What is Dr. Zubair Khalid's research focus?

Dr. Zubair Khalid specializes in molecular virology, mRNA vaccine development, and computational biology, with a focus on avian pathogens like IBDV and Avian Reovirus.

Where is Dr. Zubair Khalid currently working?

Dr. Zubair Khalid is a Postdoctoral Research Associate at the University of Maryland (UMD), specifically within the Department of Animal and Avian Sciences.

Oral Squamous Papilloma: Pathology and Features

Name: Oral Squamous Papilloma: Pathology and Features
Creator: Dr. Zubair Khalid

By Dr. Zubair Khalid, DVM, MS, PhD · 2026-09-20

An oral squamous papilloma is a benign, exophytic epithelial proliferation in which finger-like fronds of stratified squamous epithelium grow over narrow fibrovascular cores, usually without dysplasia or invasion. It is the prototypical papillomavirus-associated mucosal tumor, and in dogs the classic presentation, oral papillomatosis, is a self-limiting disease of young animals.

This lesion matters because it sits at the center of a differential diagnosis that ranges from harmless to lethal. A papilloma mouth lesion in a young dog is often a wart that will vanish on its own, while a verrucous plaque in an older animal with a chewing habit may be verrucous carcinoma. The two can look similar on gross examination. Histopathology, not appearance, separates them, and that distinction determines whether the animal needs nothing, a simple excision, or oncologic workup.

This article is educational and is not a substitute for veterinary diagnosis or treatment.

What an Oral Squamous Papilloma Is

A papilloma is a benign epithelial tumor with a branching, tree-like architecture. The World Health Organization classifies oral squamous cell papilloma as a benign, hyperplastic, exophytic proliferation with verrucous or cauliflower-like morphology and either a sessile or pedunculated base [1]. It is among the most common benign epithelial lesions of the human oral cavity, with a predilection for the hard and soft palate [1]. In humans it is often described as the fourth most common benign epithelial lesion, associated with human papillomavirus (HPV) types 6 and 11 [2].

The term squamous papillomatosis describes the multifocal form, in which many papillomas appear across the oral mucosa at once. In dogs this is the classic "oral papillomatosis" of young dogs, a contagious, viral-induced crop of warts. The solitary form is more typical of adult humans and can occur in any species.

A key structural point: a papilloma is an exophytic lesion. It grows outward from the surface. That is different from a dysplastic or neoplastic process that grows downward into underlying tissue. The exophytic growth pattern is one of the reasons papillomas are usually benign, because the proliferating epithelium stays above the basement membrane.

Etiology: The Papillomavirus Connection

Papillomaviruses are small, non-enveloped DNA viruses that infect stratified squamous epithelium. Infection is generally species-specific, and different viral types have different tissue tropisms and oncogenic potential.

In humans, HPV types 6 and 11 are the classic low-risk types linked to oral squamous papilloma [2]. A pediatric case series of 59 patients with oral and oropharyngeal squamous papillomas found that HPV typing was performed in 34 patients, with 7 positive cases: 2 low-risk and 5 high-risk subtypes [3]. Notably, no patient with prior HPV vaccination tested positive [3]. That observation is consistent with vaccine protection but does not prove causation, and it should not be overread from a single series.

In dogs, the best-characterized agent is canine papillomavirus type 1 (CPV-1). A case report documented a persistent CPV-1-induced oral papilloma in a 3-year-old Labrador retriever cross that progressed to invasive oral squamous cell carcinoma after 18 months, with CPV-1 DNA present in the carcinoma and coinfection by another papillomavirus excluded by multiple polymerase chain reaction tests [4]. This is a rare outcome, not the rule, but it is the reason a persistent papilloma deserves re-evaluation rather than indefinite observation.

Papillomavirus has also been detected in non-domestic species. In slender-horned gazelles, oral plaques, rumen and reticulum papillomas, and squamous cell carcinomas were found independently or concurrently, and PCR for the papillomavirus L1 gene was positive in tumors from six of eight affected animals [5]. Sequencing identified a novel virus provisionally named Gazella leptoceros papillomavirus 1 [5]. This confirms that papillomavirus-associated mucosal disease is a cross-species phenomenon, not a canine or human peculiarity.

The precise viral role in any single oral papilloma remains controversial in the literature [1]. Some lesions test negative for papillomavirus, and chronic irritation can produce a morphologically similar growth without viral involvement. A case report described an oral squamous papilloma with koilocytic change in a 49-year-old non-smoking man beneath a poorly maintained removable denture, with an adjacent traumatic ulcer at the denture-contact point [6]. The authors interpreted the findings as squamous papilloma with HPV-suggestive cytopathic effect plus chronic denture-associated inflammation [6]. In other words, mechanical trauma and viral infection can coexist, and both can contribute to the clinical picture.

Why Koilocytes Matter

A koilocyte is a squamous epithelial cell with a shrunken, dark, wrinkled nucleus surrounded by a clear perinuclear halo. This is the classic cytopathic effect of papillomavirus infection. Koilocytes appear in the spinous layer of the epithelium.

Koilocytes are supportive but not definitive evidence of papillomavirus. A study comparing verrucous papillary lesions found koilocytic appearance in all squamous papilloma cases, pointing toward viral association, while verrucous hyperplasia and verrucous carcinoma appeared habit-related rather than viral [7]. Koilocytes can also be seen in reactive and inflammatory conditions, so their presence must be interpreted alongside the overall architecture and the absence of dysplasia.

Gross and Histologic Features

Gross Appearance

An oral papilloma typically presents as a solitary, exophytic mass. The surface is described as papillary, verrucous, or cauliflower-like [1]. The base may be sessile (broad) or pedunculated (on a stalk). Color is usually normal to slightly pale mucosa. Size is commonly under 10 mm in diameter, and the lesion is usually slow-growing and asymptomatic [8].

Atypical presentations exist. Two cases of large, symptomatic oral squamous papilloma were reported: a 15 × 10 × 8 mm pedunculated soft palate mass with finger-shaped projections and irritating pain, plus a smaller 3 × 2 × 2 mm sessile cauliflower-like mass in the same patient, and a 20 × 10 × 6 mm papilloma on the buccal gingiva of an impacted, decayed maxillary third molar with orofacial pain and limited mouth opening [8]. These sizes exceed the typical description and show that papillomas are not always small or silent.

Histology: The Core Diagnostic Feature

The defining histologic pattern is finger-like or frond-like projections of stratified squamous epithelium supported by narrow fibrovascular cores [1]. The epithelium is hyperplastic but orderly. Maturation proceeds from basal layer to surface. The rete ridges may be elongated. Parakeratosis (retained nuclei in the stratum corneum) is common. Basilar hyperplasia and regular mitotic activity can be present without indicating malignancy [6].

A detailed histopathologic description from a denture-associated case reported hyperplastic stratified squamous epithelium forming fingerlike papillary projections over narrow fibrovascular cores, with parakeratosis, basilar hyperplasia, regular mitotic activity, koilocytes in the spinous layer, and chronic lymphocytic stromal inflammation, with absence of dysplasia or invasion confirmed [6].

Three features separate papilloma from dysplasia and carcinoma:

Absence of dysplasia. Dysplasia means disordered maturation with cytologic atypia, nuclear enlargement, hyperchromasia, and abnormal mitoses. These are not features of a simple papilloma.
Absence of invasion. The basement membrane is intact. Epithelial cells do not breach into the lamina propria or deeper.
Regular mitotic activity. Mitoses are confined to the basal and parabasal layers and are morphologically normal. Atypical mitoses suggest a different diagnosis.

The fibrovascular core is the structural scaffold. It carries blood supply to the epithelium and is the reason the lesion bleeds easily if traumatized. In a carcinoma, the supporting stroma is replaced by invasive nests and cords of malignant cells.

Comparative Features: Papilloma Versus Its Differentials

The differential diagnosis for a verrucopapillary oral lesion includes squamous papilloma, verruca vulgaris, condyloma acuminatum, verrucous hyperplasia, verrucous carcinoma, and squamous cell carcinoma. These share overlapping clinical and histologic features, and inaccurate diagnosis can lead to suboptimal outcomes [7].

Feature	Squamous papilloma	Verruca vulgaris	Condyloma acuminatum	Verrucous carcinoma	Squamous cell carcinoma
Typical cause	HPV 6/11 (low-risk)	HPV 2/4 (cutaneous)	HPV 6/11 (mucosal)	Tobacco, alcohol, chronic irritation	Tobacco, alcohol, HPV (subset)
Architecture	Finger-like fronds over fibrovascular cores	Exophytic, hyperkeratotic, papillomatous	Broad-based, acuminate, often multifocal	Broad, warty, pushing margin	Irregular, invasive, ulcerated
Koilocytes	Present	Present	Present	Usually absent	Variable
Dysplasia	Absent	Absent	Absent or minimal	Present, often marked	Present, often marked
Invasion	Absent	Absent	Absent	Present (pushing, not infiltrative)	Present (infiltrative)
Mitotic activity	Regular, basal	Regular, basal	Regular, basal	Increased, may be atypical	Increased, atypical
Behavior	Benign, often self-limiting	Benign	Benign, sexually transmitted	Locally aggressive	Malignant, metastatic potential
Site	Palate, tongue, lips, any mucosa	Lips, skin, mucocutaneous junction	Genital and oral mucosa	Buccal mucosa, gingiva, alveolar ridge	Any oral site

Squamous Papilloma vs Squamous Cell Carcinoma

This is the most important distinction. Squamous cell carcinoma (SCC) is a malignant neoplasm of squamous epithelium with invasive growth and metastatic potential. Oral SCC has a high mortality rate and a recurrence/metastasis rate reported at 45.7% of patients in one clinical review [9].

Endoscopic features can help distinguish papilloma from elevated squamous carcinoma. A study of 47 patients with oral or pharyngeal papilloma classified lesions into three patterns: salmon roe-like polyps, polyps without capillary transparency, and pinecone-like polyps, with salmon roe-like polyps most prevalent at 48.9% [10]. Squamous cell carcinomas exhibited at least one of three features: uneven or absent lobulated structure, irregular capillary morphology, and coexistence of flat lesions [10]. Papillomas showed uniform lobulated structure, homogeneous or non-visible capillaries, and no flat components [10]. When any of the carcinoma features were present, two endoscopic specialists achieved sensitivities of 100% and 97.6% for carcinoma diagnosis, with specificities of 68% and higher [10].

Those numbers come from human endoscopy. They illustrate the principle: papillomas are uniform and lobulated, carcinomas are irregular and heterogeneous. In veterinary practice, the same principle applies on gross inspection, but histopathology remains the confirmatory test.

Squamous Papilloma vs Verruca Vulgaris

Verruca vulgaris is the common cutaneous wart, caused by HPV types 2 and 4. It can occur on the lips and mucocutaneous junction. Histologically it shows papillomatosis, hyperkeratosis, and koilocytes, similar to papilloma. The distinction is largely clinical and anatomic: verruca vulgaris is a skin lesion, while squamous papilloma is a mucosal lesion. Both are benign.

Squamous Papilloma vs Condyloma Acuminatum

Condyloma acuminatum is a sexually transmitted mucosal wart caused by HPV 6 and 11. In the oral cavity it presents as a broad-based, acuminate (pointed) lesion, often multifocal. It shares the low-risk HPV association with squamous papilloma. The histologic overlap is significant, and some pathologists consider them part of the same spectrum. Condyloma acuminatum is more often multifocal and has a broader base than the typical solitary papilloma.

Squamous Papilloma vs Verrucous Hyperplasia and Verrucous Carcinoma

Verrucous hyperplasia and verrucous carcinoma are habit-related lesions, meaning they are associated with tobacco and alcohol use rather than papillomavirus [7]. Verrucous carcinoma is a low-grade variant of squamous cell carcinoma with a pushing, rather than infiltrative, invasive front. It is locally aggressive but rarely metastasizes. Verrucous hyperplasia is a precursor or early form. Both show dysplasia and, in the case of carcinoma, invasion. The koilocytic appearance in all squamous papilloma cases in one series pointed toward viral association, while verrucous hyperplasia and verrucous carcinoma appeared habit-related [7]. That contrast is a useful diagnostic clue, though not a substitute for histopathology.

Squamous Papilloma vs Salivary Gland Papillary Lesions

Intraductal salivary gland neoplasms can present as papillary masses in the oral cavity. A retrospective series identified 35 benign intraductal neoplasms, including sialadenoma papilliferum (18 cases, 31.4%), ductal papilloma (12 cases, 34.3%), and inverted ductal papilloma [11]. These arise from salivary duct epithelium, not surface squamous epithelium, and have a different histologic appearance. They are a reminder that not every papillary oral mass is squamous.

Clinical Presentation and Species Differences

Dogs

Oral papillomatosis in dogs is typically a disease of young animals, most commonly puppies and adolescents. The classic presentation is multiple, multifocal verrucous lesions populating the oral cavity, sometimes extensively [4]. Lesions may involve the lips, gingiva, tongue, palate, and pharynx. The disease is contagious among dogs and spreads by direct contact.

The clinical course is usually self-limiting. Lesions regress over weeks to months as the immune system clears the infection. This is the single most important clinical fact for a dog owner: in an otherwise healthy young dog with classic oral papillomatosis, the default approach is observation, not surgery.

Exceptions exist. A 3-year-old Labrador retriever cross had multiple and multifocal verrucous lesions that persisted despite multiple surgical ablations, azithromycin, interferon α-2b, alternative medicines, and off-label immunostimulant use, and after 18 months an aggressive lesion developed at the left mandibular first molar that progressed to well-differentiated invasive oral squamous cell carcinoma [4]. The dog was euthanized due to poor quality of life [4]. This case is rare, but it shows that persistence, progression, or atypical behavior warrants biopsy.

Cats

Oral papillomas are less commonly reported in cats than in dogs. When they occur, they are usually solitary and benign. Feline oral squamous cell carcinoma is a major clinical concern, and any oral mass in a cat should be evaluated with biopsy because the clinical appearance of benign and malignant lesions can overlap.

Humans

In humans, oral squamous papilloma is most often seen in adults aged 30 to 50 years, with the tongue and soft palate as the most common sites [2]. A pediatric series found lesions most commonly on the uvula (27 cases), followed by the tonsillar region (18), soft palate (6), and hard palate (4), with most lesions discovered incidentally [3]. Follow-up was available in 25 patients at a mean of 74.7 days post-excision, with no recurrences observed [3].

Other Species

Papillomavirus-associated oral disease has been documented in slender-horned gazelles, with oral plaques, rumen and reticulum papillomas, and squamous cell carcinomas occurring independently or concurrently in eight of 74 postmortem examinations between 1983 and 2023 [5]. All tumors were diagnosed in adults [5]. This is a reminder that comparative pathology across species can reveal shared mechanisms.

Diagnosis in Practice

Diagnosis rests on excisional biopsy with histopathology. Clinical examination can suggest a papilloma based on location, appearance, and signalment, but it cannot confirm it. The differential diagnosis includes malignant and potentially malignant lesions, and the consequences of a missed diagnosis are serious.

A case report of an oral squamous papilloma in a 58-year-old man with a history of chronic tobacco smoking emphasized that early recognition and histopathological confirmation are essential to rule out potentially malignant lesions, especially in patients with risk-modifying habits such as tobacco use [12]. The same principle applies in veterinary medicine: an older animal with an oral mass and a history of exposure to carcinogens (tobacco smoke, environmental irritants) needs biopsy, not observation.

What the Pathologist Looks For

The pathologist examines the architectural pattern (finger-like fronds over fibrovascular cores), the epithelial maturation (orderly, with koilocytes), the presence or absence of dysplasia (cytologic atypia, abnormal mitoses), and the presence or absence of invasion (breach of the basement membrane). The diagnosis of squamous papilloma requires all of the following: papillary architecture, orderly epithelial maturation, absence of dysplasia, and absence of invasion [6].

If dysplasia is present, the diagnosis shifts toward a premalignant or malignant process. If invasion is present, the diagnosis is carcinoma.

Ancillary Testing

Immunohistochemistry and molecular testing can support the diagnosis. Polymerase chain reaction (PCR) can detect papillomavirus DNA in tissue. In human oral squamous cell carcinoma, HPV DNA has been detected in saliva specimens, and a saliva-based liquid biopsy has been proposed as a non-invasive screening tool [13]. HPV DNA PCR has also been used to detect HPV in oral squamous cell carcinoma tissue, with the caveat that prevalence estimates vary widely depending on detection technique, sample size, and population characteristics [14].

In veterinary practice, papillomavirus testing is not routine for a straightforward papilloma. It becomes relevant when the diagnosis is uncertain, when lesions are persistent or recurrent, or when malignant transformation is suspected.

Clinical Relevance, Limitations and Common Mistakes

The clinical relevance of oral squamous papilloma lies in its benign nature and its self-limiting course in many cases. In dogs, oral papillomatosis often resolves without intervention. In humans, excisional biopsy is both diagnostic and curative, with no recurrences observed in a pediatric series followed for a mean of 74.7 days [3].

However, several limitations and common mistakes deserve emphasis.

Mistake 1: Assuming all oral papillomas are benign without biopsy. Most are benign, but a persistent, enlarging, or atypical lesion may be malignant or premalignant. The case of CPV-1-induced papilloma progressing to oral squamous cell carcinoma after 18 months is the cautionary example [4]. A large, symptomatic, or multiple papilloma may warrant closer surveillance because of rare links to malignant transformation [8].

Mistake 2: Confusing papilloma with squamous cell carcinoma on gross examination. Both can be exophytic and verrucous. Endoscopic features can help (uniform lobulation and homogeneous capillaries favor papilloma, irregular morphology and flat components favor carcinoma), but histopathology is definitive [10].

Mistake 3: Overinterpreting koilocytes. Koilocytes support a viral association but are not specific for papilloma. They can appear in reactive and inflammatory lesions. The diagnosis depends on the full histologic picture.

Mistake 4: Ignoring the possibility of a salivary gland origin. Intraductal salivary gland neoplasms can present as papillary oral masses and require different diagnostic and therapeutic considerations [11].

Mistake 5: Treating a self-limiting disease aggressively. In young dogs with classic oral papillomatosis, surgical excision of every lesion is unnecessary and can cause morbidity. Observation is appropriate when the diagnosis is secure and the course is typical.

Mistake 6: Failing to consider host and environmental factors. Chronic irritation, such as from a poorly maintained denture or an impacted tooth, can produce or exacerbate a papillomatous lesion [6][8]. Addressing the underlying irritation is part of management.

Individual cases require veterinary assessment. The information here is a framework for understanding the pathology, not a protocol for managing a specific patient.

Quick Review

Oral squamous papilloma is a benign, exophytic proliferation of stratified squamous epithelium with finger-like fronds over fibrovascular cores.
Koilocytes are the cytopathic hallmark of papillomavirus infection and appear in the spinous layer.
The diagnosis requires absence of dysplasia and absence of invasion.
Papillomavirus types 6 and 11 are the classic low-risk types in humans, and CPV-1 is the best-characterized canine agent.
Oral papillomatosis in dogs is usually self-limiting over weeks to months, especially in young animals.
The main differentials are verruca vulgaris, condyloma acuminatum, verrucous hyperplasia, verrucous carcinoma, and squamous cell carcinoma.
Persistent, enlarging, or atypical lesions require biopsy to rule out malignancy.

Frequently Asked Questions

What causes an oral squamous papilloma?

Most oral squamous papillomas are associated with papillomavirus infection, typically low-risk types such as HPV 6 and 11 in humans and CPV-1 in dogs. Chronic irritation can also contribute, and some lesions test negative for virus.

Is an oral papilloma in a dog contagious to other dogs?

Yes, canine oral papillomatosis is contagious among dogs and spreads by direct contact. It is most common in young dogs and usually resolves on its own as immunity develops.

How long does oral papillomatosis last in dogs?

The classic course is weeks to months. Most young dogs clear the infection and the lesions regress without treatment. Persistent lesions lasting longer than expected should be re-evaluated.

Can an oral papilloma become cancer?

Malignant transformation is rare but documented. A case of CPV-1-induced oral papilloma in a dog progressed to invasive squamous cell carcinoma after 18 months. Persistent or atypical lesions warrant biopsy.

How is an oral squamous papilloma diagnosed?

Diagnosis requires excisional biopsy with histopathology. The pathologist looks for finger-like fronds over fibrovascular cores, koilocytes, orderly epithelial maturation, and absence of dysplasia or invasion.

What is the difference between a papilloma and a squamous cell carcinoma?

A papilloma is benign, exophytic, and non-invasive, with orderly epithelium and no dysplasia. Squamous cell carcinoma is malignant, invasive, and dysplastic, with metastatic potential. Histopathology distinguishes them.