Squamous cell papilloma within the oral cavity is a localized benign hyperplasia of the oral epithelium that typically presents as a verrucous lesion (1). Microscopically, the outer layer manifests as an infolded epithelium, distinguished by features including acanthosis and hyperkeratosis, while the inner layer comprises a fibrovascular core containing well-developed blood vessels (2). Its etiology is predominantly attributed to human papillomavirus (HPV) infection (3). In addition, squamous cell papilloma can also manifest in the nasal cavity, external auditory canal, pharynx and esophagus (1,4,5). Since symptoms of squamous cell papilloma typically lack specificity, clinical presentation frequently occur during later stages of this condition, causing patients with this disease primarily seeking medical attention due to symptoms arising from obstructive effects.

Although typically benign, squamous cell papilloma have the potential for malignant transformation and recurrence (6). The primary mode of treatment involves surgical intervention, yielding favorable prognoses (7). However, whilst squamous cell papilloma mostly affect the palate, cheek, lip and tongue (8), occurrences within the mandible are seldom reported. The present case, to our knowledge, marks the inaugural documentation of such an instance in the literature, though previous incidences may have existed but were not formally recorded. The imaging characteristics of this squamous papilloma case involving the jaw closely resemble those of malignant jaw tumors. Furthermore, a history of recurrent anti-inflammatory treatment failure may heighten the risk of misdiagnosis and oversight. Consequently, the present report documented a case of squamous cell papilloma involving the mandible at the First Affiliated Hospital of Sun Yat-sen University (Guangzhou, China) in January 2023. The present report aimed to enhance the comprehension of this condition and to provide a reference for healthcare practitioners. The literature review performed in the present study encompassed databases including PubMed (https://pubmed.ncbi.nlm.nih.gov/), Google Scholar (https://scholar.google.com/) and relevant medical journals accessed between 1970 and 2023. The key words ‘squamous cell papilloma’, ‘mandible’, ‘oral cavity’ and ‘human papillomavirus’, ‘inflammatory’, ‘PTHrP’, ‘TGF-β’ and ‘chronic stress’, were used in various combinations. The search was limited to publications available in English and Chinese. Relevant articles, case reports and systematic reviews detailing the clinical characteristics, diagnosis and management of squamous cell papilloma within the jaw region were included for analysis.

In the oral cavity, squamous cell papilloma typically manifests as a papillary protrusion on the oral mucosal surface. The precise etiology of papilloma remains elusive, although it exhibits associations with various predisposing factors, including tobacco consumption, alcohol misuse, chronic oral inflammatory conditions (such as gingivitis), inappropriate alveolar bone stimulation, HPV infection and genetic susceptibility (9,10). In the oral cavity, squamous cell papilloma is commonly found in the palate, cheek, lip and tongue, where it is more commonly found in men (1). Although the most common sites of this benign tumor have been proposed to be the soft palate, lip and gingiva (1,11), the tongue was suggested to be the most common site (8,10). However, squamous cell papilloma has also been documented to occur in the trachea, nasal cavity, sinuses, external auditory canal, esophagus and throat (12-14). The majority of cases are characterized by the absence of a clear unified set of symptoms, with clinical manifestations typically arising from secondary symptoms caused by physical obstruction. These may include nasal congestion, stridor, hearing loss, discomfort or difficulty swallowing and breathing disturbances such as disruptive dyspnea (1-3).

Compared with other locations, squamous cell papilloma of the jaw is an exceedingly rare occurrence. This benign neoplasm typically originates from the stratified squamous epithelial lining of the oral mucosa (15). However, the presence of residual epithelial elements within the jaw is limited, consisting of remnants of the dental lamina epithelium, epithelial rests of Malassez and reduced enamel epithelium (16). These epithelial tissues may be the origin of some common epithelial tumors in the jaw. Furthermore, squamous cell papilloma is predominantly encountered within systemic lacunar ducts, such as those found in the esophagus, respiratory tract, external auditory canal, cervix and breast ducts. It is imperative to recognize that the trabecular bone within the jaw constitutes an extension of the cortical bone encasing the cancellous bone, which forms a complex irregular three-dimensional network unlike the characteristic lacunar duct architecture found in the aforementioned organs (17). The origin of the epithelial lesion in this case could potentially stem from the gingival epithelium or the epithelium of the jaw.

The extended period of inflammation within the patient's jawbone likely mediated a pivotal role in precipitating the tumor-like metamorphosis. This may be attributed to four underlying factors. Inflammatory induction of aberrant cell growth is one such factor. The prolonged inflammation triggering aberrant cell proliferation within the jawbone observed in the present case aligns with previous studies that also emphasized the role of inflammation in cancer development. Trinchieri (18) previously underscored the induction of inflammation promoting cancer long before tumor formation. Specifically, they observed that before tumor formation, inflammation may have a role by affecting the genetic stability of tissues, epigenetic modifications and immune responses. Various inflammatory diseases, such as inflammatory bowel diseases, chronic hepatitis, Helicobacter-induced gastritis or schistostoma-induced bladder inflammation, can all heighten the susceptibility to malignant transformation (18). Prolonged inflammation can trigger the activation of local immune cells, leading to the release of proinflammatory cytokines, such as IL-1, TNF and IL-6, along with various growth factors. Among these factors are reactive oxygen species, reactive nitrogen species and interferon-γ (19,20). These cytokines in turn stimulate cell proliferation in the neighboring tissues, including the epithelial cells residing within the jawbone. This dysregulated cellular growth may cause the inception of papilloma formation (19,20). Close inter-cellular interplay may serve as another one of the four factors. Previous studies on tumor-induced bone diseases found a close interaction between tumor cells and bone cells, termed the ‘vicious cycle’ (21,22). This concept posits that tumor cells secrete a number of factors, such as parathyroid hormone-related protein (PTHrP), provoking osteoblasts into producing receptor activator of nuclear factor κB ligand (RANKL), thereby promoting osteoclast formation and bone destruction. Consequently, this form of bone destruction leads to the release of growth factors, such as insulin-like growth factor II and transforming growth factor β3 (TGF-β3) (23), embedded in the bone matrix, further stimulating tumor growth and aggravating bone destruction. Therefore, it may be hypothesized that PTHrP secretion by the tumor cells in the papilloma may have induced RANKL production in the osteoblasts, in turn promoting osteoclast formation and bone degradation. Subsequent bone destruction by the osteoclasts may then lead to the release of intraosseous growth factors that continue to stimulate papilloma growth (24,25). In terms of soluble factors in the tumor microenvironment, cytokines and the surrounding matrix may also have served a role in the present case. Specifically, the persistent inflammation experienced by the present patient may have induced alterations in the jawbone matrix. Such alterations may encompass changes in bone matrix hardness and the cytokine profile, such as interleukin (IL) and tumor necrosis factor (TNF)-α. During the inflamed state, the dysregulated activity of TGF-β signaling may reverse the inhibition of cell proliferation (26,27). This reversal in turn can lift the inhibitory restrictions tumor cells, contributing to their aberrant growth. Furthermore, TGF-β may enhance the migratory and invasive capabilities of tumor cells (28,29), enabling them to infiltrate neighboring tissues, blood vessels or lymphatic vessels. Simultaneously, TGF-β may also dampen the immune system's ability to identify and eliminate tumors (27,29). It was also noteworthy that chronic stress and the sympathetic nervous system may have involvements in the tumor in the present cases, where the persistent inflammation may have activated the sympathetic nervous system. This conjecture is consistent with the previous findings on the role of adrenergic receptor signaling in the bone. Pierroz et al (30) previously explored the effects of β-adrenergic receptor deletion on bone phenotypes and response to mechanical stimulation in mice. It was demonstrated that mice deficient in β2-adrenergic receptors exhibited greater trabecular bone microarchitecture, with lower degrees of bone resorption and increased levels of bone formation as they aged. These alterations could include increased trabecular thickness, higher trabecular number, reduced trabecular spacing, and enhanced trabecular connectivity. Furthermore, Liang et al (31) elucidated the impact of β2-adrenergic receptor (β2-AR) signaling on osteocytes and its effect on osteoclast formation. Activation of β2-AR led to increased RANKL expression, promoting osteoclastogenesis, while also altering the balance between RANKL and OPG. Furthermore, neuropeptides crucial for bone regulation were inhibited by β2-AR stimulation. These findings highlight the significant role of β2-AR signaling in bone metabolism. Therefore, sustained inflammation can potentially trigger the release of catecholamines to exacerbate jawbone destruction (32). The patient's history of smoking may have further exacerbated the inflammatory environment, since smoking can impair the immune functions of neutrophils and increase the release of inflammatory factors in the body, such as TNF-α and IL-6 (33,34).

In the present case, the pathological immunohistochemistry results indicated HPV negativity but the presence of mottled p16 positivity. While HPV infection was not detected, p16 is commonly employed as a surrogate marker for HPV in pathology. However, elevated p16 expression does not definitively indicate the presence of HPV infection. It is worth noting that it may yield false-negative HPV results, possibly due to undetected specific HPV subtypes, low viral loads associated with infection, inadequate tissue sampling or the localized nature of HPV infection. Given these considerations, quantitative HPV DNA testing emerges as a potentially more crucial diagnostic tool. Despite the absence of detectable HPV infection through IHC examination, it remains pertinent to explore the potential involvement of HPV infection in this context. Squamous cell papilloma may be associated with HPV infection, particularly HPV subtypes 2, 4, 6, 11, 13 and 32. HPV subtypes 6 and 11 are commonly associated with benign papillomatous lesions, including squamous cell papilloma (35,36). However, in certain sites, such as the throat, squamous cell papilloma associated with various high-risk HPV subtypes, such as HPV16 and HPV18, may also pose an increased risk of cancer development (9,37). The expression of p16 is frequently utilized as a surrogate indicator for high-risk HPV types. This association arises from the correlation between HPV infection and an elevated probability of p16-positive disease advancing to malignancy. Of note, in certain instances of squamous cell papilloma, the presence of p16 positivity despite HPV negativity may imply alternative pathways or factors contributing to tumor progression. During tumorigenesis, HPV E6 and E7 proteins target the p53 and retinoblastoma proteins for degradation, respectively. This inactivates the two most important tumor suppressor genes in the cell, resulting in the aberrant overexpression of cyclin p16 (33,38,39). In addition, susceptibility of cells to HPV infection can depend on the cell type and the local microenvironment. Certain cell types and microenvironments are more conducive to HPV infection and transformation. Single-layered tonsillar crypts are particularly susceptible to cellular transformation in the head and neck region. In the head and neck region, the epithelium lining the single-layered tonsillar crypts is particularly susceptible to cellular transformation, particularly following infection with HPV. Long-term inflammation can lead to changes in epithelial continuity, creating opportunities for pathogens such as HPV to attach and infect cells, thereby promoting the formation of papilloma (40,41).

The therapeutic approaches for oral squamous papilloma typically encompass surgical excision, particularly in cases of substantial size or suspected malignancy. Radiation therapy and chemotherapy may occasionally be applied in cases of malignant transformation (22). Although early diagnosis and intervention hold paramount importance, the papilloma detected in the jaw of the patient in the present case exhibited striking imaging similarities to malignant jaw tumors, as observed in mandibular CT scans. This resemblance may be associated with the patient's prolonged pericoronal inflammation resulting from the impacted wisdom teeth. The repetitive inflammatory episodes resulted in multifocal bone destruction, as indicated by areas of decreased density observed on imaging. Concurrently, the local lamellar periosteal reactions were indicative of the reparative response by the bone triggered by inflammation. Benign neoplasms typically manifest as clearly demarcated masses; contrastingly, malignant tumors exhibit a more aggressive growth pattern, often coupled with local tissue destruction (42-44). The chronic inflammatory environment appears to have promoted the development of poorly circumscribed soft tissue masses, further complicating the differentiation between benign and malignant tumors. This observation highlights the essential requirement for the thorough evaluation of imaging results in patients with persistent inflammation. In addition, comprehensive pathological and clinical assessments are necessary to ascertain the true nature of the tumor.

In conclusion, the present case report documented the rare occurrence of squamous papilloma in the jawbone, highlighting the diagnostic challenges posed by their atypical clinical presentation. Furthermore, the scarcity of robust clinical data on squamous cell papilloma involving the jawbone presents a significant hindrance in establishing a standardized diagnostic and therapeutic protocol for such cases. The present report several key factors that can contribute to the formation of squamous papilloma within the jaw. Specifically, the prolonged inflammation triggering tumor transformation, inflammation-induced aberrant cell growth, inter-cellular interplay, cytokine and matrix effects and chronic stress-mediated sympathetic nervous system activation, are such potential key factors that offer avenues for further exploration. In addition, the association between HPV and head and neck papilloma was outlined, suggesting that sustained inflammation may heighten papilloma incidence by compromising epithelial tissue integrity, fostering an environment conducive to HPV infection. While HPV infection was not detected, p16 is commonly employed as a surrogate marker for HPV in pathology. However, elevated p16 expression does not definitively indicate the presence of HPV infection. In fact, it may yield false-negative HPV results, possibly due to undetected specific HPV subtypes, low viral loads associated with infection, inadequate tissue sampling, or the localized nature of HPV infection. In light of the limitations and knowledge gaps identified, future endeavors should focus on elucidating the intricate molecular mechanisms underlying the development of squamous papilloma. Prospective multicenter clinical trials are indispensable for bridging the currently available clinical data to deepen the understanding into the pathophysiology of this papilloma and to facilitate the development of effective diagnostic and therapeutic modalities.