Squamous Papilloma on the Hard Palate: A Rare Clinical Entity

Squamous papilloma is a benign, exophytic, soft tissue tumour caused by the rapid proliferation of stratified squamous epithelium. It typically manifests in the oral cavity as a painless, soft, non-tender, pedunculated growth that resembles a cauliflower. This case report of squamous papilloma on the hard palate sheds light on the etiopathogenesis, types, clinical features, differential diagnosis, and management modalities.


Introduction
Squamous papilloma is a benign soft tissue tumour caused by the proliferation of the stratified squamous epithelium, resulting in papillary or verruciform mass. Squamous papilloma is usually asymptomatic and often diagnosed between 10 and 50 years of age incidentally. Although literature reviews stated its common occurrence on the soft palate, uvula, and tongue [1]. Papilloma is a benign soft tissue tumour derived from epithelium on a vascular connective tissue resembling a nipple-like protuberance of a mammary gland. Papilloma is derived from a modern Latin hybrid word "papilla", meaning "nipple", the English word "papula", meaning swelling or pimple, and the Greek word "oma", meaning "tumour". Papilloma is a non-enveloped double-stranded DNA virus. This case reports the occurrence of squamous papilloma on the hard palate. Squamous papilloma clinically appears as a sessile, pedunculated mass, which is usually asymptomatic, cauliflower-like surface, appearing either the same or reddish in colour as the adjacent mucosa, and is non-tender on palpation. The various types of papillomas include fungiform papillomas (Ringertz tumour), inverted Schneiderian papillomas, cylindrical cell papillomas, multifocal papillomas, and juvenile-onset laryngeal papillomas. Papillomas are classified based on the site of anatomical location. Squamous papilloma and oral florid papillomatosis occur in the oral mucous membrane, urothelial papillomas occur in the transitional epithelium lining the urinary bladder, intraductal papillomas are those that occur in the breast, oesophageal papillomas are those that occur in the oesophagus, papillomas that occur in bronchus are called bronchial papillomas, and papillomas that occur in the choroid plexus of the brain are called choroidal papillomas. Conjunctival papillomas are those that occur in the eye near the lacrimal punctum caused by human papillomavirus (HPV) 6, 11, 16, 33, 34, and 35. Cutaneous papillomas are those that occur on the skin. Anogenital papillomas (venereal warts) are caused by HPV 2, 3, 6, 11, 16, 18, 30, 31, and 32.
Fungiform papillomas are broad-based masses that can be pink or tan in colour and include papillary or warty surface projections and usually develop close to the nasal septum and consist of unilateral obstruction and epistaxis. HPV 6, 11, 16, and 18 and the Epstein-Barr virus are the two viruses that produce papillomas that are clinically seen as pink or tan, with polypoid nodular growth that primarily emerges from the lateral nasal cavity wall or a paranasal sinus, generally the antrum.
Cylindrical cell papillomas in the nasal cavity or maxillary antrum typically present as a beefy-reddish brown mass with a multinodular surface. Clinically, several scattered soft, non-tender, flattened, or rounded papules generally are clustered and have the same colour as normal mucosa, known as multifocal papillomas caused by HPV 13 and 32. In addition, juvenile-onset HPV 6 and 11 induce laryngeal papillomatosis, which develops in the larynx during childhood and causes sudden hoarseness in children.
Risk factors for HPV include sexual transmission from infected partners, immunosuppressive states like HIV, illicit drug abuse, previous history of genital chlamydial infection, gonorrhoea, genital herpes, or trichomoniasis, and co-infection with other sexually transmitted diseases, such as Chlamydia trachomatis and herpes simplex virus type 2.

Case Presentation
A 27-year-old female reported a chief complaint of growth on the hard palate for the past six months. On eliciting the history, she stated that it started as a small growth around nine months back and gradually increased in size and attained the present size of 1.5 × 2 cm (Figure 1).

FIGURE 1: A pedunculated cauliflower-like growth on the left lateral portion of the hard palate 1 mm away from the mid-palatal raphe
On inspection, a growth measuring about 1.5 x 2 cm was present on the left lateral portion of the hard palate. The growth extended anteriorly 5 cm away from the incisive papilla, medially 0.5 cm away from the mid-palatal raphe, and posteriorly 2 cm away from the fovea palatinae. It was cauliflower-like in shape and the surface appeared more reddish near the superior aspect of the growth. All the findings regarding the site, size, shape, surface, and extent were confirmed on palpation. The growth was firm in consistency and nontender on palpation. There was no history of rapid growth, paresthesia, or numbness associated with the growth ruling out the possibility of malignancy. A thorough clinical examination revealed an absence of similar growth elsewhere in her body. Family history was not significant. Her medical history revealed seropositivity for HPV subtype 6. There was no harmful habit of smoking or tobacco chewing, alcohol, and intravenous drug abuse. A provisional diagnosis of papilloma was made based on the clinical findings of the presence of an exophytic, sessile, cauliflower-like growth. An excision biopsy of the growth was done under local anaesthesia ( Figure 2).

FIGURE 3: Histopathological examination
Hematoxylin and eosin stain (40x) revealed hyperplastic squamous epithelial cells and koilocytosis (squamous epithelial cells with coarse thick chromatin arranged in a perinuclear pattern).

Discussion
Papilloma is defined as "a benign tumour of the hyperplastic squamous epithelium occurring clinically as an exophytic, painless, asymptomatic, soft tissue mass with a cauliflower-like surface" caused by the HPV [2]. Papilloma is a non-enveloped, double-stranded DNA virus. More than 200 subtypes of papilloma have been identified. HPV 16 and HPV 18 subtypes have a high propensity for cervical cancer. The p53 protein is induced to degrade by the E6 oncoprotein that is encoded by HPV types 16 and 18. Papilloma can occur anywhere in the body and is named according to the site of location in the human body. The various types of papillomas and their site of location are described in Table 1.   Based on the potential for risk of infections, HPV is classified as high-risk and low-risk HPV ( Table 3).

Entry of HPV Into Susceptible Host
Epithelial cells are primarily infected by papillomavirus because of the epithelial tropism. The incoming virion of papillomavirus interacts with extracellular heparin sulphate proteoglycans on the basement membrane of the oral squamous epithelium following a micro-abrasion.

Nucleocapsid Uncoating and Disassembly
The L1 and L2 capsid proteins of papillomavirus undergo conformational modifications as a result of this contact, enabling the virion to be delivered into the host cell following which L2 cleavage takes place by furin, and the virion is internalised through a process related to micropinocytosis. The viral DNA is thought to remain linked to L2 during this process. Until the start of mitosis, the L2-DNA complex engages to the trans-Golgi network and stays there. The trans-Golgi network naturally vesiculates during mitosis, and the vesicle-bound viral DNA enters the nucleus. By metaphase, the viral DNA has entered the chromosomes of the host. The viral DNA can be detected linked to nuclear ND10 bodies after mitosis. The capsid proteins L1 and L2 are encoded in the late region. Between the L1 and E6 open reading frames (ORFs), the upstream regulatory region (URR) or locus control region (LCR) houses the viral replication origin as well as binding sites for cellular and viral transcription factors. There are three main phases of replication in the viral replication cycle.

Amplification
The viral E1 and E2 replication proteins support initial, confined viral DNA amplification. The viral E1 helicase is recruited when the viral E2 protein binds to its binding sites in the viral origin of replication, enabling viral replication. The viral genome is kept at a relatively low but constant copy number in the proliferating cells of a clonally enlarged population of infected cells during maintenance replication, which follows this first burst of replication.

Transmission of HPV
The transmission of HPV occurs vertically from mother to child through amniotic fluid during birth through vaginal delivery. Transmission among adults can occur through infected partners with underlying HIV. The HPV exhibits epithelial tropism and has a high affinity for tonsillar crypts and squamous epithelial lining of the oral mucous membrane. The HPV can be shed in saliva due to shedding by desquamation of squamous epithelial cells. Transmission of HPV also occurs by autoinoculation to the oral cavity by saliva. The HPV has a longer incubation period that varies from three to 10 months.
This case report presents a unique case of squamous papilloma on the hard palate. The differential diagnoses include verruca vulgaris (common warts), verruciform xanthoma, inflammatory papillary hyperplasia of the palate, Cowden syndrome (cardiofaciocutaneous syndrome), Gorlin-Goltz syndrome, and WHIM syndrome. The various differential diagnoses for papillomas are presented in Table 4.  Laryngeal papillomas occurring in the larynx can obstruct airways. Inflammatory palatal papillomatosis also occurs on the tissue-bearing surface of the hard palate among constant complete denture wearers who do not maintain or remove the dentures, even during sleeping at night. Verruca vulgaris, also called common warts, is seen among children. Verruca vulgaris occurs as pedunculated soft tissue mass with verruciform white finger-like projections on the plantar surfaces of the fingers and is commonly transmitted as a result of autoinoculation of HPV 2 and 4 by contact with saliva. Condyloma acuminatum (condyloma is a Greek word meaning round and acuminatum is a Latin word meaning to become pointed) is characterised by whitish or pinkish nodules on the hard palate, tongue, and floor of the mouth and appears as fleshy papules more commonly located in the anogenital region [5]. The various literature reviews on squamous papilloma are described in Table 5.

Year Clinical description
Ramanathan et al. [1] 2021 Squamous papilloma on the hard palate is a clinical rarity Jaya et al. [2] 2020 Squamous papilloma is characterised by painless growth Stojanov [3] 2020 Excisional biopsy of squamous papilloma is curative. Has rare recurrences Chaitanya et al. [4] 2018 The common sites of occurrence of oral papillomas include the tongue, soft palate, and uvula Babaji et al. [6] 2014 Papillomas appear like cauliflower-like painless soft tissue mass Al-Khateeb [7] 2009 22 cases (5%) among 883 benign soft-tissue masses are seen among the female population in the northern Jordanian population Cipriani et al. observed the development of HPV-related squamous cell carcinoma in two siblings with WHIM syndrome, caused by a change in the 7-transmembrane protein chemokine receptor CXCR4, which is found in a number of stem cells and progenitor cells but whose function is not fully understood. Warts, hypogammaglobulinemia, infections, and retention of mature neutrophils in the bone marrow (myelokathexis) are all symptoms of the uncommon autosomal dominant condition known as WHIM. It has also been linked to an increased risk of HPV infections [8]. Buschke-Lowenstein tumours are giant-sized condyloma acuminatum caused by HPV 16 and 18 subtypes and can have a psychological effect of anxiety and fear [9]. The various surgical treatment modalities for papilloma are presented in Table 6. The various medical management options for papilloma are presented in Table 7.

Prevention of HPV infections
The HPV vaccine, which is suggested between the ages of 9 and 24, helps to prevent papillomavirus infections. HPV vaccine administration does not completely confer protection against or prevent HPV infections (

Conclusions
Squamous papilloma is a benign soft tissue cauliflower-like growth caused by the hyperplastic proliferation of squamous epithelium induced by HPV 6 and 11. Papillomas are incidentally observed during a clinical examination. Squamous papillomas can appear clinically as sessile, exophytic growth on the hard palate. Treatment of such squamous papillomas must not be neglected. A detailed history and clinical examination are necessary, and the patient must be educated about the excision of such lesions. The recurrence rate of such papilloma is rare, except in immunocompromised patients with acquired immunodeficiency syndrome (AIDS).

Additional Information Disclosures
Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.