastic stroma. Neoplastic cells have distinct cell borders with prominent intercellular bridges, abundant brightly eosinophilic cytoplasm, and an irregularly round to oval nucleus with finely stippled chromatin and 1-3 prominent magenta nucleoli. Anisokaryosis and anisocytosis are moderate and there are an average of 52 mitotic figures per 2.37mm² with occasional atypical mitotic figures. Neoplastic cells frequently exhibit dyskeratosis characterized by individualized cells within the stratum spinosum with brightly eosinophilic cytoplasm and pyknosis. There are multifocal keratin pearls characterized by brightly eosinophilic central accumulations of compact lamellations of keratin. Within the stroma of the neoplasm, there are low numbers of melanin-laden macrophages, scattered lymphocytes, and plasma cells.  Multifocally, neoplastic cells invade and replace preexisting bone in which existing bony trabeculae are lined by increased numbers of osteoclasts in Howship's lacunae (osteolysis) and multiple foci of woven bone lined by plump osteoblasts (reactive bone formation). There is multifocal ulceration of the overlying epidermis with replacement by a serocellular crust composed of cellular debris, high numbers of neutrophils, hemorrhage, proteinaceous fluid, and fibrin. 

 

MORPHOLOGIC DIAGNOSIS:  Digit (per contributor):  Squamous cell carcinoma, subungual, breed not specified, canine.

 

Slide B:  Signalment (JPC #1619769) Seven-year-old beagle

 

HISTORY:   Abdominal skin from a beagle that was one of a large colony housed in outdoor kennels in Colorado. 

 

HISTOPATHOLOGIC DESCRIPTION:  Haired skin, abdomen (per contributor):  Arising from a hyperplastic and ulcerated epidermis and extending to the deep dermis is a poorly circumscribed, unencapsulated, infiltrative neoplasm composed of polygonal cells arranged in cords, trabeculae, and islands, with occasional individualized cells supported by a moderate amount of fibrovascular to often desmoplastic stroma. Neoplastic cells have distinct cell borders with prominent intercellular bridges, abundant amphophilic to eosinophilic cytoplasm, irregularly round to oval nuclei with finely stippled chromatin, and 1-4 distinct magenta nucleoli.  Anisocytosis and anisokaryosis are moderate and mitotic figures average 48 per 2.37mm² with occasional atypical mitotic figures.  Cords and islands often contain central, compact, eosinophilic lamellations of keratin (keratin pearls). Multifocal hair follicles and adnexa are surrounded by numerous lymphocytes, plasma cells, and neutrophils. There is focally extensive epidermal ulceration characterized by epidermal loss and replacement by a serocellular crust composed of fibrin, proteinaceous fluid, and neutrophils subtended by, lymphocytes, plasma cells, histiocytes, neutrophils, small caliber blood vessels and numerous fibroblasts contiguous with haphazardly arranged collagen bundles (granulation tissue). The remaining epithelium is markedly hyperplastic characterized by anastomosing rete ridges, an expanded stratum spinosum (acanthosis), and a stratum corneum markedly thickened by parakeratotic and orthokeratotic hyperkeratosis. Within the subcutis, there is moderate multifocal hemorrhage, fibrin, and increased clear space (edema). 

 

MORPHOLOGIC DIAGNOSIS:  Haired skin, abdomen (per contributor):  Squamous cell carcinoma, beagle, canine.

 

Slide C:  Signalment (JPC #4090973) 13-year old female domestic European shorthair cat.

 

HISTORY:   Affected skin displayed a plaque-like lesion with irregular edges.

 

HISTOPATHOLOGIC DESCRIPTION: Haired skin: Approximately 80% of the epidermis is markedly thickened by a poorly demarcated, moderately cellular, unencapsulated, and expansile intraepidermal neoplasm, which extends into the outer root sheath of underlying hair follicles. Within this area, the epidermis is expanded up to 8-10 cell layers thick by a monomorphic population of cells undergoing disorganized maturation and forming broad, nodular rete ridges, which are constrained by a basement membrane. Neoplastic cells have distinct cell borders, an abundant amount of eosinophilic cytoplasm, which occasionally contains granular golden pigment (melanin), irregularly round to oval nuclei with finely stippled chromatin and up to four prominent nucleoli. Anisocytosis and anisocytosis are moderate and mitoses average 12 per 2.37mm². Multiple follicles lined by neoplastic epithelial cells are devoid of or contain fragmented hair shafts admixed with lamellated keratin admixed with few neutrophils, amorphous karyorrhectic and cellular debris, scant hemorrhage, and fibrin. The neoplastic epithelium is multifocally eroded with a serocellular and hemorrhagic crust, infiltrated by low numbers of neutrophils, and in these areas, neoplastic epithelial cells are markedly expanded by intracellular edema to variable depths. There is similar but less severe cellular atypia at the periphery of the lesion with less prominent rete ridges and re-establishment of normal epithelial maturation. The superficial dermis is markedly expanded by congested vessels, numerous viable and degenerate neutrophils (also in perifollicular and periadnexal locations), cellular debris, and variable amounts of hemorrhage, edema, and fibrin. 

 

MORPHOLOGIC DIAGNOSIS:  Haired skin: Bowenoid in situ carcinoma, domestic European shorthair cat, feline.

 

GENERAL DISCUSSION: 

• Squamous cell carcinoma (SCC) is the most common malignant skin neoplasm in cats; second most common in dogs, following mast cell tumor
• SCC is the second most common oral tumor in dogs
• Arises from keratinocytes and commonly occurs in sun-damaged skin 
• Solar induced SCC is usually preceded by actinic keratosis; other factors that can influence its occurrence include carcinogens, genetic factors, papillomaviruses and epidermal trauma (e.g. ear notching, branding, burns and chronic inflammation)
• Predisposing factors include chronic UV exposure, lack of pigment, and thin haircoat in affected areas; most common in middle aged to older animals
• Highest incidence among short haired breeds with little skin pigmentation in both dogs and cats (predisposed dog breeds include Dalmatians, pit bull terriers, harlequin great Danes and beagles); SCC in pigmented areas more often are associated with papillomavirus (see chart below) 
• Claw bed (subungual):  Most common neoplasm of the digit in dogs and cats; often more aggressive with multiple digits affected and usually associated with large breed, black-coated dogs (especially Labrador retriever, standard poodles, giant schnauzers, dachshunds, Briards, Beaucerons and Bouvier de Flanders); case report of pigmented subungual SCC in a dog (Yang et al., J Comp Pathol. 2022)
• Multicentric squamous cell carcinoma in situ (bowenoid in situ carcinoma [BISC]):
• Middle aged to older mixed-breed cats
• Found in haired-pigmented skin and is unrelated to sunlight exposure; has been predominantly by Felis catus papillomavirus 2 (FcaPV-2)

 

PATHOGENESIS:   

• Ultraviolet (UVB) radiation is the most important carcinogenic stimulus for cutaneous SCC
• UV light > formation of pyrimidine dimers (cytosine, uracil, thymine) in DNA > nucleotide repair pathway is overwhelmed > some DNA damage remains unrepaired > transcriptional errors > neoplasia
• UV light > tumor suppressor gene mutations, particularly P53
• UV light suppresses neoplasia suppressing immune-responses
• Other associated carcinogens include tobacco, coal tar, soot, arsenic, and smegma
• Structural antigens from papillomavirus have been found in SCC  of multiple species suggesting a possible etiologic role
• Proposed pathogenesis: UV light damage to DNA of a papillomavirus-infected epithelial cell > viral inhibition of p53 prevents DNA repair and apoptosis > viral-induced epithelial proliferation > increased replication of neoplasia-prone cells
• Usually a progression, over months to years, from epidermal plaques, solar keratosis, and papillomas > carcinoma in situ > SCC

 

TYPICAL CLINICAL FINDINGS:  

• Solar induced SCC often arises in hypopigmented and/or sparsely haired regions:
• Dogs: Ventral trunk, limbs, digits, scrotum, and lips; nasal planum rarely affected, usually associated with depigmentation if affected (e.g. discouid lupus erythematosus)
• Cats: Nasal planum, pinnae, and eyelid
• Locally invasive and destructive; solar induced tend to be slow to metastasize (usually restricted to local lymph nodes); however, canine digital SCCs are more prone to metastasis but are also typically amenable to cure with excision
• May metastasize to the lungs and regional lymph nodes 

 

TYPICAL GROSS FINDINGS:  

 

TYPICAL LIGHT MICROSCOPIC FINDINGS: 

• Tumor cells breach the basement membrane to form islands, cords, and trabeculae within the dermis that are usually contiguous with the overlying epidermis; there is often formation of keratin pearls (concentric lamellae of keratin) and prominent intercellular bridges; poorly differentiated tumors may only exhibit keratinization of individual cells (dyskeratosis)
• Vesicular nuclei with one or multiple very prominent nucleoli; cytoplasm is typically abundant and eosinophilic
• Invasion is usually associated with marked desmoplasia; mitotic figures are often numerous and proportional to degree of anaplasia
• Spindle cell SCC:  
• Uncommon variant:  Large, pleomorphic, fusiform to polygonal epithelial cells are difficult to differentiate from stromal cells but are often positive for cytokeratin; recent report (Guisado et al., Vet Pathol., 2021) identified predilection for occurrence on the face (pinna>periorbital>dorsal muzzle) and often positive for p63, CK5/6, and AE1/AE3, and negative for CK8/18; also identified association with solar exposure due to presence actinic keratosis
• Bowenoid in situ carcinoma:
• Malignant change confined to the epidermis without breaking through the basement membrane
• Abrupt hyperplasia and dysplasia of the epidermis and follicular outer root sheath

 

ADDITIONAL DIAGNOSTIC TESTS:  

• Cytology:  
• Immature or dysplastic squamous epithelial cells accompanied by purulent inflammation; emperipolesis associated with well-differentiated SCC
• “Tadpole” shaped epithelial cells with blue-green hyalinized cytoplasm; may be arranged individually or in sheets; moderate to well-differentiated neoplastic cells may have perinuclear vacuolization (colorless keratohyalin granules)
• Well-differentiated tumors typically have highly keratinized, nucleated, and angular epithelial cells vs. moderately-differentiated SCCs with >50% round or oval dysplastic cells vs. poorly-differentiated SCCs with predominately round individualized cells with high N:C; lack of marked atypia does not exclude malignancy

 

• Immunohistochemistry:  
• Most carcinomas are positive for cytokeratin which may be helpful in differentiating SCC from other anaplastic neoplasms
• SCCs in dogs are positive for cytokeratin 6 and 10, which can be helpful in distinguishing them from some basosquamous variants; recent study (Kok et al. Vet Pathol., 2018) indicates CK 16 is most useful IHC for differentiating SCC (+) from basal cell carcinomas (+/-) 

 

DIFFERENTIAL DIAGNOSIS:  

Histologic differential diagnosis:

• Cutaneous:
• Squamous cell carcinoma in situ:  Confined by the basement membrane
• Basosquamous carcinoma:  Low-grade malignant tumor comprised primarily of dermal lobules of basaloid cells with centralized foci of atypical abruptly keratinized cells; +/- CK16 immunoreactivity
• Papilloma (I-V01):  Well-circumscribed, noninvasive 
• Infundibular keratinizing acanthoma (I-N01A): Well-circumscribed, noninvasive
• Actinic keratosis (solar keratosis):  Mildly elevated plaques in areas vulnerable to solar exposure comprised of thickened epidermis (predominantly deeper layers) with angular disorganize rete ridges +/- disorganization and crowding of stratum basale with loss of polarity; may exhibit dyskeratosis and solar elastosis; confined by the basement membrane and lacks cytopathic change; not always possible to differentiate from BISC in cats without IHCs   
• Subungual:  
• Keratoacanthoma (I-N31):  Benign neoplasm of nailbed epithelium; lack of neoplastic cell invasion

 

COMPARATIVE PATHOLOGY:  

• Cattle:  
• SCC: Common on the limbus, third eyelid, eyelids, conjunctiva pinna, back, distal limbs, and vulva; Herefords and Ayrshires are at increased risk
• Ocular SCC is the most economically significant neoplasm of domestic animals
• Carcinoma of the horn of cattle: Uncommon; almost exclusive to castrated male adult cattle in India and neighboring countries; infiltrates and destroys the horn core and may invade adjacent sinuses and cranial bone; recent study (Chandratre et al. J Comp Pathol., 2020) found detection of p53 gene mutation blood via PCR correlates with diagnosis of SCC of the horn in Zebu cattle  
• Horses:   Commonly affected locations include the penis, prepuce, periocular, and perianal regions
• Appaloosa, American paint horse, quarter horse, and males are predisposed
• SCC is also found in the nonglandular stomach (this is the most common gastric neoplasm in horses, D-N08); rarely reported to arise in guttural pouch
• A report of SCC with clear cell differentiation in eyelid (Stein et al. J Vet Diagn Invest; 2019)
• Multiple reports (Greenwood et al. Vet Pathol; 2020) investigating Equus caballus papillomavirus type-2 (EcPV-2) a causal factor in a subset of equine genital SCC; EcPV-2 identified in up to 10/35 (29%) SCCs arising from genital tissues but 0/22 SCCs from other locations; report of vertical transmission of EcPV-2 to fetus
• Sheep:  Muzzle, lips, eyelids, perineum, vulva (in recently sheared sheep), pinnae; Merinos may be at increased risk
• Goats:  
• Predisposed sites include udder, perianal, horn base, pinnae, eyelid, vulva 
• Angoras and Boers potentially at increased risk
• Rabbits:  75% of Oryctolagus rabbits inoculated with cottontail rabbit papillomavirus (CRPV) (Shope papilloma virus), develop papillomas and often progress to SCC;  Sylvilagus rabbits may also undergo malignant transformation, but to lesser degree; mechanical viral spread by insect vectors 
• California sea lion:  Zalophus californianus papillomavirus-1 associated with cutaneous SCC (Luff et al. Vet Pathol; 2018)
• Captive reptiles: Papillomaviral DNA amplified via PCR from SCC lesion in a Dumeril’s boa (Eleni et al. J Comp Path; 2017); cutaneous SCC of serpents most commonly reported in cloacal region; digital SCC reported in estuarine crocodile
• Free-ranging reptiles:  Case report of Emydoidea herpesvirus 2 (EBHV-2) associated mandibular SCC in a free-ranging Blanding’s turtle (Andersson et al. J Vet Diagn Invest; 2021)
• NHPs:  Most common oral and esophageal tumor; Oral cavity > skin; perineum and sex skin are predisposed; SCC reported as the most common penile neoplasm of macaques in recent study (Kirejczyk et al. Vet Pathol; 2021); papillomavirus DNA similar to HPV-16 detected in a case of penile squamous cell carcinoma 
• Cervids:  Oral SCC reported in free ranging red-deer
• Camelids:  Cutaneous SCC (and gastrointestinal SCC) reported in llamas and alpacas
• Non-domestic felids:  Captive snow leopards overrepresented and associated with papillomavirus; oral > cutaneous SCC; most common cutaneous locations include face, forelimbs and feet are often immunopositive for PuPV-2; oral SCC may be induced by PuPV-1
• Bandicoots:  Bandicoot papillomatosis and carcinomatosis viruses 1 and 2 associated with induction of premalignant changes and progression to invasive SCC; viruses are genetic intermediate between Papillomaviridae and Polyomaviridae; western barred and southern brown bandicoot affected by BPCV-1 and -2, respectively 
• Cetaceans:  Captive and free-ranging bottlenose dolphins commonly affected by orogenital papillomas (only oral papillomas identified to progress to SCC); case report of facial SCC in stranded rough-toothed dolphin (Alves-Motta et al. J Comp Pathol; 2020); both papillomaviruses and herpesviruses have been associated with oral SCC in captive and stranded cetaceans
• Bats:  Multiple cutaneous papillomas and basosquamous/squamous cell carcinomas reported in a 5-year old captive Rousettus aegyptiacus with positive immunoreactivity for bovine papillomavirus 
• Rodents:  Associated with aricular chondritis in mice; one of the two most common cutaneous tumors of gerbils (with melanoma)
• Avians:  Uncommon; most frequently reported in cockatiels, Amazon parrots, conures, and budgeriagars; recent study (Jones et al. J. Comp Path; 2020) of 45 SCCs in psittacines, raptors, and domestic fowl found majority SCC located in skin (46%) followed by uropygial gland (19.2%); same study found significantly more SCCs expressed COX-2 compared to papillomas, whereas SCC immunolabeling for E-cadherin was significantly lower compared to papillomas; SCC reported in pelicans (beak and feet most common), penguins, raptors, great Indian hornbills (casque); mandibular bone may be preferred biopsy site in the diagnosis of mandibular SCC in psitticines (Halley et al. J Vet Diagn Invest; 2020)
• Anurans:  Most commonly reported in Northern leopard frogs
• Fish:  Similar to mammalian SCC but lack keratin pearl formation  

 

Papilloma viruses associated with pre-neoplastic and neoplastic skin lesions in animals (adapted from Munday 2016, Mauldin 2016, Vitiello 2017, Greenwood 2020):

 

Animal species	Skin lesion	Papillomavirus
Cat	Feline viral plaque progressing to BISC	FcaPV-1, -2, -3
Cat	SCC	FcaPV-2
Dog	Invasive SCC	CfPV-1, -2
Dog	Canine pigmented viral plaque progressing to in-situ carcinoma and SCC	CfPV-3
Dog	In situ SCC	CfPV-7
Horse	Equine sarcoid	BPV-1, -2
Horse	Equine papillomas, in-situ carcinoma and SCC; genital SCC	EcPV2
Sheep	SCC	OaPV-3
Rabbit	Cutaneous SCC	CRPV

 

FcaPV, Felis catus papillomavirus; CfPV, Canis familiaris papillomavirus; COPV, canine oral papillomavirus; BPV, bovine papillomavirus; CRPV, cotton-tail rabbit papillomavirus; RaPV, rousettus aegyptiacus papillomavirus type I; MnPV, Mastomys natalensis papillomavirus; EcPV2, equine papillomavirus type 2; OaPV, Ovine aries papilloma virus

 

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