1-year-old, male, pit bull terrier/boxer mix, dog (Canis familiaris).This mixed breed dog was rescued and adopted at one year of age, and was initially energetic and in good health. The patient developed and was treated for diarrhea and a wheezing cough shortly after adoption. At this time, he developed a cyst-like nodule on his left front paw at the first digit nail bed. He was treated with Epsom salt bath soaks and Benadryl-«. This lesion progressed multifocally to the other paws, forming papillary, exophytic growths that spread proximally up the legs to the elbows. At the time of biopsy submission, the patient was having difficulty ambulating. Concurrently, the patient developed a hive-like rash around the face with red welts. Fine needle aspirates, cultures, and biopsies of the affected areas were submitted.

Gross Description:  

Multifocal to coalescing, well demarcated, papillary, proliferative, nodular masses expand the plantar surfaces of the feet, expanding from the foot pads, nail beds, and proximal haired skin of the lower leg. Many of the masses are reddened, ulcerated, and hyperkeratotic.

Histopathologic Description:

Haired skin: In this section of haired skin, there is a circumscribed, unencapsulated, shallow, bowl-shaped endophytic, neoplastic proliferation of the surface epithelium compressing and displacing adnexal structures in the underlying dermis. Neoplastic cells are arranged in broad infolds and papillary projections supported on thin fibrovascular cores. There is hyperplasia of the basal cells with differentiation to large polygonal, hyperplastic epithelial cells with distinct borders, abundant basophilic cytoplasm, and round to oval central nuclei with finely stippled chromatin. Frequent cells have amorphous eosinophilic intranuclear inclusions that measure 10-15 μm in diameter peripherally marginating chromatin (papillomavirus inclusions). Many other nuclei have a glassy appearance with intranuclear cytoplasmic invagination. Mitoses are 1-2 per hpf. Rare epithelial cells, especially in the stratum spinosum, have clear to pale cytoplasm with eccentric nuclei (koilocytes, viral cytopathic effect). Inverted epithelial papillary fronds are covered with a variably thick band of parakeratotic cells and some keratin material continous with acanthosis, parakeratotic and orthokeratotic hyperkeratosis of the adjacent epithelium. Inflammation infiltrating the stroma is comprised of macrophages, neutrophils, and fewer lymphocytes. In some sections, associated superficial epithelium has an overlying thick serocellular crust composed of degenerate keratinocytes, keratin material, red blood cells, degenerate neutrophils and eosinophilic cellular and pyknotic material. Neoplastic cells approach lateral surgical margins in many sections.

Morphologic Diagnosis:  

Haired skin: inverted papilloma, viral


Inverted viral papilloma

Contributor Comment:  

The papillary nature of this tumor with prominent intranuclear papillomavirus inclusions suggests that this inverted papilloma is caused by papillomavirus (PV) infection. Immunohistochemistry using monoclonal antibody against human papillomaviruses (HPV-1, 6, 11, 16, 18, and 31) using SDS-disrupted bovine papillomavirus type 1 immunogen (Millipore Billerica, MA) was positive with multifocal intense intranuclear staining.(1)

At least four different PVs are believed to infect dogs.(2) Classification of PVs is often based on the L1 gene, which encodes the viral capsid and packages viral DNA with L2, because it is the most conserved region of the PV genome.(1)1 Oral papillomatosis in dogs, characterized by multifocal cauliflower growths affecting the tongue, gingival, buccal mucosa, lips, and pharynx, is believed to be caused by the lambda papillomavirus COPV.(2) Dogs that clinically manifest oral papillomas are generally less than 3 years old, but papillomas can appear in immunosuppressed and older dogs. Papillomatosis in dogs is considered to be a self-limiting disease with spontaneous regression of tumors, so treatment is generally not recommended.(2) Occasionally, these tumors persist and undergo malignant transformation. PVs are associated with cutaneous neoplastic transformation in several species, including sarcoids in cats and horses, and squamous cell carcinoma in dogs, cats, rabbits, bandicoots, and rodents.(7)

It has been proposed that cutaneous papillomatosis is caused by a different PV. A novel, epidermotropic PV has been recently described, termed CfPV-2.(10) Unlike COPV, lesions associated with CfPV-2 appear to be restricted to the footpads, with more chronic lesions lasting greater than 6 months. Experimentally, CfPV-2 is unable to induce oral papillomas in immunocompetent dogs, and vaccination against COPV is not effective against CfPV-2.(10) In addition, chronic infection with CfPV-2 is associated with highly malignant squamous cell carcinoma with distal metastases, although the exact pathogenesis of CfPV-2-associated neoplastic transformation is not known. The link between different PVs and specific tumor manifestations is also unclear. Recently, genotyping of PVs associated with canine inverted papillomas discovered the presence of either CfPV-2, COPV, or unknown canine PVs, suggesting that more than one type of PV may cause inverted papillomas.(6)

Canine oral papillomatosis can provide a model for studying regression of warts in human PV-associated cervical papillomatosis, because the predictable nature of lesion regression in canine papillomas closely mimics regression in cervical warts. In canines, papilloma regression is associated with leukocyte influx, with an abundance of CD4+ and CD8+ lymphocytes.(8)

Differentials for this case include nail bed inverted squamous papilloma. These masses arise from nail bed epithelium, and histologically contain laminated, compact keratin within a hollow mass.(9) The nails are also grossly broken or missing; however, viral inclusions, lack of involvement of the nails, and lack of cyst formation rule out nail bed inverted papilloma. In this case, the papilloma likely originated from the skin adjacent to the nail bed, consistent with previous reports.(2) In the absence of viral inclusions, other differentials include cutaneous squamous papilloma of non-viral origin.

JPC Diagnosis:  

Haired skin: Inverted papilloma, viral.

Conference Comment:  

Two prominent histologic characteristics of viral papillomas are koilocytes and intranuclear inclusion bodies. Koilocytes, seen primarily in the spinous layer, are enlarged epithelial cells that have eccentric pyknotic nuclei surrounded by a clear halo; their ghosts may be seen in the more superficial stratum corneum.(4) In the stratum spinosum, the normal eosinophilic cytoplasm is replaced by more basophilic cytoplasm; the nuclei of the cells may contain pale basophilic (amphophilic) or smaller eosinophilic viral inclusions.(4) Some degenerating keratinocytes may also contain intracytoplasmic eosinophilic material resembling inclusions; these are not true viral inclusions, but rather merely aggregates of keratin thought to be a byproduct of the viral cytopathic effect.(4,7)

The precise role that papillomaviruses play in the development of cutaneous neoplasia in animals is not entirely understood. It has been proposed that ultraviolet light and papillomaviruses may act as co-carcinogens. Ultraviolet light causes damage to nuclear DNA, which increases the likelihood of oncogenic transformation.(3) Simultaneously, papillomavirus infection promotes epithelial proliferation.(4)

Many important papilloma viruses of animals exist and are beyond the scope of this discussion; those interested are invited to consult the references.(3,7) The chart below summarizes several papilloma viruses in animal species:
SpeciesVirusTissue(s) affectedDisease(s)
OxBovine papilloma virus (BPV) 1, 2 & 5Udder, teats, head, neck, shoulders, omasum, vagina, vulva, penis and anus; BHV-2 also affects the urinary bladderTeat frond warts; cutaneous warts; rice grain fibropapillomas; transmissible fibropapilloma in bulls
OxBPV-3SkinPapillomas of the skin
OxBPV-4Alimentary tract e.g. mouth, pharynx and upper alimentary tractBovine alimentary papillomata; associated with squamous cell carcinoma and squamous papilloma of the alimentary tract and urinary bladder
EquineBPV-1 & -2SkinSarcoid
FelineFdPV-1 & -2SkinViral plaque progressing to Bowenoid carcinoma in-situ; FdPV-2 linked to squamous cell carcinoma
FelineFdPV-2SkinSquamous cell carcinoma (SCC)
CanineCfPV-3 & -4Skin; mucous membranes of the eye, skin and genitalsPapillomas; viral plaque progressing to Bowenoid carcinoma in-situ and SCC
CanineCfPV-2SkinInverted papilloma; SCC
RabbitCRPVTongue; skinLingual papillomas; SCC
Western barred BandicootBPCV1SkinSCC


1. Balara JM, McCarthy RJ, Kiupel M, Buote MA, Wise AG, Maes RK. Clinical, histologic, and immunohistochemical characterization of wart-like lesions on the paw pads of dogs: 24 cases (2000-2007). J Am Vet Med Assoc. 2009;234:1555-1558.
2. Debey BM, Bagladi-Swanson M, Kapil S, Oehme FW. Digital papillomatosis in a confined Beagle. J Vet Diagn Invest. 2001;13:346-348.
3. Ginn PE, Mansell EKL, Rakich PM: Skin and appendages. In: Maxie MG, ed. Jubb, Kennedy and Palmers Pathology of Domestic Animals. 5th ed., vol. 1. Philadelphia, PA: Elsevier Ltd; 2007:647-648
4. Goldschmidt MH, Dunstan RW, Stannard AA, von Tscharne C, Walder EJ, Yager JA. Histological classification of epithelial and melanocytic tumors of the skin of domestic animals, 2nd series, vol. III. Washington, D.C.: Armed Forces Institute of Pathology; 1998:19-20.
5. Kusewitt DF, Rush LJ. Neoplasia and tumor biology. In: McGavin MD, Zachary JF, eds. Pathologic Basis of Veterinary Disease. 4th ed. St. Louis, MO: Elsevier; 2007:265-267.
6. Lange CE, Tobler K, Brandes K, et al. Canine inverted papillomas associated with DNA of four different papillomaviruses. Vet Dermatol. 2009;21:287-291.
7. Munday JS, Kiupel M. Papillomavirus-associated cutaneous neoplasia in mammals. Vet Pathol. 2010;47:254-264.
8. Nicholls PK, Moore PF, Anderson DM, et al. Regression of canine oral papillomas is associated with infiltration of CD4+ and CD8+ lymphocytes. Virology. 2001;283:31-39.
9. Plattner BL, Hostetter JM. Cutaneous viral papilloma with local extension and subungual cyst formation in a dog. J Vet Diagn Invest. 2009;21:551-554.
10.Yuan H, Ghim S, Newsome J, et al. An epidermotropic canine papillomavirus with malignant potential contains an E5 gene and establishes a unique genus. Virology. 2007;359:28-36.
11.Yhee JY, Kwon BJ, Kim JH, et al. Characterization of canine oral papillomavirus by histopathological and genetic analysis in Korea. J Vet Sci. 2010;11:21-25.

Click the slide to view.

Haired skin, Inverted viral papilloma, dog.

Haired skin, Inverted viral papilloma, dog

Haired skin, Inverted viral papilloma, dog.

Haired skin, Inverted viral papilloma, dog.

Haired skin, Inverted papilloma, dog. 

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