Ⅰ. INTRODUCTION
Oral squamous cell carcinoma (OSCC) frequently arises from oral potentially malignant disorders (OPMDs), a group of lesions and conditions associated with an increased risk of malignant transformation1-3. Assessment of the risk of malignant transformation largely depends on the presence and severity of oral epithelial dysplasia (OED)4,5. The World Health Organization (WHO) classifies OED into mild, moderate, and severe grades, with increasing grades generally associated with a higher risk of malignant transformation4-6. However, the current grading system is limited by substantial interobserver variability among pathologists5,7. Furthermore, malignant transformation may occur even in lower-grade dysplastic lesions owing to microenvironmental alterations and the accumulation of genetic changes, making reliance on a single biopsy potentially misleading8-10. Therefore, OED should be regarded as a dynamic disease process requiring careful long-term clinical surveillance and repeated biopsies when clinically indicated11,12. Herein, we present a case of OED that progressed to OSCC during long-term follow-up and analyze the clinical and histopathological changes associated with this progression, emphasizing the importance of early detection and timely surgical intervention.
Ⅱ. Case report
A 55-year-old woman presented to Kyungpook National University Dental Hospital (KNUDH) complaining of an ulcerative lesion on the right lateral tongue and pain aggravated by hot and spicy foods. She was a non-smoker and non-drinker with no significant medical history except for dyslipidemia.
Radiographic examination revealed a dental implant-supported prosthesis without any other significant abnormalities (Fig. 1A). Clinical examination demonstrated an erythematous ulcerative lesion on the right lateral tongue (Fig. 1B). Incisional biopsy of the lesion revealed moderate epithelial dysplasia (Fig. 1C). The lesion was subsequently excised surgically (Fig. 1D, E), and histopathological examination confirmed moderate epithelial dysplasia with clear surgical margins (Fig. 1F). Hematoxylin and eosin (H&E) staining revealed proliferation of atypical basaloid cells arising from the basal layer and extending into approximately one-half of the epithelial thickness. The dysplastic epithelial cells exhibited nuclear enlargement, hyperchromasia, mild to moderate pleomorphism, and partial loss of cellular polarity. Dense chronic inflammatory cell infiltration was observed in the underlying connective tissue. These histopathological findings were consistent with moderate epithelial dysplasia (Fig. 1F).
The patient underwent regular follow-up examinations at intervals of 1- to 3-months (Fig. 2A). During the first year after surgical excision, she remained asymptomatic, and no clinically significant findings were observed (Fig. 2B). Approximately 13 months postoperatively, an erythroplakic lesion developed on the anterior portion of the right lateral tongue (Fig. 2C). Following treatment with amoxicillin and prednisone gargle, the lesion showed clinical improvement, and the patient was subsequently monitored through regular follow-up examinations.
However, approximately 18 months after surgery, a painful erythematous lesion recurred on the right lateral tongue (Fig. 2D). Despite treatment with intralesional triamcinolone injection and continued follow-up, the lesion gradually increased in size and exhibited changes in surface texture (Fig. 2E). Given these progressive clinical changes, an incisional biopsy was performed. Histopathological examination confirmed well-differentiated squamous cell carcinoma (Fig. 2F).
Hematoxylin and eosin (H&E) staining revealed invasive nests and islands of atypical squamous epithelial cells of varying sizes and shapes infiltrating into the underlying connective tissue. Multiple keratin pearls, characterized by concentrically laminated eosinophilic structures, were observed within the invading epithelial nests, consistent with a diagnosis of well-differentiated squamous cell carcinoma.
Subsequent 18F-FDG PET/CT demonstrated small hypermetabolic lymph nodes on both sides of the neck. However, no evidence of cervical lymph node metastasis was identified on contrast-enhanced neck computed tomography (CT) or neck ultrasonography. Therefore, wide local excision was performed (Fig. 2G). Histopathological examination of the resected specimen revealed severe epithelial dysplasia without residual invasive carcinoma (Fig. 2H). Postoperative healing was uneventful, and the patient remains under regular follow-up without evidence of recurrence.
Ⅲ. Discussion
The malignant transformation (MT) of oral potentially malignant disorders (OPMDs) is a multifactorial and clinically unpredictable process1-3. Although severe epithelial dysplasia is generally regarded as a strong predictor of progression to oral squamous cell carcinoma (OSCC)13,14, this case highlights that malignant transformation may also occur in lesions initially diagnosed as moderate oral epithelial dysplasia (OED)8-10. Recent large-scale cohort studies and meta-analyses have demonstrated that even lower-grade dysplastic lesions and various OPMD subtypes may possess substantial malignant potential, with some reports indicating malignant transformation rates approximately 10% for low-grade dysplasia and exceeding 30% for high-grade dysplasia9,15,16,25,27.
The current World Health Organization (WHO) grading system for OED is primarily based on architectural and cytological alterations; however, its application is often limited by interobserver variability4,5,7. To improve diagnostic reproducibility and clinical applicability, a binary grading system categorizing lesions as low-grade or high-grade dysplasia has recently been proposed6,24. Nevertheless, no histopathological grading system can fully account for the biological heterogeneity underlying malignant transformation. In the present case, the initial biopsy revealed moderate dysplasia; however, the lesion subsequently progressed to definitive OSCC. This finding supports previous reports suggesting that histological grade alone may not reliably predict clinical behavior, as microenvironmental changes and the accumulation of genetic alterations may drive malignant transformation regardless of the initial dysplasia grade8-10. Furthermore, certain anatomical sites, particularly the lateral tongue, have been associated with an increased risk of malignant transformation and more aggressive clinical behavior17-19. Although not evaluated in our present case, specific genetic biomarkers, such as p53, cell cycle proteins, loss of heterozygosity, and proliferation markers like Ki67 and proliferating cell nuclear antigen, could serve as critical adjuncts to improve early risk assessment and clinical decision-making28.
Lesions exhibiting mixed red-and-white features (erythroleukoplakia) or lichenoid characteristics require particular attention because they are associated with a higher risk of malignant transformation than homogeneous leukoplakia20-23. Additional factors, including smoking and alcohol consumption, may further contribute to the malignant process26. In the present case, recurrent erythematous changes of the lateral tongue preceded the diagnosis of OSCC and served as an important clinical indicator of malignant transformation. This observation underscores the importance of careful longitudinal clinical assessment in patients with OED2,11,12.
The present case also emphasizes the need for vigilant long-term follow-up in all patients diagnosed with OED2,11,12. Observation alone may be insufficient for lesions regarded as “risky epithelium”; clinical changes such as increasing erythema, induration, ulceration, or surface alterations should prompt immediate re-biopsy11,12. Early recognition of these changes may facilitate timely intervention before progression to advanced disease.
This case illustrates the dynamic and unpredictable nature of oral carcinogenesis and highlights the limitations of relying solely on a single histopathological assessment. Although the initial lesion was diagnosed as moderate epithelial dysplasia, progressive clinical changes observed during follow-up ultimately led to the diagnosis of OSCC. The recurrent erythematous alterations of the lateral tongue served as a clinically significant warning sign preceding malignant transformation. Therefore, continuous integration of clinical findings and repeated histopathological evaluation remain essential for the early detection of malignant transformation in patients with OED.
