Mark A. Lerman

Bony changes in the jaws of rats treated with zoledronic acid and dexamethasone before dental extractions mimic bisphosphonate-related osteonecrosis in cancer patients

Osteonecrosis of the jaw is associated with aminobisphosphonate use in patients treated with intravenous doses for the prevention of bony metastases. A more complete understanding of the natural history of bisphosphonate-related osteonecrosis of the jaws (BRONJ), factors associated with risk, and its pathobiology has been limited by the availability of human material and the absence of clinical predictability. We now describe an animal model, developed in female Sprague-Dawley rats, in which we replicate many of the clinical, radiographic, and histologic features described in humans. Animals treated with a sequence of zoledronic acid (ZA) and dexamethosone (DX) over a one to three week period developed BRONJ-like changes following extraction of mandibular or maxillary molars. Whereas the extraction sites of control animals underwent predictable healing with rapid epithelialization, animals treated with ZA/DX demonstrated clinical and histological evidence of ulceration overlying areas of necrotic bone. In contrast to images from control animals, radiographs from animals treated with ZA/DX demonstrated poor definition of the alveolar ridge with mixed radiodensity. Modest increases in the extent of the inflammatory infiltrate were seen fourteen days after extraction in ZA-only treated animals compared to control or ZA/DX-treated rats. However, by post-extraction day 28, no differences were observed. Tissue vascularity was most pronounced in ZA-only treated animals compared to ZA/DX or control specimens. Apoptosis of epithelial cells was not observed in any experimental groups, and no evidence of Actinomyces was observed as determined by Periodic Acid Schiff (PAS) staining. The administration of ZA/DX preceding dental extractions in rats therefore results in the development of bony and soft tissue changes that are similar to those noted humans who develop BRONJ, and may provide a useful model for study of its pathogenesis, as well as strategies for its prevention and treatment.

Dental panoramic radiographic evaluation in bisphosphonate-associated osteonecrosis of the jaws

OBJECTIVES To determine the extent to which clinical and radiographic features of bisphosphonate-associated osteonecrosis of the jaw (BONJ) are correlated. DESIGN Retrospective case review. METHODS The records of 39 patients diagnosed with BONJ and examined by panoramic radiography were retrospectively evaluated. The arches were divided into sextants (n = 234) and evaluated for the following signs: sclerosis, surface irregularity, sockets, fragmentation and lysis. MAIN OUTCOME MEASURES The McNemar, Kruskall-Wallis and equivalency tests were performed to analyze the association between clinical and radiographic signs and BONJ severity. RESULTS Sixty-two out of 234 sextants were abnormal by clinical criteria and 61 out of 234 sextants demonstrated at least one radiographic abnormality. There was agreement between clinical and radiographic detection in 41 sextants. The data showed equivalency between BONJ diagnosis and both sclerosis and surface irregularity. The correlation between number of clinical sites and any radiographic finding was significant in the maxilla (P < 0.001) but not in the mandible (P = 0.178). The total number of radiographic signs per patient increased with BONJ stage. CONCLUSION Focal panoramic radiographic findings of sclerosis and surface irregularity correlate with clinical sites of BONJ. This may be a useful and reliable tool to detect early changes of BONJ or to confirm a clinical diagnosis.

Human papillomavirus-associated oral intraepithelial neoplasia

This study evaluated an unusual subset of oral epithelial dysplasia for the presence of transcriptionally active high-risk HPV subtypes and to further characterize the histological criteria for this condition. There were 20 cases diagnosed as epithelial dysplasia with marked apoptosis of the anterior oral cavity. Clinical and follow-up data were collected and histopathological features were documented. Immunoperoxidase studies were performed for p16 and in situ hybridization studies were performed for low- and high-risk HPV sub-types. Gender- and site-matched controls of conventional moderate-to-severe oral epithelial dysplasia were similarly evaluated using immunoperoxidase studies for p16 and in situ hybridization; the number of apoptotic cells for study and control cases was counted at two different tissue sites. There were 17 men and 3 women with a median age of 56 years. Seventeen lesions were described as white and five were described as rough or papillary. Thirteen were located on the lateral or ventral tongue, some extending onto the floor of the mouth. Epithelial hyperplasia with marked karyorrhexis and apoptosis were present in all the cases, along with features of conventional oral epithelial dysplasia. A statistically significant number of apoptotic cells were identified in the study cases when compared with controls (P>0.0001). Twenty cases were positive for high-risk HPV by in situ hybridization and all 19 nineteen cases evaluated for p16 demonstrated overexpression. Two patients were diagnosed with squamous cell carcinomas and one patient developed recurrent disease. We report a subset of oral epithelial dysplasia that occurs mostly in adult men on the ventral or lateral tongue and is positive for high-risk HPV and for p16. We propose use of the term ‘HPV-associated Oral Intraepithelial Neoplasia’ to characterize these lesions of the oral cavity for consistency in nomenclature with HPV-associated lesions of the lower anogenital tract. One case recurred and one developed invasive cancer.

Conservative management of bisphosphonate-related osteonecrosis of the jaws: Staging and treatment outcomes

OBJECTIVE Bisphosphonate-related osteonecrosis of the jaws is a well-established disorder in which patients treated with bisphosphonates develop exposed necrotic bone in the oral cavity. The objective of this study was to report staging and treatment outcomes in a large cohort of patients with bisphosphonate-related osteonecrosis of the jaws managed primarily with non-surgical measures. PATIENTS AND METHODS A retrospective medical record review was conducted from 1998 to 2010 of all patients referred for the management of bisphosphonate-related osteonecrosis of the jaws. Clinical findings and staging were assessed at initial consultation and each follow-up visit. Management was provided to minimize symptoms and/or achieve resolution of lesions. Treatment responses were defined based on symptoms and/or change in staging. RESULTS There were 120 records reviewed and 97 patients seen for follow-up (median 12months); 90% were cancer patients. Bisphosphonate-related osteonecrosis of the jaws was managed with observation (16%), antibiotics (55%), non-surgical sequestrectomy±antibiotics (14%), or surgery±antibiotics (14%). There were 14 patients (12%) who presented with stage 0 disease; 41%, 43%, and 5% of patients presented at stages 1, 2, and 3, respectively. Greater than 70% of patients improved, remained asymptomatic, and/or showed complete re-epithelialization when evaluated at 0-3, 3-6, 6-9, 9-12, and/or >12months. Seventeen patients developed non-infectious complications of BONJ including neuropathy (N=9), painful tongue ulcers (N=7), or pathologic fracture (N=1). Twelve patients with multiple myeloma underwent hematopoietic cell transplantation without infectious complications. CONCLUSIONS A primarily non-surgical approach appears to be a successful management strategy for bisphosphonate-related osteonecrosis of the jaws. Overall, 71-80% of patients improved or remained asymptomatic with a median follow-up of 12months.

Pigmentation of the hard palate

CASE REPORT A 57-year-old African-American female presented for implant evaluation with slate-black pigmentation of the hard palate (Fig. 1). She was unaware of this condition, and therefore the duration of the condition could not be ascertained. Extraoral examination revealed brown macular lesions on her nose, extensor surfaces of arms, and dorsa of hands (Fig. 2). She reported that these cutaneous lesions had been present for approximately 12 years. Her medical history was significant only for discoid lupus erythematosus (DLE). She was prescribed quinacrine for DLE, and she did not report the use of other prescription or over-the-counter medications. She reported an allergy to penicillin and denied a history of smoking or of alcohol use.

Granulomatous foreign body reaction to dermal cosmetic fillers with intraoral migration

OBJECTIVE We report intraoral granulomatous foreign body reactions in patients treated with calcium hydroxylapatite (CHA) or poly-l-lactic acid (PLA). STUDY DESIGN Clinical and histopathologic data were obtained from 25 patients who developed orofacial nodules or swelling after dermal filler injections. RESULTS All 25 patients were women aged 35 to 78 years (median, 55 years). All had a history of injection of CHA (n = 13) or PLA (n = 12) to the lips, nasolabial area, or mental area. Two patients developed cutaneous nodules at the sites of injections; all others presented with intraoral nodules (labial/buccal or vestibular mucosa) distant from the site of injections, suggestive of filler migration. Five of 21 cases presented with pain. Histopathologically, CHA presented as a diffuse mass of mauve-gray or beige, nonrefractile spherules, and PLA as rice- or spindle-shaped, geometric, refractile bodies within circumscribed nodules. CONCLUSIONS Cutaneous injections of CHA and PLA fillers may induce granulomatous reactions presenting as intraoral nodules distant from the injection sites.

Localized mandibular enlargement in end-stage renal disease: two case reports and a review of the literature.

Enlargement of the jaws is an infrequently reported complication of chronic kidney disease mineral and bone disorder (CKD-MBD). Two cases of localized mandibular swellings in young patients with histories of end-stage renal disease are discussed with a review of the literature. Although 17 of the first 19 cases that were reported exhibited diffuse enlargement, these reports increase the number of localized swellings to 8 and support the contention that localized expansion of the jaws as a manifestation of CKD-MBD is more common than originally recognized.

Keratosis of unknown significance and leukoplakia: a preliminary study.

OBJECTIVE The objectives were to (1) determine the frequency of specific diagnoses in a series of white lesions, and (2) describe the nature of keratotic lesions that are neither reactive nor dysplastic. STUDY DESIGN White lesions were analyzed and diagnosed as reactive keratoses, dysplastic/malignant, or keratoses of unknown significance (KUS). RESULTS Of the 1251 specimens that were evaluated, 703 met criteria for inclusion, and approximately 75% were reactive, 10% dysplastic/malignant, and 14% KUS. Excluding reactive keratoses, 43% were dysplastic/malignant and 57% were KUS. CONCLUSIONS Reactive keratoses were the most common white lesions followed by lichen planus. Dysplastic/malignant lesions constituted almost 50% of all true leukoplakias. KUS constituted the remaining cases and do not show typical reactive histopathology as well as clear dysplasia. They may represent evolving or devolving reactive keratoses but may also represent the very earliest dysplasia phenotype. Clinical findings may be helpful in differentiating the two.

Clinical Pathologic Conference Case 3: Nodular Fasciitis

Intraoral nodular nodular fasciitis is a rare entity that is important to recognize because it may simulate a malignancy clinically and histologically. The rapid growth and high mitotic index seen in nodular fasciitis may suggest a malignant neoplastic process, but it is generally considered to be a benign reactive proliferation. Recognizing the unique histologic features of nodular fasciitis is important to avoid a possible misdiagnosis as a malignancy, leading to unnecessary further treatment.

HPV-16 in a distinct subset of oral epithelial dysplasia

Human papillomavirus (HPV) 16 is the most common high-risk HPV type identified in oropharyngeal and cervical neoplasia. Recently, HPV-associated oral epithelial dysplasia with specific histopathologic features and demographics similar to HPV-oropharyngeal carcinoma has been identified. The objective of this study was to evaluate histopathologically all cases of HPV-oral epithelial dysplasia seen in one center and identify HPV types in a subset of cases. Cases with specific histopathology for HPV-oral epithelial dysplasia that were positive both by immunohistochemical studies for p16 and by in situ hybridization for high-risk types of HPV were further analyzed using QIAamp DNA Tissue Kits (Qiagen, Hilden, Germany). DNA was extracted, amplified, and digested with restriction enzymes and run on a polyacrylamide gel. Digestion patterns were visually compared with a database of known HPV digestion patterns for identification. There were 53 specimens included in the analysis. There were 47 males and six females (7.8:1), with a median age of 55 years (range 41–81). The most common site of involvement was the tongue/floor of mouth (77% of cases). Of the 53 cases, 94% exhibited parakeratosis and/or hyperkeratosis. All the cases featured karyorrhexis, apoptosis, and characteristics of conventional carcinoma in situ. The quantity of DNA extracted was sufficient for analysis in 22 cases. HPV-16 was identified in 20/22 (91%) cases. One case was associated with HPV-33 and one with HPV-58 (5% each). Eight of the 53 cases (15%) were associated with invasive squamous cell carcinomas.