Primary peri-implant oral intra-epithelial neoplasia/carcinoma in situ: a case report considering risk factors for carcinogenesis

Oral cancer ranks sixth among the malignancies in terms of worldwide prevalence, with more than 90% being pathologically squamous cell carcinoma (SCC) [1]. Oral SCC generally develops via multistep carcinogenesis. The squamous epithelium goes into irreversible change, including epithelial dysplasia and oral intra-epithelial neoplasia/carcinoma in-situ (OIN/CIS) [2], finally resulting in the development of invasive carcinoma through the accumulation of genetic abnormalities caused by persistent exposure to a carcinogen. Risk factors for oral SCCs are smoking, tobacco and betel quid chewing habits, and heavy alcohol consumption. In addition, chronic inflammation, including periodontitis, has been regarded as a possible risk factor for oral SCCs. Laprise et al. [3] conducted a case control study to estimate the extent to which high levels of periodontal disease were associated with oral cancer risk, using a comprehensive adjustment approach for confounding that involved a large set of life course variables. The authors concluded that their findings supported the hypothesis that high levels of periodontal disease increase the risk of oral cancer.

A recent report made a bold statement that dental implants also can be a cause of cancer by providing a “route of entry for squamous cell carcinoma” [4], and another report stated that dental implants can lead to SCC in at-risk patients [5]. The incidence of malignances associated with dental implants seems to be extremely low. Bhatavadekar [6] calculated the theoretical standardized incidence ratio (SIR) to be 0.0017 per million per year. However, recently, case reports of oral malignancies associated with dental implants have gradually been accumulating [7]. Raise et al. [8] pointed out that the number of such cases in the literature has increased sharply in the last decade.

In this study, we report a case of intra-epithelial neoplasia arising from peri-implant mucosa in a woman without a history of tobacco smoking or excessive alcohol consumption, and without predisposing factors for oral SCC, including leukoplakia, erythroplakia, or previous oral cancer.

A 65-year-old woman was referred to our clinic with a tumor in the right lower gingiva. Her medical history included breast cancer without metastatic lesion, diabetes mellitus, hyperlipidemia, and hypertension. She had taken orally aspirin, amlodipine, pravastatin, and bepotastine for 2 years. She drank alcohol socially, but she had no history of tobacco smoking habit.

About 10 years prior to her attendance at our clinic, her mandibular right posterior teeth had been replaced with an implant-supported porcelain-fused-to-metal restoration (three endosseous hydroxyapatite-coated titanium implants) in a dental clinic. The postoperative clinical course was uneventful, and the implant-supported restoration had functioned well. The patient had discontinued her regular follow-up for the maintenance of oral hygiene several months after the completion of the restoration. After about 7 years, she noticed a swelling on the lingual side of the gingiva around the three implants, and she visited a dental clinic. Following conservative treatment with nonsurgical measures for around 2 years, under a diagnosis of peri-implantitis, flap surgery to her lesion was performed in the dental clinic. However, the lesion around the central of the three implants did not improve, and changes to its surface properties were observed, leading to the suspicion of transformation to neoplasia. She was then referred to our clinic 3 months after the flap surgery.

The upper part of the implant body was exposed on the implant corresponding to the first molar of the right side of the mandible; this was associated with painless, elastic soft, and relatively well circumscribed gingival swelling on the lingual site. No pus drainage from the gingival sulcus was observed (Fig. 1). Periodontal disease or peri-implant disease, including peri-implantitis and peri-implant mucositis, were not observed in other regions, including the contiguous implants to the relevant middle implant. Lymphadenopathy in the neck was not detected. A panoramic radiograph showed slight vertical bone resorption around the three implants in the right side of the mandible (Fig. 2). An incisional biopsy was conducted under the suspicion of neoplasia after considering not only the clinical findings, but also the clinical course. Pathological microscopic examination of the biopsy specimen revealed thickened squamous epithelia with slight nuclear atypism and disorders of the epithelial rete pegs accompanied by moderate grade inflammatory cell infiltration. Immunohistochemical findings showed positive staining for keratin 17 (k17) and a negative staining mosaic pattern for keratin 13 (k13). High p53, p63, and Ki-67 reactivity was also observed in the basal cell layer, but negative staining for p16 (Table 1). These findings indicated to OIN/CIS. Thus, a wide local excision with rim resection of the mandible, including the three implants, was performed under general anesthesia. The postoperative clinical course was uneventful but the patient experienced paresthesia of the lower lip and mental region of the affected side. The pathological diagnosis of the resected specimen confirmed the OIN/CIS found in the biopsy specimen (Figs. 3, 4 and 5). The surgical margin was involved with epithelial dysplasia but free of OIN/CIS. After 1 year of follow-up, there was no evidence of recurrence (Fig. 6).

In our case, the persistence of peri-implant mucositis or peri-implantitis around the dental implant was implicated as being a plausible risk factor for carcinogenesis. Regular follow-up to ensure the maintenance of oral hygiene after dental implant therapy has again been shown to be important for preventing peri-implantitis, a plausible risk factor for carcinogenesis.