Verrucous carcinoma arising from a previous cystic lesion: a case report

An incisional biopsy of the lesion in the right maxillary alveolar ridge performed at the present institution showed downward growth of numerous thickened and bulbous rete ridges of squamous cells. With regard to biomarker testing, the lesion was p16 positive and had lower proliferation based on Ki-67 detection; as a result, the patient was initially diagnosed with VC (Fig. 8a). Histological examination performed after surgery showed epithelial cells with exophytic surfaces and prominent keratin layer arranged in compressed invaginating folds that proliferated downward (Fig. 8b). In addition, blunt club-shaped projections of hyperplastic epithelium rather than infiltration were observed, and the basal layer exhibited dysplasia and hyperplasia (Fig. 8c). Groups of epithelial cells proliferating within the maxilla associated with bony destruction was observed (Fig. 8d). Finally, the patient was diagnosed with VC based on the observation of exo-endophytic growth pattern, deep extension of thick, parakeratotic, squamous epithelial cell layer, and bulbous rete ridges with borders extending toward the adjacent tissue with locally invasive patterns.

The diagnosis of VC is based on histopathological findings as well as clinical symptoms, since the biopsy specimen does not always represent the full thickness of the epithelium [10]. Our patient exhibited clinical and histopathological characteristics of VC including epithelial cells with associated destruction of the bone within the maxilla and proliferation with combined dysplasia and hyperplasia. Since the patient had a cystic lesion in the same area, it was concluded that the patient had VC arising from a previous cystic lesion.

Enriquez et al. reported the first case in 1980 of VC at OC in the mandible [2]. The second case was by Anand et al. in 1994 on VC in the maxilla with odontogenic keratocysts [18]. The third case was reported by Pomatto et al. in 2011, on VC at OC in the maxilla following tooth extraction in the left posterior maxilla; the authors claimed that VC originated from post-extraction remnants and introduced the term PIOVC [8]. The fourth case was reported by Mohtashm et al. in 2008, on VC at OC in the maxilla [4]. Mohtashm et al. explained that since metastasis of VC is extremely rare, surgical exicision without radical neck dissection is the best treatment option for VC. The fifth case was reported by Imaue et al. in 2013, on VC at OC in the maxilla [19]. Similar to the present case, a dome-shaped radiopaque mass with well-defined margins was observed in the left maxilla on radiograph, with expansion toward the maxillary sinus, nasal septum, and zygomatic arch. Partial maxillectomy was performed. The sixth case was reported by Peng et al. in 2015, on VC at OC in the mandible [24]. Peng et al. summarized all reports regarding VC and explained that since PIOVC has no recurrence or metastasis, it does not require any forms of neck dissection, and removal of primary lesion alone can lead to good prognosis. The seventh case was reported by Kamarthi et al. in 2016, on VC at OC in the maxilla with confirmed verrucous transformation of the cystic lining [21].

Early histological findings of VC include keratin piling on the surface, with initiation of downgrowth of epithelial projections. With progression of VC, club-shaped fingers of hyperplastic epithelium that gradually project into rather than infiltrate the deeper tissues are observed. At this point, the epithelium is well-differentiated while the basement membrane is intact. With growth of VC, cleftlike spaces with degenerating keratin project deeply. Chronic inflammation of the connective tissues, plasma cells, and mononuclear cells may ensue [1].

Odontogenic cyst that has undergone malignant transformation is characterized by chronic infiltration of lymphocytes and plasma cells in the connective tissue of the cyst wall. Cyst walls exhibit hyperplastic epithelium, and tumor cells exhibit pleomorphism and hyperchromatism. Cholesterol crystal clefts may be observed, and they may invade fibrous cystic walls. The cyst walls may have normal epithelial surface on some parts and naive epithelial surface on the others [12].

Maxymiw and Wood reported a case of OC advanced to SCC in the mandible, and based on the finding of transition of the cellular lining of the cyst wall from benign epithelium to carcinoma, it was confirmed that OC originated from carcinoma. In this case, malignant transformation occurred through chronic infiltration by lymphocytes and plasma cells of the cyst walls’ connective tissues. Cysts are partially or fully lined with dyskeratotic squamous epithelium. The stratified squamous epithelium with linings can transform to invasive SCC from the normal squamous epithelium and proliferate into the connective tissues of the cyst [17].

Verrucous carcinoma arising from OC is characterized by the transformation of the lining epithelium of the cyst to verrucous hyperplastic epithelium. In addition, moderate chronic inflammatory cells infiltrate the fibrous cystic wall. Proliferation of hyperparakeratotic-stratified squamous cyst lining epithelium can occur, and down-growth of broad and bulbous epithelial ridges with pushing-border invasion, which is generally observed in VC, can occur in the fibrous cystic wall. Thick prominent rete pegs with well-preserved basement membrane and well-differentiated squamous cells which penetrate deeply into the underlying tissue are also observed. Cell nuclei is prominent, and cellular pleomorphism is observed, with mild dysplasia, focal dyskeratosis, and atypical squamous cells. In addition, mitotic figures of the basal and parabasal epithelial cells are observed [2, 20].

Most reports indicate that surgical excision of the primary lesion is sufficient for VC, and VC shows higher 5-year survival rate than SCC. McClure et al. reported that although more aggressive excisions are necessary for large tumors, neck dissection is not necessary, since in most cases, VC is inflammatory rather than metastatic even in cases with lymphadenopathy at preoperative examinations [10]. However, Walvekar et al. recommended that considering the uncertainty of pathological diagnosis in cases with suspicious lymphadenopathy, it is reasonable to perform selective neck dissection such as SOHND. According to his analysis of 101 cases of VC within the oral cavity, the rate of recurrent VC was 28%, and the 5-year survival rate after surgery was 77.6% [23].

Ackerman reported that while radiotherapy may be effective for small superficial VC, surgical excision must be accompanied for cases with VC affecting a large area [1]. Few studies have reported that irradiation of VC, which is radiosensitive, can cause high-recurrence rates and anaplastic transformation of the neoplasm leading to rapid metastatic dissemination [3, 10].

Gardner analyzed 25 cases of carcinoma arising from OC and reported patients’ mortality rate of 20% within 10–24 months after surgery [12]. In studies including 27 cases each of carcinoma arising from OC, Eversole et al. reported a 2-year survival rate of 53% and Schiwmmer et al. that of 63% [6, 25]. In a study including 116 cases, Bodner et al. reported that 46% of cases with PIOSCC underwent surgery, and 38% underwent surgery and radiotherapy; follow-up revealed a 2-year survival rate of 62% and 5-year survival rate of 38%; and only 6 out of 116 cases with neck metastasis; however, despite the low rate of neck metastasis, neck dissection was performed in 59 of 116 cases (51%) [7].

In the seven reported cases of VC arising from odontogenic cystic lesion, excluding the present case report, neck dissection and radiotherapy were not performed. In this case report, neck dissection was performed due to PET/MRI characteristic of enlarged lymph node, but radiotherapy was not performed. Surgical excision of the primary lesion led to good prognosis. As suggested by the criteria, VC which is less malignant than SCC, with primary lesion in the jaw without distant lesion, low metastatic potential, and low recurrence rate may lead to good prognosis.

Our patient showed cystic lesion surrounded by the cortical bone at the site of carcinoma since 8 years ago, clear histological characteristics of VC, bony destruction of the maxilla, and cancer cell infiltration of the jaw; based on these findings, the patient was diagnosed with PIOVC. However, based on the diagnostic criteria for PIOSCC, the presence of radiolucent cystic lesions at the site of VC observed 8 years ago, characteristics of the carcinoma cells differentiating within the bone, and absence of distant lesion, as well as previous reports, the patient was diagnosed with VC arising from odontogenic cystic lesion.

In conclusion, this case report highlights that patients with OC must be promptly diagnosed and managed due to the possibility of malignant transformation of OC. Careful monitoring of lesions through CT is necessary for patients with OC. In addition, their prognosis must be carefully observed through regular follow-up x-ray examination. As reported in previous studies, surgical excision of the primary lesion without neck dissection can lead to good prognosis of PIOVC. However, if a patient exhibits combined lymphadenopathy, the possibility of future occurrence of metastasis must be completely eliminated through selective neck dissection.