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Read-Only Case Details Reviewed: Oct 2010
AFIP SYSTEMIC PATHOLOGY

JPC SYSTEMIC PATHOLOGY

INTEGUMENTARY SYSTEM

November 2019

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 exophytic neoplasm composed of epithelial cells that form papillary projections supported by fine fibrovascular cores and stroma. Neoplastic cells progress from a hypertrophied stratum basale to a thickened stratum spinosum (acanthosis) and stratum granulosum. Cells of the stratum basale are often elongate and aligned perpendicular to the stroma. 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. Mitotic figures average 1-2 per HPF. Cells within the stratum spinosum and granulosum 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 (cytopathic change, koilocyte). Cells of the stratum granulosum contain many prominent, large, irregularly-shaped keratohyalin granules. There is prominent orthokeratotic and parakeratotic hyperkeratosis with few multifocal aggregates of ghost cells. Multifocally, the tips of papillary projections are necrotic with multiple foci of hemorrhage. Throughout the dermis and epidermis are increased numbers of neutrophils with fewer lymphocytes, plasma cells, and macrophages.

 

MORPHOLOGIC DIAGNOSIS: Skin, lip margin: Papilloma, viral, Redbone coonhound, canine

 

Slide B

Signalment (JPC# 2790107): A dog

 

HISTORY: None

 

HISTOPATHOLOGIC DESCRIPTION: Haired skin: Expanding the dermis and arising from and elevating the epidermis is a focal, 10mm diameter, crateriform, endophytic, well circumscribed neoplasm composed of epithelial cells that progress from a hypertrophied stratum basale to a thickened stratum spinosum (acanthosis) and stratum granulosum and form papillary projections around a 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. Mitotic figures average 2 per HPF. Within the mid- to upper levels of the stratum spinosum there are numerous koilocytes and cells with viral cytopathic effect as well as many irregular intracytoplasmic keratohyaline granules. There are very rare, 10um, basophilic, smudgy, intranuclear viral inclusion bodies. There is prominent orthokeratotic and parakeratotic hyperkeratosis and few multifocal aggregates of ghost cells. Multifocally, there are periadnexal and diffuse dermal infiltrates composed of moderate numbers of lymphocytes, plasma cells, fewer macrophages, and 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 hypertrophied stratum basale to a thickened stratum spinosum (acanthosis) and stratum granulosum and form multiple, elongated, arborizing papillary projections widely separated by lamellated keratin and supported by long, thin fibrovascular cores. Basal cells are columnar, have oval nuclei with stippled chromatin, and 1-3 magenta nucleoli. Mitotic figures average 3 per HPF. Cells of the stratum spinosum have a moderate amount of eosinophilic cytoplasm, distinct cell borders, prominent intercellular bridging, oval nuclei with finely stippled chromatin, and 1-4 bright magenta nucleoli. Within the outer stratum spinosum and stratum granulosum, there are rare koilocytes and cells with viral cytopathic effect as well as numerous intracytoplasmic keratohyalin granules. The superficial dermis there 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:

·      Family Papillomaviridae (formerly papovaviridae); a nonenveloped, 55nm diameter icosahedral virus with single, circular, double stranded (ds) DNA

·      Papillomaviruses (PVs) are grouped into genera; most of the 100+ human PVs (HPVs) are classified within the alpha and beta PVs

·      “alpha”: Oncogenic “high risk” mucosal types; benign mucosal or cutaneous lesions

·      “beta”: Cutaneous PVs that rarely cause lesions without immunosuppression

·      “delta”: Causes benign fibropapillomas in ungulates; unique ability to infect multiple species and cause equine sarcoids

·      “lambda”: Associated with skin lesions in the dog and cat; Felis domesticus PV1 (FdPV-1) and canine oral PV (COPV)

·      Cattle, horses and dogs are most commonly affected

·      Strong tropism for cutaneous and mucosal squamous epithelium

·      Most papillomaviruses are host- and often site-specific, except for bovine papillomavirus (BPV), which has been associated with equine sarcoids and feline cutaneous fibropapillomas (also called feline sarcoids)

·      Induce benign cutaneous tumors: Viral papilloma and fibropapilloma;

·      Not all papillomas are caused by or contain virus (e.g. – squamous papillomas without koilocytes or keratohyalin granules)

·      Papillomas are exophytic, hyperkeratotic masses composed of a hyperplastic epidermis supported by a fine fibrovascular stroma

·      Fibropapillomas are nodules or plaques with a predominant dermal fibroblastic proliferation covered by a hyperplastic, hyperkeratotic epidermis

 

PATHOGENESIS:

·      Infection is through direct and indirect contact with other animals of the same species that have lesions such as warts, sarcoids, and/or papillomas

·      Interaction leads to virus entry through abrasions or breaks within the stratified epithelium of mucosae or skin and subsequent infection of the stratum basale

·      Virus likely uses capsid proteins (bovine L1 major capsid protein and L2 minor capsid protein) to enter into the cells of the stratum basale

·      The exact receptors for virus entry into target cells have not been clearly identified, but heparin sulfate proteoglycans and α6β4 play a role in attachment and entry

·      There is a proposed mechanism for the promotion of solar-induced cutaneous neoplasms caused by papillomaviruses

 

TYPICAL CLINICAL FINDINGS:

·      Immunocompromised animals have increased susceptibility to papillomavirus infection

·      Exophytic lesions may regress due to cell-mediated immune attack but some may persist or undergo malignant transformation (i.e squamous cell carcinomas)

·      Inverted papillomas do not undergo spontaneous regression

 

TYPICAL GROSS FINDINGS:

·      Papillomas single to multiple white, flat, smooth nodules to elevated, crusty, fissured, horny masses

·      Canine papillomas are most numerous on the lips and muzzle and within the mouth and can spread to the palate and pharynx before regressing

·      Bovine papillomas are flat with a broad base

·      Inverted Papillomas are cup / “flask” shaped proliferations of hyperplastic epidermis that extend into the dermis; contain a central core of keratin

·      Bovine fibropapillomas vary from small, firm nodules to large cauliflower-like growths and are usually grayish to black

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

·      Papillomas: Exophytic projections (1-2cm in length) of mature, heavily keratinized, squamous epithelium on delicate connective tissue cores; elongated rete ridges at the periphery slant toward the center; dilation of capillaries

·      Viral papillomas display viral cytopathic effects: evident in the upper levels of the epithelium, include giant keratohyalin granules and koilocytes

·      Koilocytes: definition varies depending on the source

·      Mauldin Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals 2016: Ballooning degeneration and enlarged, condensed, or multiple nuclei

·      Hargis Pathologic Basis of Veterinary Disease 2017: Keratinocytes with clear cytoplasm and pyknotic nuclei; keratinocytes especially of the upper stratum spinosum that are swollen with clear cytoplasm or perinuclear halo and a pyknotic nucleus

·      Goldschmidt Surgical Pathology of Tumors of Domestic Animals 2019: Shrunken, pyknotic nucleus surrounded by a clear halo

·      Langohr Vet Pathol 56(6) Image Challenge: Keratinocytes with clear cytoplasm and pyknotic nuclei

·      Variable degrees of orthokeratotic to parakeratotic hyperkeratosis of the stratum corneum

·      Inverted papillomas: Histologically 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

·      Verruca plana (flat warts): Flat, plaque-like lesions with epidermal hyperplasia, hyperkeratosis, and viral cytopathic effects

·      Fibropapillomas: Predominance of dermal fibroblastic proliferation with overlying acanthosis, hyperkeratosis, and rete ridges

 

ULTRASTRUCTURAL FINDINGS:

·      Icosahedral, 50-55 nm, non-enveloped virions that fill the nuclei (nuclear inclusion) of keratinocytes

·      Large dense cytoplasmic granules are keratohyaline granules

 

ADDITIONAL DIAGNOSTIC TESTS:

·      There are no in vitro culture methods available for papillomaviruses

·      Detection is by southern blot hybridization, in situ hybridization (ISH), polymerase chain reaction (PCR), immunohistochemistry (IHC)

·      Newly developed mini-array test targets nucleic acid using enzyme-linked antibodies

 

DIFFERENTIAL DIAGNOSIS:

Viral papilloma:

·      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: No koilocytes or 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 without a central keratinized core

 

COMPARATIVE PATHOLOGY:

Cats

·      Cutaneous papillomavirus infection (FcaPV 1 & 2) results in the formation of a feline viral plaque; those caused by FcaPV-2, and less likely FcaPV-4 can progress to Bowenoid in situ carcinomas (BISCs) then can progress to invasive SCCs (ISCCs)

·      Due to the degradation of Rb with subsequent increase in p16 p53 is not affected

·      PVs (BPV 1 & 2, FeSarPV) are associated with feline sarcoids (a.k.a.- feline cutaneous fibropapillomas) which are uncommon dermal neoplasms that tend to occur on the head, nose, lips, or digits of young cats

Dogs

·      At least 5 different clinical syndromes are recognized: Cutaneous papilloma, canine oral papillomatosis (COPV), inverted papilloma, pigmented plaque, or pigmented papules

·      Oral papilloma is typically associated with CPV1 and cutaneous with CPV2

·    Increasing incidence of CPV1-associated transformation of both oral and cutaneous papillomas to SCC

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 SCC in older horses and does not spontaneously resolve

·      Equine ear papillomas (aural plaques): EcPV 3-6 causes bilaterally symmetric lesions on the pinnae

·      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 papilloma viruses have been associated with cattle

·      BPV-1, 2 and 5: Cutaneous fibropapillomas

·      BPV-1 is associated with papillomas or fibropapillomas of the glans penis of young bulls

·      BPV-2 is also associated with fibropapillomas of the esophagus, esophageal groove, and rumen

·      BPV-3: Cutaneous squamous papillomas; atypical warts

·      BPV-4: Squamous papillomas of the alimentary tract (only affects the squamous mucosa) and urinary bladder

·      BPV-6, 9, and 10: Teat papillomas

·      Bracken fern (Pteridium aquilinum) is immunosuppressive and therefore permissive of severe papillomatosis and is a cofactor to malignant transformation of BPV-4 infected cattle to squamous cell carcinoma in the upper alimentary tract; and ingestion in conjunction with BPV 1, 2, and 4 may cause epithelial and mesenchymal neoplasms within the urinary bladder due to E5 & E7 expression

Ovine

·      Ovine papillomavirus (OaPV-1 and OaPV-2) causes fibropapillomas in sheep

·      Squamous cell carcinoma (most common skin neoplasm in sheep) is associated with OaPV-3 (Vitiello Vet Pathol 2017)

Rabbit

·      Infected with 2 papillomaviruses; both belong to the genus Kappapapillomavirus

·      Cottontail rabbit papillomavirus (CRPV); also called Shope papilloma virus

·      Rabbit oral papilloma virus (ROPV); occurs in Oryctolagus rabbits

Others

·      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

·      Hamsters and mice: Delta-PVs have been reported to cause fibrosarcomas

·      Papillomavirus was first discovered in NMRI-nude mouse colonies (MusPV), causes mucocutaneous lesions in T-cell-deficient strains of mice

·      Norway rats: in Europe shown to have rat papilloma virus-1 (RnPV1) and rat papillomavirus-2 (RnPV-2)

·      Northern Fulmar: Fulmarus glacialis papillomavirus 1 reported on the interdigital foot mass of a (Gaynor Vet Pathol 2015)

·      Bonobos and chimpanzees: Oral epithelial hyperplasia (oral papillomatosis) affects the mucosa tongue, lips, and cheeks

·      Snow leopards: in captivity develop oral papillomas due to PuPV-1 (UuPV-1); can undergo transformation to oral squamous cell carcinoma

 

REFERENCES:

1.    Barthold SW, Griffey SM, Percy DH. Pathology of Laboratory Rodents and Rabbits. 4th ed. Ames, IA: Wiley Blackwell Publishing; 2016;19, 122, 175, 260-261.

2.    Diegel KL, Danilenko DM, Wojcinski ZW. The Integumentary System. In: Walling MA, Haschek WM, Rousseaux CG, Bolden B, Mahler BW. Fundamentals of Toxicologic Pathology. 3rd ed. San Diego, CA: Elsevier; 2018: 807.

3.    Gang DG, Sim CH, Lee TJ, Kong JY, Hong IH. Sebaceous cell differentiation in a canine oral papilloma. J Vet Diagn Invest. 2018;30(4):569-571.

4.    Gaynor AM, Fish S, Duerr RS, Dela Cruz Jr. FN, Pesavento PA. Identification of a Novel Papillomavirus in a Northern Fulmar (Fulmarus galcialis) With Viral Production in Cartilage. Vet Pathol. 2015;52:553-561.

5.    Goldschmidt MH, Goldschmidt KH. Epithelial and Melanocytic Tumors of the Skin. In: Meuten DJ ed. Tumors in Domestic Animals. 5th ed. Ames, IA: John Wiley & Sons, Inc; 2017: 91-95.

6.    Goldschmidt MH, Munday JS, Scruggs JL, Klopfleisch R, Kiupel M. In: Kiupel M, ed. Surgical Pathology of Tumors of Domestic Animals, Volume 1: Epithelial Tumors of the Skin. Washington DC, C.L Davis Foundation; 2019: 25-40.

7.    Gross TL, Ihrke PJ, Walder EJ. Skin Diseases of the Dog and Cat: Clinical and Histopathologic Diagnosis. Ames, IA: Blackwell; 2005: 567-575.

8.    Hargis AM, Myers S. The integument. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Elsevier; 2017:1069-1071.

9.    Higgins D, Rose K, Spratt D. Monotremes and Marsupials. In: Terio KA, McAloose D, St. Leger J., eds. Pathology of Wildlife and Zoo Animals. San Diego, CA: Elsevier; 2018: 466.

10. Labelle P. The eye. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Elsevier Mosby; 2016:1297.

11. Lowenstine LJ, McManamon R, Terio KA. Apes. In: Terio KA, McAloose D, St. Leger J., eds. Pathology of Wildlife and Zoo Animals. San Diego, CA: Elsevier; 2018: 385-386.

12. Luff J, Rowland P, Mader M, Orr C, Yuan H. Two Canine Papillomaviruses Associated With Metastatic Squamous Cell Carcinoma in Two Related Basenji Dogs. Vet Pathol. 2016;53:1160-1163.

13. Mauldin EA, Peters-Kennedy J. Integumentary system. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 1. 6th ed. St. Louis, MO: Elsevier Inc; 2016: 706-712.

14. Munday JS, Fairley RA, Atkinson K. The Detection of Felis catus papillomavirus 3 DNA in a feline bowenoid in situ carcinoma with novel histologic features and benign clinical behavior. J Vet Diagn Invest. 2016;28(5)612-615.

15. Munday JS, Fairley RA, Mills H, Kiupel M, Vaatstra BL. Oral Papillomas Associated With Felis catus Papillomavirus Type 1 in 2 Domestic Cats. Vet Pathol. 2015:52(6):1187-1190.

16. Munday JS, Kiupel M. Papillomavirus-Associated Cutaneous Neoplasia in Mammals. Vet Pathol. 2010;47(2):254-264.

17. Scagliarini A, Casa G, Trentin B, et al. Evidence of zoonotic Poxviridae coinfections in clinically diagnosed papillomas using a newly developed mini-array test. J Vet Diagn Invest. 2016;28(1):59-64.

18. Terio KA, McAloose D, Mitchell E. Felidae. In: Terio KA, McAloose D, St. Leger J, eds. Pathology of Wildlife and Zoo Animals. San Diego, CA: Elsevier; 2018: 271-272.

19. Uzal FA, Plattner BL, Hostetter JM. Alimentary system. In: Maxie MG, ed. Jubb, Kennedy and Palmer’s Pathology of Domestic Animals. Vol 2. 6th ed. St. Louis, MO: Elsevier Saunders; 2015:26,43-44.

20. Vascellari M, Mazzei M, Zanardello C, et al. Felis catus Papillomavirus Types 1, 2, 3, 4, and 5 in Feline Bowenoid in Situ Carcinoma: An In Situ Hybridization Study. Vet Pathol. 2019;56(6):818-825

21. Vitiello V, Burrai GP, Agus M,, et al. Ovis aries Papillomavirus 3 in Ovine Cutaneous Squamous Cell Carcinoma. Vet Pathol. 2017;54(5):775-782.

22. Zachary JF. Mechanisms of microbial infection. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 6th ed. St. Louis, MO: Elsevier Mosby; 2016:227-228.

23. Zhu KW, Affolter VK, Gaynor AM, Dela Cruz Jr. FN, Pesavento PA. Equine Genital Squamous Cell Carcinoma: In Situ Hybridization Identifies a Distinct Subset Containing Equus caballus Papillomavirus 2. Vet Pathol. 2015;52:1067-1072.

 

 

Papilloma viruses associated with pre-neoplastic and neoplastic skin lesions in animals (adapted from Munday and Kiupel Vet Pathol 2010):

Animal species

Skin lesion

Papillomavirus

Cat

Feline viral plaque progressing to BISC

FdPV-1, -2

Cat

SCC

FdPV-2

Dog

Canine pigmented viral plaque progressing to ISC and SCC

CfPV-3, -4

Dog

Endophytic papilloma and SCC in immunosuppressed dogs

CfPV-2

Dog

Vaccine-induced cutaneous SCC

COPV

Horse

Equine sarcoid

BPV-1, -2

Horse

Equine papillomas, ISC and SCC

EcPV2

Sheep

SCC

OaPV-3

Rabbit

Cutaneous SCC

CRPV

Western barred Bandicoot

Cutaneous SCC

BPCV-1

Egyptian fruit bat

Basosquamous carcinoma

RaPV-1

Natal multimammate mouse

Keratoacanthoma and SCC

MnPV

European harvest mouse

Sebaceous carcinoma

MmPV

 

FdPV, Felis domesticus 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

 


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