According to 2020 consensus of World Health Organization (WHO), oral potentially malignant disorders (OPMD) refer to oral lesions that can be malignantly transformed in the future. Especially, leukoplakia/erythroplakia and oral lichen planus (OLP) are included in OPMD [1]. Meanwhile, oral epithelial dysplasia (OED) is a histopathological term indicating increased malignant risk [2]. OLP and leukoplakia are the most prevalent OPMD, with prevalence in the Asian population being 0.84% and 12.77%, respectively [3,4]. According to a systematic review conducted by Giuliani et al. [5], the malignant transformation rate (MTR) of OLP is reported to be 1.40%. In contrast, the MTR of oral leukoplakia is reported to be 9.70% [6].

We present a case of OLP with OED on both ventral side of the tongue at first, which progressed consecutively to oral squamous cell carcinoma (OSCC) over a period of 5-10 years. Additionally, we examine a case of clinically leukoplakia with OED on the ventral side of the tongue that also developed into OSCC after 7 years. We aim to present the clinical course and progression of these cases, which had combined diagnoses of OPMD and OED, along with clinical photographs depicting each stage.

The study protocol of this study was approved by the Institutional Review Board (IRB) of the School of Dentistry at Seoul National University (S-D20220036). The IRB waived the need for informed consent from the patient.

1. Case 1

In 2012, a 54-year-old male patient presented the hospital for the first time, primarily complaining of pain on both ventral sides of the tongue and sensitivity to spicy or salty foods. He was a non-smoker with no significant medical history, aside from medication for benign prostatic hyperplasia, and there was also no family history of cancer.

Erythema and whitish reticulations were observed on both ventral sides of the tongue (Fig. 1A, C). An incisional biopsy was performed on the right side of the tongue by the Department of Oral Maxillofacial surgery, and the biopsy results confirmed OLP with mild OED (Fig. 1B). Histologic features of right ventral tongue revealed a number of rete pegs, liquefaction degenerations, and band like infiltration of lymphocytes. And the mild epithelial dysplasia was also described. One year later, biopsy from the left ventral tongue also revealed mild OED. The patient was referred to the Department of Oral Medicine in 2013, and his symptoms improved with a 0.1% dexamethasone gargle. Regular check-ups were conducted every 1 to 3 months, along with regular biopsies.

In 2017, an incisional biopsy of the slightly thicker whitish plaque lesion on the left tongue confirmed well-differentiated squamous cell carcinoma (SCC) (Fig. 1D, E). A partial glossectomy was subsequently performed, revealing stage 1 cancer with a size of 4×3 mm, a depth of invasion of 3 mm, and no invasion of surrounding nerves and blood vessels. Immunohistochemistry for CK-pan was positive, and the left lesion has since healed and is currently being followed up.

During regular follow-up of the right lesion, a biopsy performed in August 2019 revealed hyperkeratosis and acanthosis (Fig. 2A). A subsequent biopsy in November 2020 diagnosed moderate OED (Fig. 2B), while a repeated biopsy in March 2021 showed moderate to severe OED (Fig. 2C). Six months after the last biopsy, an indurated nodule was observed, and the biopsy result indicated less well-differentiated SCC (Fig. 2D). Surgical resection of the right ventral tongue was performed, revealing stage 1 (pT1cN0M0) with a size of 1.4 cm, a depth of invasion of 2 mm, and the presence of lymphovascular invasion. The lesion has since healed and is currently under follow-up.

2. Case 2

In 2014, a 38-year-old male patient first visited the hospital with complaints of pain on the right side of the tongue. His medical history included gallbladder polyp, duodenal polyp and colon polyp, as well as ulcerative colitis. He did not smoke or consume alcohol, and three of his mother’s sisters had a history of cancer.

Ulcer with surrounding erythema were observed exclusively on the right ventral surface of the tongue. In 2015, an incisional biopsy of the right ventral lesion confirmed clinically leukoplakia and mild OED (Fig. 3A). Histologic feature of right ventral tongue showed hyperkeratosis and acanthosis. Symptoms improved with the use of 0.1% dexamethasone solution gargle, and regular check-ups were conducted. The second incisional biopsy from the erythematous lesion, performed in 2016 confirmed moderate to severe OED (Fig. 3B). A biopsy from the speckled lesion performed in 2017 diagnosed severe OED (Fig. 3C), and multiple verrucous whitish lesions were observed in 2021 and the biopsy confirmed OSCC (Fig. 3D). The surgical resection of the right ventral tongue revealed stage 1 OSCC, measuring 0.6 cm, with no invasion of the surrounding nerves and blood vessels. The lesion has since healed and is under follow-up in the Department of Oral and Maxillofacial surgery.

Oral and Maxillofacial cancer accounts for approximately 1.6% of all cancers, and with tongue cancer specifically representing 0.3% of all cancers in Korea [7]. The five-year survival rates for patients with tongue cancer, classified by pathological tumor-node-metastasis staging are 87.4% in early stage (stage 1, 2) and 43.3% in late stage (stage 3, 4), highlighting the critical importance of early detection [8]. Over 90% of oral cancer are SCC [9]. Since most SCC is visible to clinician, it is essential to carefully examine the superficial appearance of the oral mucosa. The tongue is one of the most commonly affected sites within the oral cavity, alongside the lip and floor of the mouth [10].

We presented two cases involving the development of OSCC on the ventral side of the tongue. Case 1 described a patient with OLP with OED on the both sides of ventral tongue, which progressed to OSCC over a 10-year period. Case 2 involved a patient with clinically leukoplakia with OED who also developed OSCC. According to a review by Moore et al. [11], the ventral surface of tongue is the most cancer-prone area in oral cavity. Both cases demonstrate a favorable prognosis due to the early detection of cancerous lesions during follow-up after surgical treatment. Smoking and alcohol consumption is risk factor associated with oral cancer, but it is still unclear if smoking increases malignant transformation of OED [12]. Since both cases show malignant transformation in non-smoker, we emphasize close follow-up of OED lesion regardless of smoking status.

In Case 1, the initial histological diagnosis was OLP with OED. It can be difficult to distinguish lichen planus and OED using histologic features. In some cases, the distinction between lichen planus and dysplasia is impossible [2]. Because of these lesions, where diagnosis was indeterminate, the term “lichenoid dysplasia” was introduced in 1985 [13]. The latest WHO criteria classify the presence of OED as an exclusion criterion for OLP, and it is now recommended that the term “lichenoid dysplasia” should not be used [2]. Aghbari et al. [14] stated that if dysplasia was excluded, malignant transformation of OLP is rare. Gonzalez-Moles et al. [15] reviewed controversies regarding malignant transformation of OLP. According to Gonzalez-Moles et al., MTR of OLP is overrated since diagnostic criteria of OLP is quite obscure. Most studies included malignant transformation of epithelial dysplasia, oral lichenoid lesion, graft versus host disease, which are exclusion criteria for diagnosis of OLP. The MTR of OED has been reported in numerous previous studies. According to systematic analysis by Shariff and Zavras [16], OED has an MTR of approximately 10.5%. Additionally, Iocca et al. [17] found that severe OED has 2.4 times higher MTR compared to mild or moderate OED. The grading system of OED was inspired by the grading system of cervical intraepithelial neoplasia, but there have been many changes over time. Currently, the most widely used grading system is the WHO’s 3-grade system, with the most recent edition being the 2017 version. OED grades are classified into mild, moderate, and severe, considering the depth of cytologic changes, the degree of architectural change in the epithelial tissue, and the degree of cellular atypia [2].

Several interventions regarding epithelial dysplasia, including surgical and non-surgical methods, were reported [18]. Brennan reviewed effectiveness of topical bleomycin application, systematic cis-retinoic acid application, lycopene application, laser ablation, surgical excision. Brennan concluded that there is insufficient evidence to conclude which method is the most effective management method of OED. In contrast, studies including systematic reviews [19], indicate that surgical excision of dysplastic lesions improves clinical outcomes, including metastasis-free survival and overall survival rates. Therefore, we recommend early surgical excision of severe oral dysplastic lesions to prevent malignant transformation.

Our case report exemplifies prior research on the malignant transformation of OED. Firstly, both cases affirm the established finding that the ventral surface of the tongue is the most prevalent site of OSCC [16]. Secondly, our cases indicate a high MTR of OED, underscoring the necessity for diligent follow-up [16,17]. In both cases, mild dysplasia progressed to severe dysplasia and ultimately to OSCC. Several clinical and genetic features of OPMD are known to predict malignant transformation [20]. A large lesion size, nonhomogeneous texture, red color, and human papilloma virus infection have a strong association with malignant transformation. Some genetic biomarkers have been investigated as predictors for malignant transformation of OPMD. The most common biomarkers include p53, proliferation markers (such as Ki67 and proliferating cell nuclear antigen), cell cycle proteins, and loss of heterozygosity. In our cases, clinical features such as indurated nodules, a mixed white and red appearance, and thick verrucous plaques were closely monitored, enabling the prompt detection of early OSCC through biopsy of the relevant site. As dentists, we have a unique advantage in observing the tongue in the oral cavity, allowing us to meticulously examine the mucous membrane for any malignant changes in color or appearance, which facilitates early detection of OSCC.

No potential conflict of interest relevant to this article was reported.

Data sharing is not applicable to this article because no new data were created or analyzed in this study.

None.

Conceptualization: HKP. Data curation: YK, HKP. Visualization: YK, HKP. Writing - original draft: YK. Writing - review & editing: HKP.