Gingival Squamous Cell Carcinoma: An Enigmatic Diagnostic ChallengeKey Clinical MessageThe similarities of Gingival Squamous Cell Carcinoma with common periodontal lesions could cause a delay in diagnosis or even a misdiagnosis. In cases with suspected gingival lesions, differential diagnosis of squamous cell carcinoma should always be considered because it can have a favorable prognosis, if the treatment is initiated early.AbstractOral squamous cell carcinoma (OSCC) is one of the highly invasive malignancies globally, accounting for the vast majority of all oral cancers, i.e., more than 90%. Carcinomas of the gingiva represent a distinct subgroup of OSCC, constituting approximately 12% of all OSCC cases. These neoplasms might mimic the inflammatory and reactive state of the periodontium, often leading to a delay in diagnosis and hence, poorer prognosis.An atypical case of gingival squamous cell carcinoma in a 48-year-old female patient has been reported here. The patient presented with a 3-month history of pain and burning sensation in the lower left back region of the jaw. Clinical examination showed a proliferative lesion extending from the marginal gingiva to the buccal vestibule adjacent to teeth 36 and 37. Given the clinical manifestations and differential diagnosis of infectious granulomatous lesions and malignant neoplasms, an excisional biopsy was performed and a diagnosis of well-differentiated squamous cell carcinoma was made. The patient was subsequently referred to the Oral and Maxillofacial Surgery Department for further treatment, which included surgical excision of the tumor with segmental mandibulectomy and selective neck dissection.Therefore, the lesion must be identified early, to start treatment, stop metastases, and enhance the prognosis.Keywords: Gingiva, malignancy, misdiagnosis, squamous cell carcinomaIntroductionAs the most common malignant neoplasm affecting the structures of the oral cavity, squamous cell carcinoma (SCC) accounts for over 90% of all oral malignant lesions [1]. The lateral/ventral aspect of the tongue and floor of the mouth are considered the most common sites for intraoral SCC, excluding the carcinoma of the lip vermilion (which has a different etiology) [2]. Gingival lesions comprise approximately 12% of all intraoral cases [1]. Compared to the maxilla, the mandible has a higher likelihood of having gingival SCC, most of which are located in the molar region [3]. However, gingival carcinoma is frequently diagnosed too late, or often misdiagnosed because it resembles common benign inflammatory lesions. Early-stage carcinoma can mimic an erosion, small ulcer, exophytic mass, or a periodontal lesion. They can also present as an asymptomatic erythematous or white lesion, or both [4]. So, when treating gingival lesions, especially in elderly patients, the SCC of the gingiva should be taken into account when making a differential diagnosis. To begin treatment early and improve the prognosis, it is imperative to diagnose gingival lesions as soon as possible.Here, we document a rare case of a 48-year-old female patient with gingival squamous cell carcinoma on the left mandibular posterior area.CASE HISTORY AND EXAMINATIONA 48-year-old female patient was presented at the Periodontics Department, with the chief complaint of pain and burning sensation on the lower left posterior region of the jaw for three months. The pain was spontaneous, continuous, severe in intensity, non-radiating type, aggravated on taking hot and spicy foods and touching while relieved on taking analgesics. Medical history was non-significant. There was no history of alcohol and tobacco abuse, both in smoked and smokeless form, and no positive family history of malignancy. According to the patient, she had visited a private dental clinic for the same problem, as soon as she started developing the clinical symptoms i.e., 3 months before reporting to our department. She mentioned that the sole intervention she received was oral prophylaxis followed by two courses of antibiotics (a combination of Amoxicillin and Metronidazole), as prescribed by a private dental practitioner. Since there was no improvement in the clinical symptoms, the patient was referred to our department.Upon extra-oral examination, a single, non-tender, mobile, and firm submandibular lymph node was palpated on the left side. Intra-oral examination revealed an ulcer-proliferative lesion extending from the marginal gingiva to the buccal vestibule, measuring approximately 15mm\(\times\ \)8mm  adjacent to teeth 36 and 37, with irregular necrotic margins (Figure 1). Uniformly white plaques were also evident, seen on the underlying vestibular fundus, as well as on the mesial attached gingiva adjacent to tooth 35. Intra-oral Periapical Radiograph (IOPAR) of the region revealed bone loss on the furcation area in relation to 36, while the interdental bone on both sides was intact (Figure 2). Complete blood investigations were done, which were within the normal range.DIFFERENTIAL DIAGNOSIS, INVESTIGATIONS AND TREATMENTIn view of the clinical manifestations, we made a differential diagnosis which included Squamous Cell Carcinoma (SCC), verrucous carcinoma, homogenous leukoplakia as well as Necrotizing Ulcerative Periodontitis (NUP). However, because of lesion’s persistence and poor responsiveness to medical therapy, NUP was excluded from the differential diagnosis and a strong suspicion of non-infectious and non-inflammatory disease was considered. Under local anesthesia, every visible part of the lesion was removed and sent for histopathological analysis. (Figure 3, 4)Histopathological examination revealed dysplastic keratinized stratified squamous epithelium overlying the fibro-cellular connective tissue stroma. The underlying stroma was infiltrated with tumor cells forming islands and sheets. The tumor cells showed dysplastic features such as increased cytoplasmic ratio, cellular and nuclear pleomorphism, anisocytosis, anisonucleosis, atypical mitotic figures, and abundant keratin pearl formation (Figure 5). Intense inflammatory cell infiltration comprising chiefly of lymphocytes and plasma cells was also noted. These microscopic features led to the final diagnosis of well-differentiated squamous cell carcinoma (TNM staging: T1N1M0,).T (Size of the primary tumor) – T1, because the size of the primary tumor was <2cmN (Regional lymph node involvement) – N1, because it was positive for lymph node level IB metastasisM (Distant metastasis) – M0, because of no distant metastasisThe patient was then referred to the Department of Oral and Maxillofacial Surgery for further treatment, where a wide local excision of the lesion with segmental mandibulectomy and selective neck dissection (lymph node level I-IV), followed by removal of regional lymph nodes was done under general anesthesia. The patient was then referred to Kathmandu Cancer Hospital for radiotherapy, 5 daily fractions a week fractionated for seven weeks, each session of 50 Gy.OUTCOMES AND FOLLOW UPThe patient is still being monitored, two years after the end of the treatment and she is not exhibiting any signs of recurrence at present. However, the patient presented with the signs of radiation mucositis. (Figure 6)DISCUSSIONAccording to the estimates from the GLOBOCAN project in 2018, there are at least 354,864 new cases of oral cancer (mostly SCC) worldwide each year, i.e., 2.0% of all malignancies [5]. It is approximated that carcinoma of the oral cavity in conjunction with lip cancer ranks sixth among all cancers in Nepal and fourth among cancers in men [6]. Gingival carcinoma represents a rare but distinct subgroup of OSCC. Carcinoma of the gingiva is an insidious disease that often lacks the clinical manifestation of the malignant tumor and hence is misdiagnosed as other inflammatory conditions of the periodontium, subsequently influencing the patient’s prognosis and chance for survival. Usually originating from keratinized mucosa in a posterior location, it frequently destroys the underlying bone, resulting in tooth mobility [7].Tobacco abuse, either in smoked or smokeless form, alcohol consumption, and betel nut chewing can be regarded as significant contributing factors to SCC, even though the exact etiology of this condition is unknown [4]. However, Yoon et al [8] and Meleti et al [9] stated that there is no strong correlation between gingival SCC and traditional risk factors. In contrast, Souza et al [10] have documented a strong correlation between smoking and alcohol intake and gingival SCC. The majority of case studies [3] have documented a predilection of gingival SCC for mandibular arches, however, Lubek et al. discovered nearly equal amounts of gingival lesions in both arches [11]. The average age of onset of gingival SCC is similar to that of other intra-oral SCC. Historically, it was considered as the disease of the elderly but there has been a recent shift in the prevalence of these lesions in younger patients who do not meet the established risk factors [12]. Since isolated cases of gingival SCC in pediatric patients have also been reported, clinicians should not discount the possibility of gingival SCC in this patient population [13].The diagnosis of gingival SCC is quite difficult due to its resemblance to other periodontal inflammatory conditions as well as to other pre-malignant conditions. In the present case, uniform white plaques seen on the vestibular area of the underlying tooth may be suggestive of homogenous leukoplakia, which has a very low malignant transformation rate. Brooks et al, in a case report, described a case of SCC of the gingiva in a 60-year-old female patient, with an unexpected clinical presentation. The patient displayed persistent gingival bleeding with a moderately inflamed and ulcerated border on the maxillary right molar region. She had previously experienced right-sided stage 2 breast cancer. An incisional biopsy was carried out after taking into account her medical history and the possibility of metastases. According to the histopathological analysis, the lesion was identified as a moderate to well-differentiated gingival SCC [4]. Another similar case was reported by Khan et al, where the clinical presentation of the patient was misleading giving the diagnosis of Necrotizing Ulcerative Periodontitis (NUP), yet the diagnosis of well-differentiated SCC was confirmed by the histopathological results [15].In cases of refractory chronic periodontal diseases, the clinician must be skeptical of any changes in the morphology of the gingiva, for instance, desquamations, ulcerations, papillae loss, and verrucous and hyperplastic growths, as these may be early clinical indicators of the upcoming malignancy. If suspicious gingival lesions remain after the etiological agents have been removed for longer than two weeks, a thorough history, clinical examination, and biopsy should be carried out for histopathological analysis in order to rule out malignancy and improve success and survival rates of the treatment.Therefore, when treating rare periodontal disorders, gingival SCC should always be taken into account as a differential diagnosis. In situations like these, periodontists can be lifesavers because they can help rule out this aggressive disease even in the absence of risk factors.Author ContributionsGitanjali Subedi – Conceptualization, Data curation, Methodology, Writing – original draftManoj Humagain – SupervisionArjun Hari Rijal – Validation, Writing – review and editingSimant Lamichhane – Writing – review and editingPratibha Poudel – InvestigationSachita Thapa - ResourcesREFERENCESCapote-Moreno A, Brabyn P, Muñoz-Guerra MF, et al. 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