Victoria L. Woo

Inhibition of Oral Mucosal Cell Wound Healing by Bisphosphonates

PURPOSE Bisphosphonates (BPs) are a widely used class of drugs that are effective in the treatment and prevention of osteoporosis, hypercalcemia of malignancy, and bone metastases associated with multiple myeloma, breast cancer, and other solid tumors. In the past several years there have been numerous reports describing the occurrence of osteonecrosis of the jaws (ONJ) associated with these drugs. Whether the ONJ lesion initiates in the oral mucosa or derives from the underlying bone is not well understood. In this report we describe the effect of pamidronate, a second-generation BP, on oral mucosal cells. MATERIALS AND METHODS Murine oral keratinocytes were isolated and exposed to pamidronate at a range of clinically relevant doses. Cellular proliferation was measured using a MTS/PMS reagent-based kit and wound healing was examined with a scratch assay. To determine whether oral keratinocytes undergo apoptosis following exposure to pamidronate, TUNEL, caspase-3, and DAPI apoptosis assays were performed. RESULTS We show that BP pretreatment of oral mucosal cells inhibits proliferation and wound healing at clinically relevant doses, and that this inhibition is not due to cellular apoptosis. CONCLUSIONS To our knowledge this is the first report investigating the effect of nitrogen-containing BPs on oral mucosal cells. This study suggests that BPs inhibit oral keratinocyte wound healing which may play a significant role in the initiation of ONJ.

Potential pathophysiological mechanisms in osteonecrosis of the jaw

Bisphosphonates are used in the treatment of hypercalcemia of malignancy, skeletal complications associated with metastastic bone disease, Pagets disease, and osteoporosis. Osteonecrosis of the jaw (ONJ) is a recently described clinical condition that has been associated with the use of nitrogen‐containing bisphosphonates. Reports describing this entity first appeared in the literature in 2003. While there have been significant numbers of case reports and a limited number of retrospective and prospective studies examining risk factors associated with ONJ, the pathophysiology of this condition remains elusive. In this review, we explore proposed mechanisms underlying ONJ development and identify potential areas for future investigation.

Phosphaturic mesenchymal tumor, mixed connective tissue variant, of the mandible: Report of a case and review of the literature

Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome that results in renal phosphate wasting with hypophosphatemia. In most cases, the underlying cause of TIO is a small mesenchymal neoplasm that is often difficult to detect, resulting in delayed diagnosis. One such neoplasm is the phosphaturic mesenchymal tumor, mixed connective tissue variant (PMTMCT), an unusual entity with unique morphologic and biochemical features. Most of these tumors are found at appendicular sites with only rare cases reported in the jaws. We describe a PMTMCT involving the mandible in a patient with a protracted history of osteomalacia. A review of the current literature is provided with emphasis on the clinical and histologic features, etiopathogenesis, and management of PMTMCT in the setting of TIO.

The expression of the receptor for glycation endproducts (RAGE) in oral squamous cell carcinomas.

Advanced glycation endproducts (AGEs) and their receptors, receptor for advanced glycation endproducts (RAGE), are novel groups of molecules with roles in inflammation, cytokine activation, and promotion of cell growth. Recently, RAGE has been implicated in the progression and metastasis of several epithelial tumors. The expression of RAGE was examined in 38 oral squamous cell carcinoma (OSCC) cases by immunohistochemistry. In the OSCCs, RAGE positivity, interpreted as more than 25% positive cells, was detected in 10 of 10 well-differentiated, 3 of 4 well-to-moderately differentiated, 3 of 9 moderately differentiated, 1 of 7 moderate-to-poorly differentiated, and 0 of 8 poorly differentiated tumors. The staining percentage was significantly higher in well-differentiated tumors compared to moderately (P < .05) and poorly differentiated (P < .05) tumors. All normal mucosa samples were RAGE-positive. Western blot analysis for RAGE was performed on 2 OSCCs and 2 normal oral mucosa samples. Higher expression was observed in the normal tissues compared to the OSCCs. Our results show that RAGE immunoreactivity correlates with histologic differentiation in OSCC.

Oral Lichenoid Drug Eruption: A Report of a Pediatric Case and Review of the Literature

Abstract:  Lichenoid drug eruptions are seen most frequently on the skin and seldomly affect the mucosal surfaces. Oral involvement—known as oral lichenoid drug eruption—is more common in the adult population and has been associated with numerous medications. Pediatric‐onset oral lichenoid drug eruption is an exceptionally rare finding with only isolated cases published in the literature. The nonspecific appearance and latent presentation of pediatric oral lichenoid drug eruption can cause confusion in diagnosis and treatment. We report a case of oral lichenoid drug eruption occurring in a 15‐year‐old and explore challenges in the clinical and histologic recognition of this condition.

Gingival squamous cell carcinoma in adolescence

Squamous cell carcinoma (SCC) is a rare finding in the adolescent population, with most cases occurring in patients with underlying heritable diseases or immunologic conditions. Moreover, the incidence of oral SCC in this age group is extremely low. While isolated cases of adolescent oral SCC have been documented, most have been primary tongue or lip lesions. We report 4 cases of gingival SCC occurring in otherwise healthy adolescent patients. The preliminary clinical impressions ranged from factitial injury to inflammatory tissue. Microscopic similarities, including overlap with pseudoepitheliomatous hyperplasia and keratoacanthoma, were seen. Review of the literature indicates that adolescent gingival SCC is extremely rare and a challenging diagnosis for the clinician and pathologist alike. Diagnostic pitfalls, possible etiologic factors, and the prognostic outlook of this condition are discussed.

Expansile radiolucency of the mandible

A 27-year-old female presented for evaluation of an expansile lesion of the left posterior mandible. She reported that the swelling began several months prior and had progressively enlarged, now causing her intermittent pain. On further questioning, she denied paresthesia or significant compromises in function, including disruptions in eating, speaking, or swallowing. Extraoral examination revealed facial asymmetry attributed to a diffuse swelling of the left mandible. No compressibility or crepitus was noted on external palpation of the affected side, and the overlying skin was normal in appearance, without evidence of erythema. On intraoral examination, it was noted that the buccal and lingual cortices were expanded from tooth #18 to #23. The overlying gingiva and alveolar mucosa were pink, with no appreciable bruits or pulsations on auscultation. Examination of the associated teeth showed grade I mobility of tooth #18 and grades II and III mobility of teeth #24 and #23, respectively. All involved teeth tested vital with cold and electric pulp testing. The patient was edentulous in the regions of teeth #19, #20, #21, and #22 and teeth #28, #29, and #30. She stated that the left mandibular teeth had been extracted to treat an “abscess” 2 months prior. No history was provided regarding the missing right mandibular teeth. Examination of a panoramic radiograph revealed a large, multilocular radiolucency with well-defined borders extending from the mesial aspect of tooth #18 to the distal aspect of tooth #25 and encroaching on the inferior border of the mandible (Figure 1). The lesion enveloped the roots of teeth #23 and #24 and caused mild displacement of the teeth mesially. Distinct scalloping of the inferior mandibular cortex was seen. Internally, the lesion was predominately radiolucent, with focal evidence of radiopaque trabeculations.