Primary intraosseous squamous cell carcinoma (PIOSCC) is a rare form of odontogenic carcinoma arising within the jaw. PIOSCC has no initial connection with the oral mucosa and possibly develops from residual odontogenic epithelium or an odontogenic cyst or tumor (1). Diagnosis of PIOSCC can be difficult as it must be differentiated from other odontogenic carcinomas, including malignant ameloblastoma, SCC arising from the overlying oral mucosa, primary tumors of the maxillary sinus or nasal mucosa, and metastatic tumors from other primary sites (2–4).

The present study reported the case of a 59-year-old male patient who was initially diagnosed with a cystic mandibular lesion in 1988, which was definitively diagnosed as a keratocystic odontogenic tumor (KCOT) in 2006. From 1988 to 2013, the patient experienced at least five recurrences and corresponding treatments. Eventually, the lesion underwent malignant transformation to form a well-differentiated squamous cell carcinoma in the mandible.

PIOSCC is an uncommon neoplasm of the mandible, which was first described by Loos in 1913 (5). The term primary intraosseous carcinoma (PIOC) was previously used to describe this type of lesion as per the earlier editions of the World Health Organization (WHO) classification for histological typing of odontogenic tumors. However, the new WHO classification (2005) replaces PIOC with PIOSCC, and details three subtypes of lesion: Solid, KOTC-derived and odontogenic cyst-derived (1).

The main obstacle limiting a thorough understanding of the clinical, pathological and bio-behavioral profiles of PIOSCC is the rarity of the condition. However, common criteria for PIOSCC have been established based on published case reports as follows: i) The absence of another primary tumor on chest radiographs to exclude metastasis; ii) the absence of an ulcer in the oral mucosa overlaying the tumor; and iii) histopathological evidence of transition of the epithelial lining into squamous cell carcinoma (2–4, 6,7).

Determining the incidence of PIOSCC derived from odontogenic lesions is difficult. When the disease is not observed at an early stage, it is difficult to demonstrate the actual site of malignant transformation as the carcinoma may destroy the structures of the original lesion. For the current patient, medical records were available prior to malignant transformation. Furthermore, a typical KCOT structure was still apparent in tissue sections acquired in 2013. Therefore, a diagnosis of PIOSCC subsequent to KCOT was not difficult to establish.

The pathogenesis of PIOSCC remains unclear. For the present case, we speculated that a key factor for malignant transformation was chronic inflammation from the infection of odontogenic lesions. The patient suffered long-term chronic inflammatory stimulation following surgical treatments. Tissue sections supported this theory, with lymphocytic and neutrophilic infiltration of the stroma evident. Previous incision and drainage of the lesion might have led to this inflammatory cell infiltration. Such an inflammatory microenvironment, as is present in the epithelium lining KCOT lesions, confers a high risk for carcinogenesis, as recently described by Sukegawa et al (8).

The WHO classification of odontogenic cysts and tumor (2005) designates an odontogenic keratocyst (OKC) as a KCOT due to the tumor-like character and aggressive biological behavior, although certain disputes continue regarding OKC classification. Regardless of whether KCOTs are cystic lesions or tumors, their biological behavior is clear. Certain KCOT linings exhibit characteristics of epithelial dysplasia, and can develop into squamous cell carcinoma. However, not all studies of OKC/KCOT contain information regarding malignant potential. Perhaps of more importance to KCOT management than malignant transformation is the tendency of these lesions to recur. The recurrence rate for KCOT ranges from 0 to 62%, with lesions typically reappearing within 5–7 years (1,9).

KCOT is conventionally treated using curettage or enucleation. However, the high number of recurrences and subsequent repeated treatments may have promoted malignant transformation in the present patient. This suggests that regional osteotomy should be carried out following several recurrences of KCOT to reduce the risk of malignant transformation. Furthermore, avoidance of secondary infection of the lesion may also reduce the risk of malignancy by limiting inflammation in the region.

The treatment of patients with carcinomas arising in cysts has varied from local block excision to radical resection, with or without radiation or adjunctive chemotherapy. According to previous studies, the prognosis is quite poor, with 5-year survival rates ranging from 30 to 40% (3). However, metastases to regional lymph nodes have been demonstrated in only a limited number of cases.

The current study presents a case of PIOSCC developing from pre-existing KOCT based upon medical history, clinical examination and histopathological findings. Long-term chronic inflammation and multiple recurrences may aggravate the risk for malignant transformation of KCOT lesions.