# Intraosseous Squamous Cell Carcinoma Associated with Denosumab-Induced Osteonecrosis of the Jaw
## 3 Discussion  
PIOSCC is a rare neoplasm characterized by the presence of intraosseous squamous cells that are probably derived from residual odontogenic epithelium [2]. The World Health Organisation (WHO) has divided PIOSCC into three types: solid-type carcinoma, carcinoma arising from a keratocystic odontogenic tumour, and carcinoma arising from an odontogenic cyst [3]. The differential diagnosis of PIOSCC should include carcinomas of an odontogenic nature, such as malignant ameloblastoma, SCC of the overlying oral mucosa, and metastases of other primary neoplasms in the jaw. It should be taken in consideration that in up to 5% of patients with mandibular malignant cells, these are not detectable on imaging tests [9] and that whenever a diagnosis of PIOSCC is given, the existence of a distant primary tumour should be excluded [2]. The patient described in this article had a whole-body negative tumour CT scan. The term MRONJ was introduced by the American Association of Oral and Maxillofacial Surgeons (AAOMS 2014) to include all forms of drug-induced osteeonecrosis of the jaw [8]. The following criteria must be addressed for a clinical diagnosis of MRONJ:  
1. Presence of exposed bone (or bone that can be probed through an intraoral or extraoral fistula) in the maxillofacial region for a period of 8 weeks. 2. Current or previous treatment with antiresorptive agents (bisphosphonates or deno-sumab) or antiangiogenic agents. 3. No history of radiotherapy or metastatic disease in the jaw. Although histological criteria are not included in this definition, routine histological confirmation should be performed to support the diagnosis and to exclude malignancy [9; 10]. The risk of developing osteeonecrosis of the jaw is 0.01% in patients with osteoporosis and up to 15% in patients who have been treated with high doses of bisphosphonates or antiresorptives for malignant diseases [10; 11]. Risk factors associated with its development are oral surgery procedures, odontogenic infections, and concurrent treatment with chemotherapeutic agents or corticosteroids. Figure 7: **(A)** Hematoxylyn-eosin-stained section from the lesion showing invasive squamous cell carcinoma (SCC) characterized by sheets and nest of squamous epithelial cells containing abundant eosinophilic cytoplasm, round to oval nuclei, and prominent nucleoli. They show keratinization and horn pearl formation (original magnification \(\times\)10). **(B)** SCC bone invasion site (stain, H&E; magnification, \(\times\)10). Denesumab is a drug that is included in the category of monoclonal antibodies (IgG2) and is used in pathologies with a high risk of bone fractures such as osteoporosis in postmenopausal women and bone loss associated with hormonal suppression in men with prostate cancer [11]. Its mechanism of action is due to its binding to the receptor activator of nuclear factor kappa-B ligand (RANK-L), preventing the maturation, function, and survival of osteoclasts, thus improving bone mineral density and reducing the probability of fracture [12]. This prevents the interaction of RANK-L/RANK and inhibits the formation, function, and survival of osteoclasts, causing a decrease in bone resorption in trabecular and cortical bone. The risk of developing MRONJ is higher in patients who require a higher dose of administration and an intake period longer than 2 years [13]. Although the literature reports a low incidence of MRONJ resulting from the use of denosumab, when it does occur, it involves severe functional and masticatory disorders, with a major impact on the patient's quality of life. It is noteworthy that most the adverse effects of denosumab occur at doses of 120 mg, while side effects at doses of 60 mg are directly related to the duration of treatment [12]. [PERSON] et al. [14] report that monthly subcutaneous injections of denosumab at a dosage of 120 mg were more effective than zoledronic acid (4 mg monthly) in patients with breast cancer and bone metastases.