JPC SYSTEMIC PATHOLOGY

INTEGUMENTARY SYSTEM

November 2022

I-V01

 

Slide A

Signalment (JPC# 4104820-00): A 1-year-old, male neutered, redbone coonhound

 

HISTORY: Multiple firm, gray, raised, pedunculated, cauliflower-like masses along the lip margin for 2-3 weeks duration.

 

HISTOPATHOLOGIC DESCRIPTION: Skin, lip margin: Extending from the hyperplastic epidermis is an unencapsulated, exophytic neoplasm composed of squamous epithelial cells that progress from a hyperplastic stratum basale to a thickened stratum spinosum (acanthosis) and stratum granulosum, forming papillary projections supported by fine fibrovascular cores and overlain by prominent orthokeratotic and parakeratotic hyperkeratosis. Within the stratum basale, neoplastic cells have variably distinct cell borders, a moderate amount of eosinophilic cytoplasm, and round to elongate nuclei with finely stippled chromatin and 1-4 distinct nucleoli. There are up to 20 mitotic figures per 2.37 square millimeters. Within the strata spinosum and granulosum, neoplastic cells are often enlarged with abundant finely granular, amphophilic cytoplasm and clear cytoplasmic vacuoles and have eccentric vesiculate or occasionally pyknotic nuclei surrounded by a clear halo and 1-3 prominent magenta nucleoli (koilocyte). In the stratum granulosum, neoplastic cells contain many large, irregularly-shaped keratohyalin granules. Multifocally, the tips of papillary projections are necrotic with multiple foci of hemorrhage. Throughout the superficial dermis there are perivascular infiltrates of moderate numbers of lymphocytes, plasma cells, macrophages, and fewer neutrophils which occasionally transmigrate the epithelium. 

 

MORPHOLOGIC DIAGNOSIS: Skin, lip margin: Papilloma, viral, redbone coonhound, canine.

 

Slide B

Signalment (JPC# 2790107): A dog 

 

HISTORY: None

 

HISTOPATHOLOGIC DESCRIPTION: Haired skin: Arising from the epidermis and expanding the dermis is a well-demarcated, crateriform, endophytic neoplasm composed of squamous epithelial cells progressing from a hyperplastic stratum basale to a thickened stratum spinosum (acanthosis) and stratum granulosum and forming papillary projections into a 7 mm central keratin-filled cavity. Neoplastic cells have distinct cell borders, a moderate amount of eosinophilic cytoplasm, and round to oval nuclei with finely stippled chromatin and 1-4 prominent magenta nucleoli. There are 20 mitotic figures per 2.37 square millimeters. The stratum spinosum contains scattered keratinocytes with pale, swollen, vacuolated cytoplasm and pyknotic nuclei occasionally surrounded by a clear halo (koilocytes), rare 10 µm smudgy intranuclear viral inclusion bodies, and scattered single cell necrosis. The stratum granulosum frequently contains large irregular intracytoplasmic keratohyalin granules. There is prominent orthokeratotic and parakeratotic hyperkeratosis and few multifocal aggregates of ghost cells. Within the adjacent compressed dermis, there is a diffuse infiltrate of moderate numbers of lymphocytes, plasma cells, and fewer macrophages with few small areas of hemorrhage.

 

MORPHOLOGIC DIAGNOSIS: Haired skin: Papilloma, inverted, viral, breed unspecified, canine.

 

ETIOLOGIC DIAGNOSIS: Canine cutaneous papillomatosis

 

CAUSE: Canine papillomavirus

 

Slide C

Signalment (JPC# 1498137): A cow

 

HISTORY: Other animals of various ages in the herd had similar cutaneous lesions that persisted in some animals up to 4 years.

 

HISTOPATHOLOGIC DESCRIPTION: Haired skin: Projecting from the dermal-epidermal junction is a plaque-like, verrucous, exophytic neoplasm composed of squamous epithelial cells that progress from a hyperplastic stratum basale to a thickened stratum spinosum (acanthosis) and stratum granulosum and form multiple, elongate arborizing papillary projections separated by lamellated keratin and supported by long, thin fibrovascular cores. Neoplastic cells in the stratum basale have distinct cell borders with a scant amount of eosinophilic cytoplasm, oval nuclei with stippled chromatin, and 1-3 magenta nucleoli. Mitotic figures average 3 per HPF. Neoplastic cells of the stratum spinosum have more abundant eosinophilic cytoplasm, and there are rare koilocytes with swollen vacuolated cytoplasm and pyknotic nuclei. The superficial dermis is expanded by a mild perivascular infiltrate composed of lymphocytes, plasma cells, and few neutrophils.

 

MORPHOLOGIC DIAGNOSIS: Haired skin: Papilloma, viral, breed unspecified, bovine.

 

ETIOLOGIC DIAGNOSIS: Bovine cutaneous papillomatosis

 

CAUSE: Bovine papillomavirus (BPV)

 

CONDITION: Cutaneous warts, verrucae vulgaris

 

GENERAL DISCUSSION: 

• Viruses of the family Papillomaviridae are non-enveloped, circular, 55nm diameter icosahedral viruses with double stranded DNA
• Associated with proliferative skin lesions that are typically benign and self-limiting but may play a role in development of malignancy
• Papillomaviruses induce or are associated with: squamous papillomas, inverted papilloma, canine pigmented viral plaques, feline viral plaques, Bowenoid in situ carcinoma, invasive squamous cell carcinoma, fibropapillomas (equine/feline sarcoids), and others 
• Not all papillomas are caused by or contain virus

 

PATHOGENESIS:

• Most papillomaviruses are host and site-specific, except for bovine papillomavirus (BPV, associated with equine/feline sarcoids)
• Disrupted stratified epithelium in direct or indirect contact with infected individual à viral invasion of stratum basale cells (invasion proteins and receptors not definitively identified)à nonpermissive infection of stratum basale cells (no infective virions produced) à permissive infection of suprabasilar epithelial cells (virus replicates in nuclei) à viral proteins inhibit cell cycle arrest à epithelial hyperplasia or neoplastic transformation; cell lysis à virus released into environment 
• If regression occurs, it is the result of cell-mediated immunity and cytotoxic T cells 
• If portion of the virus genome is integrated into host genome, may lead to malignant transformation byinactivating tumor suppressors p53 and pRb; may also induce malignancy by infecting fibroblasts (sarcoids) 

 

TYPICAL CLINICAL FINDINGS:

• Immunocompromised animals have increased susceptibility to infection
• May regress due to cell-mediated immune attack but some may persist or undergo malignant transformation (squamous cell carcinoma)
• Most inverted papillomas do not spontaneously regress 
• Canine pigmented viral plaques: mini schnauzers, pugs, Shar Peis predisposed; do not regress 
• Feline viral plaques: regress in young cats; in older cats may progress to squamous cell carcinoma (Bowenoid in situ carcinoma, I-N04) 

 

TYPICAL GROSS FINDINGS:

• Papilloma (exophytic): 1-2 cm, wart-like, filiform, hyperkeratotic mass; single or multiple; may possess cutaneous horn

• Canine papillomas: most numerous on the lips and muzzle, within the mouth; can spread to the palate and pharynx before regressing
• Bovine papillomas: flat with a broad base

• Inverted papilloma (endophytic): cup/flask shaped proliferations of hyperplastic epidermis that extend into the dermis; contain a central core of keratin
• Viral plaques: discrete, raised, flat lesions; may be hyper- or hypo-pigmented; canine pigmented viral plaques tend to occur on ventrum/limbs/neck; equine viral plaques occur on concave pinnae (aural plaques) or genitalia
• Fibropapillomas: flat, verrucous, or nodular; usually grayish to black (classic examples are bovine fibropapillomas, equine and feline sarcoids)

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Viral papillomas display viral cytopathic effects in the upper levels of the epithelium:
  1. Koilocytes: definition varies depending on source
     • Mauldin 2017: swollen eosinophilic to lightly basophilic cytoplasm and enlarged, condensed, or multiple nuclei
     • Welle 2022: swollen keratinocytes with a clear cytoplasm and perinuclear halo 
  2. Intranuclear inclusion bodies
  3. Large, irregular keratohyalin granules (in exophytic types)
  4. Variable degrees of orthokeratotic to parakeratotic hyperkeratosis
  5. Degenerating keratinocytes with eosinophilic cytoplasmic inclusions (represent aggregates of keratin) – may be confused for poxvirus 
• Papilloma (exophytic): Radiating exophytic projections of mature keratinized squamous epithelium with orthokeratotic to parakeratotic hyperkeratosis; projections contain delicate dermal cores; elongated rete ridges at the periphery slant toward the center; prominent stratum compactum may result in grossly visible cutaneous horn
• Inverted papilloma (endophytic): Similar to squamous papillomas except the mass is endophytic with a central core of keratin (orthokeratotic or parakeratotic) lined by hyperplastic squamous epithelium with centripetal papillary projections
• Viral plaques (verruca plana, flat warts): Flat, plaque-like lesions with epidermal hyperplasia, hyperkeratosis, and viral cytopathic effects; in canine pigmented viral plaques, viral cytopathic effects are rarely seen 
• Fibropapillomas: Predominance of dermal fibroblastic proliferation with variable  acanthosis, hyperkeratosis, and rete ridges in the overlying epidermis

 

ULTRASTRUCTURAL FINDINGS:

• Icosahedral, 50-55 nm, non-enveloped virions that fill the nuclei 
• Large dense cytoplasmic granules are keratohyalin granules

 

ADDITIONAL DIAGNOSTIC TESTS:

 

DIFFERENTIAL DIAGNOSIS:

Viral papilloma or viral plaque:

• Squamous cell carcinoma (I-N04): Invasive neoplasms and elicit a desmoplastic response in the surrounding stroma; there is often formation of keratin pearls or keratinization of individual cells in less differentiated tumors
• Squamous papilloma: Lack koilocytes and giant keratohyalin granules

Inverted papilloma:

• Infundibular keratinizing acanthoma (I-N01A): Complex wall of anastomosing epithelial trabeculae
• Subungual keratoacanthoma (I-N31): Islands, sheets and trabeculae of epithelial cells, lacks granular cell layer, lacks viral cytopathic change

 

COMPARATIVE PATHOLOGY:

Cats

• Feline viral plaques: result of cutaneous papillomavirus infection (FcaPV 1 & 2); regress in young cats; progression to Bowenoid in situ carcinomas (BISCs) and possibly invasive SCCs associated with FcaPV2, older age, and immune suppression (I-N04)
• Feline exophytic papillomas: rare; on eyelid or nasal planum; probably caused by FcaPV-1; novel papillomavirus recently isolated in one papilloma on the nose of a cat (Munday JS 2022)
• Feline sarcoids (feline cutaneous fibropapilloma): rare; nose, lips, digits of young to middle-aged rural cats, histologically identical to equine sarcoids; associated with feline sarcoid-associated PV which is thought to be a novel bovine papillomavirus (Mauldin 2017) or bovine papillomavirus-14 (I-N17)

Dogs

• Oral papilloma typically associated with CPV1 and CPV13; occasionally affects conjunctiva and external nares (Mauldin 2017); most conjunctival papillomas are not viral-induced.
• Cutaneous papilloma typically associated with CPV2; also CPV1 and CPV7
• Inverted papillomas occur in young adult dogs and are associated with CPV 1, CPV 2, CPV 6; in a recent study of 19 inverted papillomas, 11 cases were PCR positive for CPV1 and 3 were positive for CPV2; all PCR positive cases showed viral cytopathic change (Orlandi 2021)

Horses

• Three clinical syndromes caused by Equus caballus papillomaviruses (EcPV 1-7)

• Classic equine viral papillomatosis: EcPV-1 causes self-limiting cutaneous papillomas on the muzzle and lips of young horses 
• Equine genital papillomas: EcPV-2 causes penile papillomas and penile SCC in older horses; nonregressive (Greenwood 2020); 
• Equine ear papillomas (aural plaques): EcPV 3-6 causes bilaterally symmetric lesions on the pinnae; only in horses > 1 year of age; do not spontaneously resolve 

• Equine sarcoids (most common skin tumor of horses) have been associated with BPV-1, 2, and 13 and are common on the head, legs, and ventral trunk (I-N17)

Bovine: Thirteen bovine papillomaviruses described 

• BPV-1: fibropapillomas of the teats and glans penis in young animals, spontaneously regress; also cause papillomas of the rumen 
• BPV-2: fibropapillomas of the head, neck, shoulder, sometimes legs/teats in young animals, rumen, esophagus; spontaneously regress; also causes equine sarcoid 
• BPV-3: atypical warts (low, flat with frond-like projections), anywhere on body, regression is rare 
• Teat firbopapillomas are associated with BPVs 1, 2, 5 
• Teat papillomas are associated with BPVs 6, 7, 9, 10 
• Bracken fern (Pteridium aquilinum) is immunosuppressive and creates environment permissive to papilloma virus infection; also a cofactor to malignant transformation of BPV-4 infected cattle to squamous cell carcinoma in the upper alimentary tract; ingestion in conjunction with BPV 1, 2, and 4 may cause epithelial and mesenchymal neoplasms within the urinary bladder due to E5 & E7 expression (U-T11, U-N04)

Sheep and goats:

• Ovine papillomavirus (OaPV-1 and OaPV-2) causes fibropapillomas in sheep 
• OaPV-3 associated with squamous cell carcinoma 
• Teat papillomas associated with BPV-2
• Capra hircus papillomavirus 1 has been isolated from healthy skin 

Rabbits: can be infected with two papillomaviruses

• Cottontail rabbit papillomavirus (CRPV): AKA Shope papillomavirus; can infect both Sylvilagus new world rabbits and Oryctolagus rabbits; in Silvilagus rabbits they are  generally benign but can produce debilitating large cutaneous horns; in Oryctolagus rabbits lesions are few and small but frequently progress to squamous cell carcinoma 
• Rabbit oral papillomavirus (ROPV): occurs in Oryctolagus, natural infection common in domestic rabbits, commonly affects oral/labial mucosa, generally spontaneously regress and do not cause malignant transformation 

Others

• Mice: MusPV discovered in nude mouse colony with oral/nasal papillomas; genetically related to rat papillomavirus 
• Rats: two papillomaviruses in isolated in subclinically infected wild rats 
• Hamsters: MsPV-1 isolated from neoplastic lesions treated with carcinogen DMBA; PsPV1 isolated from anogenital lesion of Siberian hamster 
• Wild canids: oral papillomatosis of wild coyotes is usually self-limiting; lamdapapillomavirus 2 has been isolated from dogs, coyotes, and grey wolves with possible transmission between species 
• Western barred and southern brown bandicoots (endangered marsupial): Cutaneous papillomatosis and carcinomatosis caused by BPCV1 and BPCV2 is a significant cause of mortality; lesions on the digits and lip mucocutaneous junctions  (Higgins 2018)
• Nonhuman primates: papillomatous growth and warts reported in numerous species; up to 12 rhesus papillomaviruses have been identified and some are linked to cervical/penile neoplasia; one cynomologous macaque papillomavirus identified and associated with cervical neoplasia 
• Cetaceans: proliferative mucosal lesions (cutaneous less common) associated with papilloma viruses; at least 5 papillomavirus variants; horizontal transmission in bottlenose dolphins common
• Snow leopards: in captivity develop oral papillomas due to PuPV-1 (UuPV-1); can undergo transformation to oral squamous cell carcinoma 
• Cheetahs: novel feline papillomavirus (Acinonyx jubatus papillomavirus type 1) isolated in recent report of 15 cheetahs with sublingual papillomas with histologic evidence of viral cytopathic change (Steenkamp 2022)
• Captive felids: papillomas most common oral neoplasm in one study, 39 total cases (including 30 in snow leopards); half of the cases had viral cytopathic change (Scott 2021)
• Giraffes, non-domestic bovids, pronghorn antelope and other wild ungulates: cutaneous viral papillomas and fibropapillomas reported; sarcoid-like lesions associated with BPV-1 and BPV-2 rarely reported in antelope and giraffes.  
• Deer: Fibropapillomas associated with delta papillomavirus (fibroma virus) (I-V02)
• Camelids: Camelus dromedaries papillomavirus types 1 and 2 are relatively common in old world camels; in new world camelids fibropapillomas associated with unique papilloma virus.
• Fish: Several species of fish develop “idiopathic epidermal proliferation”, mostly benign; some are viral associated; stomatopapillomas in eel can prevent eating and cause starvation, virus suspected but not proven; winter flounder papillomas also suspected to be from viral infection
• Avian species: papilloma-virus cause typical proliferative cutaneous lesions in finches (feet), canaries (beak), and the African grey parrot (face); non-virus associated papillomas also occur; increasing evidence that Psittacid herpesvirus 1 (Pacheco’s disease) may be involved in internal papillomatosis in psittacines (Schmidt 2015); in a recent study neither PsHV-1 or Psittacid papillomavirus 1 PsHV-1 were isolated from 14 papillomas and squamous cell carcinomas 
• Sea turtle: Chelonid alphaherpesvirus 5 (in conjunction with environmental/host factors) causes fibropapillomatosis, documented in all species but primarily affects green sea turtles, increased prevalence in older sea turtles; lesions may be plaque-like or exophytic, may be on skin or cornea, plastron/carapace, or may be internal; causes fibroblast proliferation followed by epidermal hyperplasia and hyperkeratosis; intranuclear inclusion bodies are rare 

 

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