Methotrexate-Related Lymphoproliferative Disorder in Patients With Osteonecrosis of the Jaw: A 3-Case Report and Literature Review.

Patients with immunodeficiency or immunosuppression are at risk of developing a lymphoproliferative disorder (LPD). Methotrexate (MTX) is an iatrogenic cause of LPD, which in up to 50% cases occurs in extranodal sites. The occurrence of MTX-related LPD with osteonecrosis of the jaw (ONJ) has rarely been reported. Moreover, there are no clear diagnostic criteria and treatment strategies for management of these lesions. In the present cases, discontinuing MTX and debridement of the necrotic bone were effective. This report describes 3 cases of MTX-related LPD in patients with longstanding rheumatoid arthritis (RA) who presented with ONJ. The first patient was a 74-year-old man with RA who had received treatment with MTX for 7 years before presenting with ONJ and submental lymphadenopathy. The second patient was a 79-year-old woman who had been treated for 21 years with MTX and who presented with ONJ. The third patient was a 67-year-old man who had been treated with MTX for more than 15 years. In all 3 cases, biopsy, histology, and immunohistochemistry using a panel of lymphoid markers (Epstein-Barr virus [EBV], CD79a, CD20, PAX-5, CD3, and CD30) resulted in the diagnosis of EBV-driven T-cell, B-cell, and Hodgkin-like LPD. All 3 patients recovered after cessation of MTX and surgical debridement. Biopsy examination, diagnostic immunohistochemistry using lymphoid immune markers, and imaging studies using computed tomography, magnetic resonance imaging, and positron-emission tomographic computed tomography were useful for the correct diagnosis of this condition.

Axitinib-related osteonecrosis of the jaw.

Tyrosine kinase inhibitors (TKIs) are oral chemotherapy drugs used primarily to treat leukemias, renal cell carcinomas, gastrointestinal stromal tumors, and neuroendocrine tumors. Within this group, a number of drugs have already been implicated in jaw necrosis. Axitinib (Inlyta) is a novel TKI currently licensed for the treatment of renal cell carcinoma. We report the first case, to our knowledge, of jaw necrosis solely related to this medication and review the literature surrounding TKIs and their implication in osteonecrosis of the jaw.

Spontaneous bone formation after mandible segmental resection in "krokodil" drug-related jaw osteonecrosis patient: case report.

We report a case of a 48-year-old male patient with "krokodil" drug-related osteonecrosis of both jaws. Patient history included 1.5 years of "krokodil" use, with 8-month drug withdrawal prior to surgery. The patient was HCV positive. On the maxilla, sequestrectomy was performed. On the mandible, sequestrectomy was combined with bone resection. From ramus to ramus, segmental defect was formed, which was not reconstructed with any method. Post-operative follow-up period was 3 years and no disease recurrence was noted. On 3-year post-operative orthopantomogram, newly formed mandibular bone was found. This phenomenon shows that spontaneous bone formation is possible after mandible segmental resection in osteonecrosis patients.

Stage 3 Medication-Related Osteonecrosis of the Posterior Maxilla: Surgical Treatment Using a Pedicled Buccal Fat Pad Flap: Case Reports.

PURPOSE: Stage 3 medication-related osteonecrosis of the jaw (MRONJ) sometimes requires surgical treatment for resolution of the pathology and, in many cases, leads to oroantral communication in the posterior maxilla. The buccal fat pad flap is considered the best surgical choice for closure of large oroantral communications because it provides primary closure and guarantees adequate bone protection with sufficient blood supply for an effective bone healing process. MATERIALS AND METHODS: Five consecutive patients affected by stage 3 posterior maxillary MRONJ were treated with surgical removal of the necrotic bone and primary closure of the oroantral communication using a buccal fat pad flap. RESULTS: In each case, the size of the flap was always sufficient to perfectly close the defect without tension. There were no postoperative complications and the average postoperative hospital stay was 3 ± 1 days. The patients were seen at monthly follow-ups; after 12 ± 4 months of follow-up, no problems were noted in the treated area. CONCLUSION: Despite the limited number of cases, the results of this study suggest that, for stage 3 posterior maxilla MRONJ, managing the site with a pedicled buccal fat pad flap and primary closure might guarantee adequate bone protection with sufficient blood supply for an effective bone healing process.

Bisphosphonate-induced osteonecrosis of the maxilla presenting as a cicatricial ectropion.

CASE REPORT: A 63-year-old gentleman, who was being treated with bisphosphonates for multiple myeloma, presented with a cicatricial ectropion of the lower eyelid, without exposure keratopathy. A CT scan demonstrated extensive destruction of bone with an infraorbital fracture surrounded by sclerotic bony changes. The patient was managed conservatively with discontinuation of bisphosphonate therapy and topical ocular lubricants. The patient's condition remained unchanged a year after this initial management.

[Oral toxicity of targeted anticancer therapies]. / Toxicité endobuccale des thérapies ciblées anticancéreuses.

While toxicity of targeted anticancer therapies on the oral mucosa seems relatively frequent in clinical practice, it has not been properly characterized to date, apart from aphthous-like lesions due to mTOR inhibitors. Herein, we report the main oral lesions associated with these new therapies, with a description of the most frequent but also the most characteristic clinical manifestations of these drugs, such as anti-EGFR-induced mucositis, BRAF-inhibitor-associated hyperkeratosis, benign migratory glossitis and osteonecrosis of the jaw observed with angiogenesis inhibitors, as well as lesions more specifically linked with imatinib.

Osteonecrosis of the maxilla related to long-standing methamphetamine abuse: a possible new aspect in the etiology of osteonecrosis of the jaw.

BACKGROUND: Osteonecrosis of the jaw (ONJ) related to toxic effects of illicit drugs such as cocaine is not very common and might be overshadowed today by the incidence of bisphosphonate-related osteonecrosis of the jaw. However, we present a case which suggests a close relationship between abuse of the illicit drug methamphetamine (MA) and ONJ. CASE REPORT: A 44-year-old male with extended osteonecrosis of the maxilla admitted chronic abuse and synthesis of MA for at least the previous two decades. Furthermore, he confessed self-extracting teeth since he became addicted to MA. However at presentation, he had been successfully cured of his addiction to MA. A step-by-step surgical treatment was planned using computer-aided design/computer-aided manufacturing techniques. After resection of necrotic bone, a vascularized osteomyocutaneous fibular flap was applied secondarily. DISCUSSION: Two possible mechanisms, alone or in combination, could possibly lead to MA-related ONJ. Self-extraction of teeth as a psychopathologic behavior of self-destruction among MA abusers results in wounds that allow unhindered invasion of microorganisms causing osteomyelitis and ONJ, while on the other hand, the heating of white phosphor releases toxic phosphorous vapor, which could be inhaled and consequently cause ONJ of the maxilla. However, since the worldwide prevalence of MA abuse is remarkably high, a relationship between MA abuse and ONJ will offer a new aspect in the etiology of ONJ and might present a further therapeutic challenge.

Adjuvant aqueous ozone in the treatment of bisphosphonate induced necrosis of the jaws: report of two cases and long-term follow-up.

Bisphosphonate induced necrosis of the jaws (BONJ) does not have a unique protocol of treatment and many therapeutic approaches have been arising in oral medicine with debatable results. A male and a female attended the University Oral Surgery Clinic presenting oral bone lesions induced by intravenous and oral bisphosphonates respectively as complications of dental extraction. Treatment included daily mouthwashes and weekly intra oral irrigations with 4 mg/L of aqueous-ozone, antibiotic therapy and sequential superficial debridment for sequestrectomies. Long-standing follow-ups showed complete mucosa covering of exposed bone area and resolution of purulent secretion. Antibacterial and antifungal properties of aqueous ozone may have played important roles in the treatment. The outcome measured intra oral examination and panoramic radiographs of the affected bone. The application of aqueous ozone daily mouthwashes and weekly professional irrigation were safe; free from adverse effects, easily of handling and worked as an important adjuvant therapeutic strategy for the treatment of BONJ.

A clinico-pathologic correlation.

A 66-year-old female was referred to our department for evaluation of exposed bone in the hard palate. She was asymptomatic at the time of her initial consultation; however, she was concerned about a non-healing lesion that had been present for five months. The patient reported having injured her hard palate while eating sometime in November 2011. Subsequently she was followed by her general dentist, who had noticed improvement of the area. Approximately three months later, she noticed worsening of the lesion along with discomfort. She was conservatively managed at that point with penicillin and chlorhexidine mouth rinse without any improvement of her condition.

Comparison of destructive periodontal disease in blue iris mink to PCB 126-induced mandibular and maxillary squamous epithelial proliferation in natural dark mink.

Mink (Mustela vison) exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-like chemicals have been reported to develop mandibular and maxillary squamous cell proliferation that results in the destruction of alveolar bone and eventual tooth loss. This jaw lesion has been reported in wild mink collected from areas contaminated with TCDD-like compounds and is a potential biomarker for exposure to these chemicals. The blue iris strain of domestic mink is prone to develop severe periodontal disease, which results in destruction of bone and tooth loss that is grossly similar to the lesion induced by exposure to TCDD-like chemicals. A histological assessment of jaws from blue iris mink and natural dark mink exposed to 3,3',4,4',5-pentachlorobiphenyl (PCB 126) was done to determine whether the oral lesions are similar. The jaw tissue from the blue iris mink had lesions indicative of lymphoplasmacytic gingivitis and osteomyelitis, caused by inflammation entering the dental sulcus, while the jaw tissue from the mink exposed to PCB 126 exhibited squamous epithelial proliferation. Therefore, it was determined that the tooth loss and bone destruction seen in these mink are of different origin despite the similarity of the gross clinical signs.

Severity of periodontal disease in individuals chewing betel quid with and without tobacco.

BACKGROUND: The deleterious effects of chewing betel quid (BQ) with or without tobacco on periodontal health are poorly addressed. The aim of this study was to investigate the severity and extent of periodontal disease among individuals chewing BQ with and without tobacco. METHODS: One hundred twenty individuals (70 BQ chewers: 35 with tobacco and 35 without tobacco) and 50 control individuals (non-chewers) were included in this study. Sociodemographic data and information regarding BQ chewing habit were collected using a questionnaire. Plaque index, bleeding on probing and probing pocket depth were measured. Numbers of missing teeth were recorded and marginal bone loss was measured on panoramic radiographs. Statistical analyses were performed using 1-way analysis of variance and Bonferroni post hoc test. RESULTS: The socioeconomic status of subjects in the control group was significantly higher as compared with those chewing BQ either with or without tobacco. Plaque index, bleeding on probing and probing pocket depth were greater in subjects chewing BQ with tobacco than in those chewing BQ without tobacco and the controls. Subjects chewing BQ with tobacco had fewer teeth than those chewing BQ without tobacco and the controls. Marginal bone loss was higher in subjects chewing BQ with tobacco than in those chewing BQ without tobacco and the controls. CONCLUSIONS: The severity of periodontal disease is enhanced in subjects chewing BQ with tobacco as compared with those chewing BQ without tobacco. Subjects with a low socioeconomic status and poor education are significantly more likely than others to develop periodontal disease.

Chloroquine-induced hyperpigmentation of the hard palate.

This article reports a rare case of extensive palatal pigmentation secondary to long-term chloroquine treatment. Chloroquine was originally used as an antimalarial agent, but it is now widely used as an adjunct in the treatment of autoimmune diseases. Adverse effects of chloroquine usually include skin changes such as bullous pemphigoid, exacerbation of psoriasis, and pigmentation of the skin and mucous membranes as well as retinopathy, gastrointestinal alterations, and neuromuscular disorders. Extensive oral pigmentation is an uncommon feature of an adverse drug effect, and diagnosis should be based on clinicopathological findings.

Comparison of effects of clodronate and zoledronic acid on the repair of maxilla surgical wounds - histomorphometric, receptor activator of nuclear factor-kB ligand, osteoprotegerin, von Willebrand factor, and caspase-3 evaluation.

BACKGROUND: The aim of this study was to compare clodronate and zoledronic acid regarding their influence on the repair of surgical wounds in maxillae (soft tissue wound and tooth extraction) and their relation to osteonecrosis. MATERIAL AND METHODS: Thirty-four Wistar rats were allocated into three groups according to the treatment received: (i) 12 animals treated with zoledronic acid, (ii) 12 animals treated with clodronate and (iii) 10 animals that were given saline solution. All animals were subjected to tooth extractions and surgically induced soft tissue injury. Histological analysis of the wound sites was performed by means of hematoxylin-eosin (H&E) staining and immunohistochemical staining for receptor activator of nuclear factor-kB ligand (RANKL), osteoprotegerin (OPG), von Willebrand factor, and caspase-3. RESULTS: The zoledronic acid group showed higher incidence of non-vital bone than did the clodronate group at the tooth extraction site. At the soft tissue wound site, there were no significant differences in non-vital bone between the test groups. RANKL, OPG, von Willebrand factor, and caspase-3 did not show significant differences between the groups for both sites of surgical procedures. CONCLUSION: Both of the bisphosphonates zoledronic acid and clodronate are capable of inducing maxillary osteonecrosis. Immunohistochemical analysis suggests that the involvement of soft tissues as the initiator of osteonecrosis development is less probable than has been pointed out.

The use of pedicled buccal fat pad combined with sequestrectomy in bisphosphonate-related osteonecrosis of the maxilla.

The use of pedicled buccal fat pad flap (BFP) has proved of value for the closure of oroantral and oronasal communications and is a well-established tool in oral and maxillofacial surgery. Otherwise, the perceived limitations of surgical therapy for bisphosphonate-related osteonecrosis of the jaws (BRONJ) have been widely discussed, and recommendations have largely been made to offer aggressive surgery only to stage 3 patients refractary to conservative management. Oroantral communication may be a common complication after sequestrectomy and bone debridement in upper maxillary BRONJ. We report a case series of stage 3 recalcitrant maxillary BRONJ surgically treated with extensive sequestrectomy and first reconstruction using pedicled BFP. All the cases presented an uneventful postoperative healing was uneventful without dehiscence, infection, necrosis or oroantral communication. We postulate that managing initially the site with BFP and primary closure may ensure a sufficient blood supply and adequate protection for an effective bone-healing response to occur. This technique may represent a mechanic protection and an abundant source of adipose-derived adult stem cells after debridement in upper maxillary BRONJ. We evaluate in this work results, advantages and indications of this technique.

Imatinib-associated hyperpigmentation of the palate in post-HSCT patient.

Pigmentation of the oral mucosa can indicate a wide range of lesions or conditions. Some drugs are associated with pigmented lesions of oral cavity. Imatinib mesylate (Gleevec(®)) is a protein inhibitor used in the management of several hematological malignancies associated with dermatological side effects, like hyperpigmentation. We report the case of a 38-year-old male post-HSCT patient who had been using imatinib mesylate for over 5 years and presented with blue pigmentation on the hard palate, the left side of the nose and both ear lobes. The differential diagnosis of hyperpigmented lesions in the oral mucosa is also presented.

Nationwide survey for bisphosphonate-related osteonecrosis of the jaws in Japan.

PURPOSE: A nationwide retrospective cohort study was conducted by the Japanese Society of Oral and Maxillofacial Surgeons to assess the occurrence of bisphosphonate (BP)-related osteonecrosis of the jaws (BRONJ) during 2006 to 2008 and to elucidate the outcome and factors associated with remission of BRONJ. MATERIALS AND METHODS: A written questionnaire, including the clinical characteristics, management, and outcome of patients with BRONJ, was sent to 248 institutions certified as training facilities by the Japanese Society of Oral and Maxillofacial Surgeons in 2008. RESULTS: A total of 568 patients with BRONJ, including suspicious cases, were registered. Of these 568 patients, 263, including the maxilla in 81, the mandible in 160, and both in 22, met the working definition of BRONJ proposed by the American Association of Oral and Maxillofacial Surgeons. The patients included 219 women (83.3%) and 44 men (16.7%). Of these patients, 152 (57.8%) had received intravenous BPs, 104 (39.5%) had received oral BPs, and 7 (2.7%) had received both. The mean duration of administration until onset of BRONJ was 23.6 months for intravenous BPs and 33.2 months for oral BPs. BRONJ was stage 1 in 42 patients (16.0%), stage 2 in 187 (71.1%), stage 3 in 32 (12.2%), and unknown in 2. Of these patients, 34.2% had remission of BRONJ, 46.0% had persistent or progressive disease, and 19.7% died of malignancy or were lost to follow-up. Statistical analysis revealed that surgical treatment, including tooth extraction, sequestrectomy, and segmental mandibulectomy, contributed to the remission of BRONJ. In contrast, conservative treatment, concurrent anticancer drugs, poor oral hygiene, and the use of intravenous BPs did not. CONCLUSIONS: The relative ratio of BRONJ related to the use of oral BPs was greater in Japan than in the United States and European Union. Surgical treatment contributed to remission of BRONJ, and conservative treatment, concurrent anticancer drugs, poor oral hygiene, and intravenous BPs did not.

Osteonecrosis maxilar: una problemática onco-odontológica / Maxillary osteonecrosis: an onco-odontologic problematic

Los bifosfonatos fueron sintetizados en el siglo XIX por químicos alemanes, los cuales buscaban prevenir el depósito industrial de carbonato de calcio en sus chimeneas. Más tarde se observó la gran afinidad de la droga con el tejido óseo y que además inhibía la conversión de fosfato de calcio amorfo a hidroxiapatita (HA), lo cual reducía la velocidad de disolución de los cristales óseos. Por lo antedicho, estos compuestos sintéticos son utilizados hace más de tres décadas para el tratamiento de desórdenes esqueletales: osteoporosis, enfermedad de Paget, hipercalcemia asociada a mieloma múltiple y metástasis óseas propias de cáncer de próstata y mama, osteogénesis imperfecta y displasia fibrosa. Recientemente se han descripto algunos casos de osteonecrosis maxilar a causa de tratamiento crónico con bifosfonatos, a altas dosis en la prescripción de dichas drogas utilizadas como terapéutica oncológica.

Biphosphonates, synthesized in the mid 19th century by German chemists, were initially used in industry due to their capacity to prevent the deposits of calcium carbonate, which made them especially useful in avoiding the deposit of calcium salt in pipes. Later it was shown that they had great affinity with osseous tissue, where they inhibitedthe conversion of amorphous calcium phosphate in hydroxyapatite and they reduced the dissolution speed o the later. Biphosphonates are synthetics compounds used in the treatment of various metabolic and malignant bone diseases: Osteoporosis, Paget Disease, Hypercalcemia, Multiple Mieloma, Metastatic breast cancer and Metastatic prostate cancer, Osteogenesis Imperfecta, Fibrous Dysplasia. Recently, have been described some cases of Osteonecrosis of the jaw because of biphosphonate treatment in high doses for oncology administration.