November 2022

I-V02 (NP)

Signalment (JPC# 1818935): White-tailed deer (Odocoileus virginianus)

HISTORY: Proliferative dermal mass

HISTOPATHOLOGIC DESCRIPTION: Haired skin: Expanding the dermis, elevating the overlying mildly hyperplastic epidermis, effacing adnexal structures, and extending to cut borders is a non-encapsulated, moderately cellular neoplasm composed of spindle cells arranged in long, interlacing streams and bundles on a moderate collagenous matrix. Neoplastic cells have indistinct cell borders, a scant amount of pale eosinophilic, fibrillar cytoplasm, and one oval to fusiform, vesiculate nucleus with finely stippled chromatin and one variably distinct nucleolus. There is mild anisocytosis and anisokaryosis. The mitotic rate is 1 per 2.37mm². There is mild epidermal hyperplasia characterized by acanthosis, rete ridge formation, and orthokeratotic hyperkeratosis. Numerous cells within the stratum spinosum and granulosum are enlarged with abundant, finely granular, amphophilic cytoplasm with clear cytoplasmic vacuoles and eccentric, vesiculate or pyknotic nuclei surrounded by a clear halo and 1-3 prominent magenta nucleoli (viral cytopathic effect, koilocytes). Cells of the stratum granulosum contain many prominent, large, irregularly-shaped keratohyalin granules. The superficial dermis multifocally contains many macrophages with intracytoplasmic melanin and free melanin granules (pigmentary incontinence).

MORPHOLOGIC DIAGNOSIS: Haired skin: Fibropapilloma, White-tailed deer (Odocoileus virginianus), cervid.

ETIOLOGY: Fibroma viruses (FV) (family Papillomaviridae, genus Delta-papillomarvirus)

ETIOLOGIC DIAGNOSIS: Cutaneous cervid papillomaviral fibropapillomatosis

GENERAL DISCUSION:

Cutaneous fibroma or fibropapilloma, caused by fibroma viruses (delta papillomavirus), are one of the most commonly reported tumors of white-tailed deer; usually incidental finding; most common in white tailed deer, roe deer and European moose, but also documented in a wide variety of cervids
Papillomaviruses: 50-55 nm diameter, non-enveloped, double stranded DNA virus that reproduces in keratinocyte nuclei; most are species specific (see exception below, delta papillomavirus)
Papillomavirus genera:

Alpha papillomaviruses include oncogenic mucosal types
Beta papillomaviruses includes lesions that may be associated with immunosuppression
Delta papillomaviruses is associated with benign fibropapillomas in cats and ungulates (these have the unique ability to infect multiple species)

PATHOGENESIS:

Papillomaviruses:

Infection with papillomavirus through defect in epithelium (via direct contact with contaminated surfaces or materials that might abrade the skin, e.g. scratching posts, sparring) à virus infects cells of the stratum basale à dysfunction of genes that regulate cell proliferation, differentiation, and adhesion à benign neoplastic transformation
Viral receptors on cells of the stratum basale have not been clearly identified; however, an integrin (α6 β4) and potentially heparin sulfate proteoglycans mediate the attachment and entry of virions into target cells.
Benign transformation involves nonpermissive cells of the stratum basale where the virus does not integrate into target cell genes and viral genes, and gene products like oncoproteins are expressed in low amounts

TYPICAL CLINICAL FINDINGS:

Large lesions may interfere with vision, respiration, food intake, or locomotion
May spontaneously regress with time

TYPICAL GROSS FINDINGS:

Smooth to verrucous, pedunculated to pendulous dermal masses
Solitary or multiple
Up to 25 cm in diameter
Most often on head and neck, but can include legs and oral mucosa

TYPICAL LIGHT MICROSCOPIC FINDINGS:

Predominance of dermal proliferation with the presence of acanthosis and hyperkeratosis with down growth of rete ridges in the epidermis (i.e. proliferating epidermal and dermal components)
- Dermal cells arranged in haphazard whorls and fascicles of dense collagenous connective tissue (contrast with granulation tissue)
Non-encapsulated mass of neoplastic fibroblasts supported by a collagenous matrix
Evidence of viral cytopathic effects within the epidermis: keratohyaline granules in the stratum granulosum, koilocytes, and intranuclear inclusions
- 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
  - Welle Pathologic Basis of Veterinary Disease 2022: Individual keratinocytes that are pale, rounded, swollen, sometimes vacuolated with enlarged (sometimes shrunken) nuclei
  - Goldschmidt Surgical Pathology of Tumors of Domestic Animals 2019: Shrunken, pyknotic nucleus surrounded by a clear halo
Tumor regression involves perivascular lymphocyte infiltration and hyalinization of the connective tissue matrix

ULTRASTRUCTURE:

    Papillomaviruses:  Icosahedral, 50-55 nm diameter, non-enveloped virions in nuclei of keratinocytes

ADDITIONAL DIAGNOSTIC TESTS:

    Viral antigen can be demonstrated by immunofluorescence, immunohistochemistry, and PCR in fresh and formalin fixed tissues

DIFFERENTIAL DIAGNOSIS:

Squamous cell carcinoma
Sarcoma

COMPARATIVE PATHOLOGY:

Selected papillomavirus-induced/associated tumors:

Cattle: BPV-1, 2, 5, 8 (cutaneous fibropapilloma); BPV-3, 6, 7, 9-13 (cutaneous papilloma, I-V01C); BPV-1, 2, 4, 5 (papilloma of the alimentary tract and urinary bladder, often in association with bracken fern ingestion)
Rabbit: Rabbit fibroma virus (Shope fibroma, I-V09A); cottontail papilloma virus (Shope papilloma); rabbit oral papillomavirus (oral papilloma)
Sheep: OPV-3 (SCC) (Vitiello Vet Pathol 2017)
Canine: CPV 1, 2, 3, 7 (SCC, I-V01A, I-V01B)
Equine: BPV-1, 2 (associated with equine sarcoid, I-N17)
Feline: FcaPV-1, 2, 3, 4, 5 (Viral plaque progressing to BISC, SCC)

REFERENCES:

Barthold SW, Griffey SM, Percy DH. Pathology of Laboratory Rodents and Rabbits. 4th ed. Ames, IA: Wiley Blackwell Publishing; 2016: 260-261.
Cheville NF, Lehmkuhl, H. Cytopathology of viral diseases. In: Cheville, NF, ed. Ultrastructural Pathology: The Comparative Cellular Basis of Disease. 2nd ed. Danvers, MA: Wiley-Blackwell; 2009:343-347.
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.
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: Saunders Elsevier; 2016: 706-707.
Howerth EW, Nemeth NM, Ryser-Degiorgis MP. Cervidae. In: Terio KA, McAloose D, Leger JS, eds. Pathology of Wildlife and Zoo Animals. London, United Kingdom: Academic Press is an imprint of Elsevier; 2018:154-155.
Stanton, JB, Zachary JF. Mechanisms of microbial infection. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:171-294.
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.
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.
Welle MM, Linder KE. The Integument. In: Zachary JF, ed. Pathologic Basis of Veterinary Disease. 7th ed. St. Louis, MO: Elsevier; 2022:1209-1219.