Introduction

Squamous cell carcinoma (SCC) is the most common malignant neoplasm of the oral cavity ¹. Factors such as tobacco use and alcohol consumption are associated with the pathogenesis of SCC in this location ², and it is more frequently observed in men around 60 years of age ³. However, in recent years, there has been a rise in cases of oral squamous cell carcinoma (OSCC) in young adults under the age of 40 ^(4,5. In this group, risk factors such as tobacco use, alcohol consumption ^2,4, and high-risk human papillomavirus (HPV) are not associated. Although HPV plays a role in oropharyngeal SCC, it has not yet been linked to cases of OSCC in this age group, whose pathogenesis remains unclear ^(6,7.

OSCC may be preceded by oral potentially malignant disorders (OPMDs), such as oral leukoplakia (OL) and oral erythroplakia (OE) ⁸. Malignant transformation rates of up to 34% have been reported in OL and up to 50% in OE ^(8-10. Notably, proliferative verrucous leukoplakia (PVL), a non-homogeneous variant of OL, also shows high transformation rates ^11,12. Although numerous studies have focused on the chemopreventive treatment of OL ¹³, surgical excision is currently considered the gold standard ⁽¹². Like OSCC, OPMDs have also been observed in young patients. A literature review reported that out of 1,246 patients with PMODs, 115 (9.2%) were under 40 years of age, had no associated risk factors, and some progressed to SCC ¹⁴. The etiology of OSCC and OL in this population remains unknown ^(14). Therefore, early detection and accurate diagnosis of OPMDs are essential to prevent OSCC.

This report presents a case of microinvasive OSCC preceded by an undiagnosed OPMD in a young patient without associated risk factors. The objective is to illustrate the clinical and histopathological presentation of this rare case and to discuss future directions for research on similar cases.

Case report

Informed consent was obtained from the patient for the publication of this case report, and she authorized its dissemination. This case report complies with the recommendations and guidelines of the Declaration of Helsinki.

A 39-year-old female patient, allergic to metals and a vegetarian supplemented with vitamin B12, denied both smoking and alcohol consumption. She presented to the Oral Medicine Clinic at the University of Chile with a complaint of a lesion on the left lateral border of the tongue, with an 8-year evolution. She described periods of exacerbation and remission accompanied by burning sensations and reported having previously been diagnosed and treated by another professional for recurrent aphthous stomatitis, without achieving clinical resolution.

Extraoral physical examination revealed no abnormalities. Intraoral examination showed a red plaque with ulcerated areas located on the left lateral border of the tongue. The lesion was oval-shaped, with diffuse margins, reddish coloration, and measured 3 cm at its greatest diameter (Figure 1). An incisional biopsy was performed under the clinical suspicion of OE and was sent to the Pathology Department of the Faculty of Dentistry (SAP-FO).

Histological sections revealed severe epithelial dysplasia, characterized by cellular and nuclear pleomorphism, hyperchromatism, mitotic figures, and dyskeratosis. There was also apparent discontinuity of the basement membrane and detachment of epithelial cells, which occasionally invaded the adjacent connective tissue (Figure 2).

Immunohistochemical staining with pancytokeratin confirmed microinvasion; however, there was no evidence of infiltration into muscle tissue, blood vessels, or nerve tissue (Figure 3, A and B). The final diagnosis was microinvasive OSCC.

The patient was referred to the Head and Neck Surgery Department of a regional referral hospital, where she underwent surgical treatment, including a partial glossectomy and excisional biopsy of the cervical sentinel lymph node, also on the left side. Histopathological analysis of the surgical specimen confirmed the diagnosis from the incisional biopsy and showed that the margins were free of dysplastic and/or neoplastic tissue. The sentinel lymph node showed no evidence of neoplastic involvement.

The patient has been under clinical follow-up through routine consultations for two years following treatment, with no signs of lesion recurrence (Figure 4).

Discussion

PMODs of the oral cavity present with a variety of clinical manifestations. OL is described as a white plaque with uncertain malignant potential, and its diagnosis can only be confirmed after ruling out other specific conditions ^9,10,14,15. OE, another PMOD, is similarly defined as a bright red plaque that cannot be clinically or pathologically characterized as another disease ¹⁵.

Clinically, OE appears as a red plaque that may have a granular surface, while histopathologically it may exhibit epithelial dysplasia or even frankly invasive SCC ⁽¹⁶. In this case, the symptoms, clinical features, and histopathological findings suggest that although the final diagnosis was microinvasive SCC, it was preceded by a misdiagnosed OE. Thus, errors or omissions in clinical diagnosis and professional management can enable the development of malignant neoplasms at the site ⁽¹⁷, negatively affecting the patient’s prognosis.

A systematic review of the literature aimed to characterize OL and OE in young patients ⁽¹⁴. It analyzed case series of patients diagnosed with OL and OE, identifying 115 individuals under the age of 40 with OPMDs, all of them presenting with OL. This finding highlights that OE is a OPMD rarely reported in young adults. However, this case demonstrates that individuals in this age group can develop OE and, subsequently, OSCC. Therefore, OE should be included in the clinical differential diagnosis regardless of age and confirmed by incisional biopsy when suspected.

A shift in the epidemiology of OSCC has been observed. While the number of new cases in patients over 40 years of age has declined in recent years, there has been a 106% increase in OSCC diagnoses among young adults under 40 ⁽¹⁸, as exemplified by this case. In this age group, risk factors such as tobacco use, alcohol consumption ⁽², and HPV infection ⁶⁾ do not appear to play a significant role. However, genetic alterations are suspected to be associated with the rising incidence of OSCC in this population ^(19,20, which frequently presents at advanced clinical stages at the time of diagnosis, suggesting greater biological aggressiveness ²¹. Although this report describes a case of microinvasive OSCC, it is understood that it was preceded by OE, which remained misdiagnosed for eight years.

For this specific case, p16 immunohistochemical analysis was not performed. Based on the patient’s medical history, along with clinical, histological, and immunohistochemical findings, it was concluded that the SCC originated from a prior OE, thereby ruling out a possible association with HPV. Identifying potential factors linked to the development of certain SCC cases remains a challenge. One study reported that germline alterations in DNA repair genes are associated with an increased risk of developing head and neck cancer at an early age, specifically in patients under 49 years old ²². Similar findings emerged from our recent systematic review of the literature on germline genetic variations in patients with SCC ²³. These insights could guide future research and help clarify the occurrence of SCC and OPMDs in young adults without identifiable risk factors, as illustrated by this case.

Microinvasive SCC is described as an early stage of squamous cell carcinoma ²⁴. A literature review noted that it is commonly located on the tongue and may present clinically as spots, plaques, or ulcers ⁽²⁵. In line with this, microinvasive OSCC may manifest as OL or OE, as observed in this case, highlighting the importance of incisional biopsy for accurate diagnosis.

Histopathologically, microinvasive SCC is defined as being confined to the superficial stroma or lamina propria ²⁶. In this case, basement membrane discontinuity was observed, along with the detachment of epithelial cells that remained superficial within the connective tissue. However, the presence of inflammatory infiltrate at the site can hinder visualization of the basement membrane’s integrity or obscure microinvasion, potentially leading to diagnostic uncertainty ⁽²⁷. In such scenarios, immunohistochemical staining with epithelial markers, such as pancytokeratin, can assist in detecting microinvasion, as demonstrated here.

Studies and case reports on microinvasive SCC are scarce, and no standardized epidemiological, clinical, histopathological, treatment, or follow-up parameters have been established ²⁵. However, a multicenter study by Ferreira and Costa et al. ²⁸ on SCC in patients under 40 years of age reported multiple cases exhibiting microinvasion into connective tissue. It remains unclear whether this pattern is specific to this age group or reflects earlier diagnoses in younger individuals. Nevertheless, surgical excision has been the treatment of choice in such cases ⁽²⁵, as was done in the case presented here.

Conclusion

Delay in the diagnosis of OPMDs may compromise lesion progression and negatively affect the patient’s prognosis when SCC develops-whose incidence has risen in young adults without associated risk factors. Microinvasive SCC presents both clinical and histopathological challenges due to its potential for very superficial invasion or the possibility of being obscured by inflammation. Therefore, we suggest that immunohistochemical staining with pancytokeratin may serve as a valuable tool in the histopathological diagnosis, enabling confirmation of invasion or its absence in the connective tissue.

In addition, we underscore the importance of further studies on SCC and OPMDs in young adults to identify currently unknown contributing factors, including genetic investigations in this population. This emerging area of research could improve the diagnosis, prognosis, and treatment of cases like the one reported here.