An 86-year-old woman with a history of multifocal OSCC, previously treated with wide excision of lesions from the right buccal mucosa, right border of the tongue, right floor of the mouth and right labial mucosa, along with right lateral cervical lymphadenectomy and right hemiglossectomy, presented with a new lesion on the palate approximately 4 years later. Intraoral examination revealed an ulcerative lesion with an irregular surface on the left hard palate. Incisional biopsy and magnetic resonance imaging (MRI) of the maxillofacial region confirmed OSCC of the left hard palate. Around 18 months later, the patient developed a new erosive-ulcerative lesion on the right hard palate. Histological examination confirmed OSCC. The patient underwent partial right maxillectomy, extending into the soft palate. Histological analysis revealed OSCC involving muscle tissue and affecting the lateral resection margins, with focal involvement of the medial, posterior, and deep margins. The patient is undergoing clinical and radiological follow-up at another hospital.

A 72-year-old woman, denture wearer, presented with a lesion on the left mandibular region. Intraoral examination revealed an ulcerative mass on the edentulous ridge of the IV-V sextant and left buccal mucosa. Incisional biopsy confirmed the diagnosis of OSCC. The patient underwent hemimandibulectomy, left lateral cervical lymphadenectomy, and postoperative radiotherapy. Histological examination revealed OSCC infiltrating the submucosal connective tissue and left mandibular bone. The patient has been on clinical and radiological follow-up. Nearly 34 months later, the patient presented with proliferative, verrucous white lesions on the masticatory mucosa of the IV-V sextant as well as an atrophic-erosive lesion on the left buccal mucosa. Mapping biopsies were performed, revealing proliferative verrucous leukoplakia on the masticatory mucosa and Cis on the left buccal mucosa. Five years later, an incisional biopsy confirmed the diagnosis of OSCC of the left border of the tongue, left hard palate and recurrence of the left buccal mucosa. She underwent full-thickness excision of the lesions at the Plastic Surgery Unit of our hospital and is currently in close follow-up.

A 70-year-old woman, denture wearer, presented with pain and a non-healing ulcer on the right buccal mucosa. Intraoral examination revealed an ulcerated mass with indurated margins in the same region. Contrast-enhanced MRI of the face and neck demonstrated lesion extension to the right alveolar and masticatory mucosa, along with hyperplastic cervical lymph nodes. Incisional biopsy followed by histopathological analysis confirmed an OSCC infiltrating the full thickness of both mucosal and cutaneous layers, with cortical bone involvement. The patient underwent surgical resection of the lesion, mandibulectomy, and bilateral lateral cervical lymphadenectomy. Fourteen months later, she developed a white verrucous lesion on the right hard palate. Histological examination of a biopsy specimen confirmed Cis, and the lesion was surgically excised. At 29 months post-initial diagnosis, the patient re-presented with a new mass on the left buccal mucosa. Incisional biopsy confirmed recurrent OSCC, and MRI revealed an oval-shaped lesion extending to the fifth sextant. The patient is currently undergoing further diagnostic evaluation and therapeutic management at the Plastic Surgery Unit of our institution and in follow-up at our clinic.

A 78-year-old woman, denture wearer, with a history of proliferative verrucous leukoplakia (PVL) presented with pain and burning sensations on the left border of the tongue. Intraoral examination revealed widespread hyperkeratotic white lesions on the tongue, buccal mucosa, a verrucous mass on the left edentulous ridge and left hard palate, as well as leukoplakic and erythroplakic lesions on the left buccal mucosa and upper lip. Multiple incisional biopsies were performed, and histological analysis showed no malignancy or significant changes. The patient was placed on regular follow-up. Six months later, the patient returned with a new leukoplakic-erythroplakic lesion on the left hard palate, and a biopsy confirmed low-grade dysplasia. Over a year after the last biopsy, a granular, irregularly surfaced mass appeared on both the left and right hard palates. Histological examination confirmed the suspicion of OSCC. The patient was referred for wide excision of the lesion at the Plastic Surgery Unit of our hospital.

An 86-year-old woman presented with lesions on the gingiva of both the upper and lower jaws. Intraoral examination revealed a verrucous exophytic mass on the edentulous ridge of the IV-V-VI sextant and a heterogeneous, hyperkeratotic lesion with erosive areas on the masticatory mucosa of the II sextant. The patient underwent incisional biopsies of both lesions, and histological analysis confirmed the diagnosis of OSCC. Subsequently, the patient underwent facial and cervical MRI with contrast, which revealed an oval mass with irregular margins in the gingival mucosa of the alveolar ridge in the fourth, fifth, and sixth sextants, with invasion into the mandibular bone. The patient was referred to the Oncology and Plastic Surgery Units for further diagnostic and therapeutic management. The patient died six months following the diagnosis of OSCC.

A 62-year-old woman, denture wearer, with a history of left border of the tongue OSCC, presented with new oral lesions. Intraoral examination revealed erosive-ulcerative lesions affecting the left gingival fornix, edentulous ridge in sextants IV-V-VI, and the left buccal mucosa. Histopathological analysis confirmed OSCC of the masticatory vestibular mucosa in sextant V, prompting radical excision. Two years later, leukoplakic and erosive-ulcerative lesions recurred at the same sites, necessitating further excision and mandibulectomy. Histopathological evaluation was negative for OSCC. After another 2 years, a nodular lesion on the left border of the tongue was diagnosed as Cis. Surgical excision confirmed OSCC recurrence, leading to hemiglossectomy and adjuvant radiotherapy. Approximately 9 months post-treatment, the patient developed a granulomatous neoformation on the masticatory vestibular mucosa in sextant III, with histopathology confirming OSCC. Five months later, leukoplakic and erythroplakic lesions emerged on the left vestibular mucosa (sextants V-VI) and ventral tongue. Biopsy and subsequent left maxillectomy with cervical lymphadenectomy confirmed OSCC, involving the retromolar trigone. She remains under close clinical and radiological follow up at our hospital.

A 63-year-old woman, denture wearer, with a prior diagnosis of oral lichen planus (OLP), presented with an ulcerative lesion on the left buccal mucosa and an erythematous area on the left palatal pillar. Histopathological analysis confirmed OLP without evidence of dysplasia. One year later, the patient developed new reticular and erosive-ulcerative lesions on the left buccal mucosa. Biopsy revealed Cis. Surgical excision and reconstruction of the left buccal mucosa were performed, with histological analysis confirming moderately differentiated OSCC. Six months later, a verrucous lesion on the edentulous ridge of the III sextant was biopsied and confirmed as OSCC. The lesion was surgically excised in its entirety. Two months later, during a follow-up visit, the patient presented with a new ulcerative lesion on the left hard palate. MRI showed that the lesion also involved the left maxillary sinus. The patient was subsequently referred to the Otolaryngology department of our institution for complete excision of the lesion, which confirmed the new OSCC. The patient is currently under follow-up at our hospital.

An 87-year-old woman, denture wearer, with a prior diagnosis of PVL with high grade dysplasia of the right buccal mucosa presented with painful new intraoral lesions. Intraoral examination revealed verrucous exophytic lesions on the right buccal mucosa and an ulcerative lesion on the floor of the mouth and right ventral tongue. Multiple biopsies confirmed a diagnosis of OSCC of the right buccal mucosa. The patient underwent wide excision of the lesion with ipsilateral neck dissection. Histopathological analysis confirmed OSCC, moderately differentiated. Two years later, the patient developed other verrucous and ulcerative lesions on the right lower labial mucosa, right lingual margin, and left buccal mucosa. Histopathological examination confirmed the presence of new OSCCs in these locations and the lesions were excised entirely at our hospital. Given the patient's history of PVL, prior OSCC, and extensive surgical treatments, she is under clinical and radiological surveillance every two months to monitor for further recurrences or new oral lesions.

Most studies report a significant gender disparity in OSCC incidence, with a male-to-female ratio of approximately 4:1. Nonetheless, the primary risk factors for OSCC remain consistent across genders, with tobacco use and alcohol consumption being the most significant (37–39).

Despite the limited sample size, our series consisted exclusively of women. This disparity may suggest a potential gender influence in the pathogenesis of OSCC, possibly linked to gender-specific genetic mechanisms.

Females may be more susceptible to FC due to the combined effects of estrogen-mediated epithelial proliferation, differential expression of X-linked genes, sex-specific differences in carcinogen metabolism, and heightened immune and inflammatory responses that may result from female-biased regulation of innate and adaptive immunity, all of which contribute to the persistence and clonal expansion of genetically altered epithelial fields (40).

According to Jayam et al. (2010), individuals presenting with multiple oral lesions may exhibit distinct genetic susceptibility, including reduced DNA repair capacity and increased mutation rates. Gender-related differences, particularly in females, may influence the frequency and severity of these alterations through mechanisms such as hormonal factors, gene expression, immune system variability, epigenetic modifications and environmental exposures (41).

While some studies have shown an increase in OSCC among younger women, our findings highlight a different but equally under-recognized subgroup: elderly women without well-known risk habits, presenting with recurrent or multifocal OSCC (9, 42).

Notably, Karuveettil et al. also reported a higher prevalence of OSCC in women compared to men among non-smokers over the age of 50. This difference may be associated with various risk factors, including chronic mucosal irritation, to which women may be more frequently exposed (43).

Regarding oral FC, recent studies, such as the one by Park et al. (2022), have highlighted that most cases occur in females (35).

Another important finding is that three out of eight patients had a prior history of proliferative verrucous leukoplakia (PVL), a condition known to occur more frequently in female patients. Therefore, the results should be interpreted with caution, as the prevalence of OSCC observed in these women may be partly attributable to this underlying clinical condition (36).

In the present study, the mean age of the patients was 75.5 ± 10.3 years. This finding aligns with several studies on OSCC, which report an earlier onset in men and a later diagnosis in women, in patients without exposure to tobacco and/or alcohol. Moreover, of the 8 patients included in this study, 6 were denture wearers (75.0%), and only 1 was a former smoker.

Chronic irritation from poor oral hygiene, compromised dentition, missing teeth, and ill-fitting dentures has been proposed as a contributory factor in OSCC development due to its potential to induce persistent mucosal trauma and inflammation (44, 45).

Evidence suggests that chronic trauma may contribute to OSCC development through two primary mechanisms: direct mechanical damage to DNA, supported by increased activity of DNA repair enzymes in affected tissues, and sustained inflammation. The latter involves the release of cytokines and tumor necrosis factor, which drive oxidative stress, leading to genetic and epigenetic alterations. These changes can impair DNA repair, disrupt cellular signaling, inhibit apoptosis, and promote angiogenesis, thereby facilitating carcinogenesis (46–48).

A review by Singhvi et al. demonstrated that chronic mechanical irritation caused by ill-fitting dental prostheses may be considered a risk factor for the development of OSCC, with lesions most commonly occurring on the lateral border of the tongue. However, no significant association was found between the duration of prosthesis use and OSCC incidence (44).

Our data, although in a limited series, seems to support this hypothesis. Most tumors in our series were located on the lateral and ventral surfaces of the tongue, areas particularly susceptible to mechanical irritation potentially caused by factors such as misaligned teeth, poorly fitting dentures, or other sources of chronic mucosal irritation. Additionally, the buccal mucosa was also significantly affected reinforcing the idea that these regions are prone to chronic irritation (46).

Field cancerization theory offers a compelling explanation for the multifocal nature of OSCC. It suggests that carcinogenic exposure or genetic instability affects large areas of the mucosa, leading to multiple primary tumors. Synchronous lesions are diagnosed concurrently or within six months of the primary tumor, while metachronous lesions arise later (29).

The development of OSCC at distinct sites has been explained by three main theories: the theory of independent lesion onset, which suggests that carcinogen exposure induces genetic alterations across multiple areas of the mucosa; the theory of cellular migration, where malignant cells spread either through micro metastasis or intra-epithelial migration; the theory of lesion clonality, which proposes that multiple lesions arise from a single malignant clone (49–51).

In our cohort, three patients presented with synchronous OSCC, three with metachronous lesions, and two developed both types over time.

Some tumors may originate from the same group of damaged cells, while others may develop independently, but all share exposure to carcinogens. FC of the oral cavity suggests that OSCC may not be an isolated event but rather an anaplastic process affecting multiple cells simultaneously. Over time, these abnormal regions may merge, forming larger atypical areas, even after the primary tumor is surgically excised, explaining the emergence of second tumors and recurrences (28).

The FC concept is especially relevant in OSCC, where widespread genetic or epigenetic alterations in the oral mucosa may lead to uncontrolled cellular proliferation and the emergence of tumors at multiple sites. Two models describe this phenomenon: the polyclonal model, in which mutations occur independently at several sites, and the monoclonal model, where mutated cells migrate and establish new lesions from a common origin (31).

Moreover, phylogenetic analysis in previous studies, such as that by Gabusi et al., has demonstrated that histologically normal mucosa can harbor genetically distinct subclones related to the primary tumor, supporting the concept of a genetically altered but phenotypically normal “second field tumor.” This intra-field heterogeneity, also observed among non-neoplastic mucosal samples, suggests that preneoplastic fields are not genetically uniform a finding with potential implications for prognosis and treatment planning (52).

The present study possesses some limitations, including the small sample size that restricts the generalizability of our findings. Although all patients in our series lacked conventional risk factors and some had signs of chronic mucosal irritation, our retrospective design does not allow causal conclusions but suggests a potential association worthy of investigation in future prospective studies. Furthermore, the advanced mean age (75.5 years) could also play a confounding role, given the higher prevalence of edentulism and use of dentures in older populations. It is important to consider that approximately half of the included patients had a previous history of OPMD, a factor that may influence the risk of developing OSCC. Moreover, a potential bias of our study is the lack of molecular clonal analysis to determine the monoclonality of multiple neoplastic lesions, limiting our ability to clearly distinguish true second primary tumors, arising independently within a genetically altered field, from local recurrences derived from clonal expansion. Previous studies have successfully used mitochondrial DNA sequencing of the D-loop region to assess clonality and clarify the genetic relationships among lesions (53).

The use of molecular biomarkers offers a promising approach for improving early detection and risk stratification of OSCC, especially in patients without traditional risk factors. MicroRNAs, particularly miR-21, are emerging as non-invasive biomarkers due to their stability in bodily fluids and regulatory roles in carcinogenesis. These markers may aid in identifying genetic alterations in the oral mucosa, enabling targeted surveillance and early intervention (54).

While all patients in our series lacked conventional risk factors and presented chronic mucosal trauma, our retrospective design does not allow causal conclusions but suggests a potential association worthy of further investigation in future prospective studies.

Despite these limitations, our findings underscore the critical need for long-term surveillance, especially in women without traditional risk habits, as this enables early detection of synchronous and metachronous tumors and contributes to improved clinical outcomes, prognosis, and quality of life.

In this context, as highlighted by Farahani et al., the use of next-generation sequencing and immune profiling may provide valuable insights into the molecular mechanisms underlying secondary primary tumors in non-smoking and non-drinking OSCC patients (55).

Moreover, the implementation of artificial intelligence-based tools may represent a promising approach for the early detection and longitudinal monitoring of OSCC, particularly in patients without conventional risk factors. Recent studies have demonstrated the use of machine learning algorithms for the automated classification of oral lesions, achieving high sensitivity and specificity in distinguishing malignant from benign lesions through clinical imaging data (56, 57).

Finally, chronic mucosal irritation from dental prostheses should receive greater clinical attention as a potential risk factor for OSCC. This perspective may help shift the clinical focus beyond genetic predisposition and toward modifiable environmental factors that remain underappreciated in current practice.