Evaluation of EWSR1/FUS rearrangements by FISH and NKX2.2 immunoexpression in simple bone cysts of the jaw.

OBJECTIVE: Recent studies have identified recurrent rearrangements of EWSR1 or FUS with NFATC2 in extragnathic simple bone cysts (SBCs). We investigated the presence of EWSR1 or FUS rearrangements and the immunophenotypic expression of NKX2.2 and CD99 in a series of SBCs of the jaw. STUDY DESIGN: We retrieved 10 cases of SBC of the jaw from the University of Pittsburgh archives. Of the 10 cases, we were able to evaluate 8 by immunohistochemistry for CD99 and NKX2.2 and 7 by fluorescence in situ hybridization (FISH) for EWSR1 and FUS rearrangement using EWSR1 and FUS break-apart probes. RESULTS: All 8 cases evaluated by immunohistochemistry expressed CD99 but were negative for NKX2.2, and all 7 cases assayed using FISH were negative for EWSR1 and FUS rearrangements. CONCLUSIONS: In contrast to the SBC of extragnathic sites, we found no presence of EWSR1 and FUS rearrangements by FISH in the SBC of the jaw, suggesting that this entity may be etiologically/molecularly distinct and reflects a non-neoplastic reactive process. However, as these lesions tend to be paucicellular, FISH may not be the appropriate technique for identifying EWSR1/FUS fusions. Other techniques should be used to evaluate them in future studies.

Pediatric Oral Pathology: Odontogenic Cysts.

Cysts encountered in the head and neck typically arise from epithelium that would normally be programmed to form teeth or tooth-supporting structures (odontogenic epithelium). These cysts come with a confusing array of similar-sounding names and histopathologic features that are sometimes shared between conditions. Here we describe and contrast the relatively-common lesions: hyperplastic dental follicle, dentigerous cyst, radicular cyst, buccal bifurcation cyst, odontogenic keratocyst, glandular odontogenic cyst, and the less-common gingival cyst of the new-born and thyroglossal duct cyst. The goal of this review is to help clarify and simplify these lesions for the general pathologist, pediatric pathologist, and surgeon.

Clinicopathologic Study of Sialadenoma Papilliferum of the Minor Salivary Glands: A Series of 8 New Cases With BRAF V600E Mutation-specific Immunohistochemical Analysis.

Introduction. Sialadenoma papilliferum (SP) is a rare benign neoplasm that usually arises in the minor salivary glands. Recently, it was demonstrated that SP shares similar molecular genetic alterations (BRAF V600E or HRAS mutations) with its morphologic analog, syringocystadenoma papilliferum. Methods. We sought to perform clinicopathologic and immunophenotypic (BRAF V600E and SOX10) analyses on 8 new cases of SP. Results. The cases were from 4 males and 4 females, with ages ranging from 28 to 81 years (average: 64 years). The common locations were the hard palate (n = 3) and buccal mucosa (n = 3). Histopathologically, 7 cases were classic and 1 case was oncocytic. BRAF V600E immunohistochemistry (IHC) was positive in all classic SP, involving both the exophytic and endophytic components, but negative in the oncocytic SP. SOX10 was positive in the endophytic ductal cells of the evaluated classic SP but was negative in the oncocytic SP. Conclusions. We report 8 new cases of this rare salivary gland neoplasm, using BRAF V600E and SOX10 IHC to further support the following points: (1) the functional role of BRAF V600E mutation, RAS/mitogen-activated protein kinase signaling pathway in the pathogenesis of classic SP of salivary glands by IHC; (2) the analogous relationship between SP, syringocystadenoma papilliferum, and papillary seromucinous adenocarcinoma with sinonasal papilloma-like surface component (PSASP-like surface); (3) endophytic ductal component in classic SP arises from the intercalated ducts and not the excretory ducts; and (4) oncocytic SP is distinct from classic SP.

MAML2-Rearranged Mucoepidermoid Carcinoma of the Parotid Gland: A Report in a 20-Month-Old Toddler.

Malignancies of salivary gland origin are rare in children. Mucoepidermoid carcinoma (MEC) is the most common histologic type of salivary gland neoplasm in pediatrics. We report a rare case of parotid MEC in a 20-month-old female patient. The tumor was composed of nests of epidermoid cells with nuclei appearing vesicular, pleomorphic, and hyperchromatic with an admixture of mucous cells and cystic spaces within a prominent connective tissue stroma. Immunohistochemically, the epidermoid cells showed cytokeratin 7 and P63 positivity, and mucous cells were positive for mucicarmine. Molecularly, this case was positive for MAML2 rearrangement by FISH. To our knowledge, this is one of the youngest cases of MEC of the parotid gland reported in the English literature.

HMGA2 Immunoexpression is frequent in salivary gland pleomorphic adenoma: immunohistochemical and molecular analyses of PLAG1 and HMGA2 in 25 cases.

The main oncologic events in pleomorphic adenoma (PA) are the translocations of Pleomorphic adenoma gene 1 (PLAG1) on chromosome 8q12 and High-mobility group AT-hook 2 (HMGA2) on chromosome 12q14.3 with various fusion partners. These translocations result in the transcriptional up-regulation of PLAG1 and HMGA2 proteins. We carried out a preliminary evaluation of PLAG1 translocation by fluorescence in-situ hybridization (FISH), immunohistochemistry (IHC) and HMGA2 IHC on twenty-five archived formalin-fixed paraffin-embedded tissues of PAs and its clinicopathologic features. Only eight cases were successfully hybridized and 50% of the interpretable cases were considered positive for PLAG1 translocation. PLAG1 IHC was only positive in 2 (8%) of the 25 cases stained, including one of the positive PLAG1 translocation cases. HMGA2 IHC was positive in 12 (48%) of the 25 cases stained including 2 (50%) of the 4 cases identified with PLAG1 translocation by FISH, 3 (75%) of the 4 cases negative for PLAG1 translocation by FISH and 7 (41%) of the 17 cases with failed hybridization. Overall, 15 (60%) of the 25 PA cases demonstrated PLAG1 and/or HMGA2 alterations confirmed either by FISH or IHC. In conclusion, PLAG1 and HMGA2 alterations were confirmed either by FISH or IHC in this cohort and HMGA2 alteration is a common event in PAs of salivary gland.

Clear Cell Odontogenic Carcinoma of the Mandible Harboring EWSR1 Rearrangement: Report of a Massive Jaw Tumor and Review of Diagnostic Considerations.

Clear cell odontogenic carcinoma (CCOC) is a low-grade malignant neoplasm that affects the jaws. We report an 18 cm massive case of mandibular CCOC in a 43-year-old female. The tumor was composed of nests and cords of round to polygonal monomorphic clear cells separated by prominent stromal hyalinization. Immunohistochemically, the tumor cells showed focal cytokeratin 5/6 positivity and intracytoplasmic PAS-positive granules and were negative for S100 and after diastase treatment (PAS-D). Molecularly, this case was positive for EWSR1 rearrangement by FISH. The following should be included in the histopathological differential diagnosis: hyalinizing clear cell carcinoma of the salivary gland, clear cell variant of central mucoepidermoid carcinoma, clear cell variant of calcifying epithelial odontogenic tumor, and metastatic renal cell carcinoma. CCOC is a rare entity, with only 79 cases reported in the mandible. This case highlights the propensity for CCOC to exhibit invasiveness, destructive nature, and facial disfigurement if left untreated.

SATB2 and MDM2 Immunoexpression and Diagnostic Role in Primary Osteosarcomas of the Jaw.

Primary osteosarcomas of the jaw (OSJ) are rare, accounting for 6% of all osteosarcomas. This study aims to determine the value of SATB2 and MDM2 immunohistochemistry (IHC) in differentiating OSJ from other jawbone mimickers, such as benign fibro-osseous lesions (BFOLs) of the jaw or Ewing sarcoma of the jaw. Certain subsets of osteosarcoma harbor a supernumerary ring and/or giant marker chromosomes with amplification of the 12q13-15 region, including the murine double-minute type 2 (MDM2) and cyclin-dependent kinase 4 (CDK4) genes. Special AT-rich sequence-binding protein 2 (SATB2) is an immunophenotypic marker for osteoblastic differentiation. Cases of OSJ, BFOLs (ossifying fibroma and fibrous dysplasia) of the jaw, and Ewing sarcoma of the jaw were retrieved from the Departments of Oral Pathology and Oral Medicine, Faculty of Dentistry, Obafemi Awolowo University and Lagos State University College of Medicine, Nigeria. All OSJ retrieved showed histologic features of high-grade osteosarcoma. IHC for SATB2 (clone EP281) and MDM2 (clone IF2), as well as fluorescence in situ hybridization (FISH) for MDM2 amplification, were performed on all cases. SATB2 was expressed in a strong intensity and diffuse staining pattern in all cases (11 OSJ, including a small-cell variant, 7 ossifying fibromas, and 5 fibrous dysplasias) except in Ewing sarcoma, where it was negative in neoplastic cells. MDM2 was expressed in a weak to moderate intensity and scattered focal to limited diffuse staining pattern in 27% (3/11) of cases of OSJ and negative in all BFOLs and the Ewing sarcoma. MDM2 amplification was negative by FISH in interpretable cases. In conclusion, the three cases of high-grade OSJs that expressed MDM2 may have undergone transformation from a low-grade osteosarcoma (LGOS). SATB2 is not a dependable diagnostic marker to differentiate OSJ from BFOLs of the jaw; however, it could serve as a valuable diagnostic marker in differentiating the small-cell variant of OSJ from Ewing sarcoma of the jaw, while MDM2 may be a useful diagnostic marker in differentiating OSJ from BFOLs of the jaw, especially in the case of an LGOS or high-grade transformed osteosarcoma.

A clinicopathologic study of secretory carcinoma of minor salivary gland: a series of 4 cases and diagnostic considerations.

OBJECTIVE: Secretory carcinoma (SC) of salivary gland is a recently described low-grade malignant neoplasm of the salivary gland, characterized by rearrangement of the ETV6 gene. SC of salivary gland shares striking morphologic, immunophenotypic, and molecular similarity to SC of breast. STUDY DESIGN: We report the clinicopathologic features of 4 ETV6-rearranged SCs of minor salivary gland and histopathologic diagnostic considerations. RESULTS: Two cases were located in the lip, 1 in the soft palate, and 1 in the mandibular vestibule. No patient presented with regional or distant metastases at diagnosis. All cases were positive for S100 protein and mammaglobin, and all cases were negative for p63. All cases were positive for ETV6 rearrangement. CONCLUSIONS: SC of the minor salivary glands are rare. Because of its shared histopathologic features with other salivary gland tumors, positivity for ETV6 gene rearrangements is recommended before rendering a diagnosis of SC of salivary gland.

MYB-NFIB Translocation by FISH in Adenoid Cystic Carcinoma of the Head and Neck in Nigerian Patients: A Preliminary Report.

Adenoid cystic carcinoma (AdCC) is a relatively rare malignancy of head and neck sites such as the salivary glands, lacrimal gland, sinonasal region, and pharynx and may arise in other exocrine glands. The oncologic event in AdCC is the translocation between MYB proto-oncogene transcription factor (MYB) and nuclear factor I/B (NFIB) resulting in t(6;9)(q22-23;p23-24). We carried out a preliminary evaluation of MYB-NFIB translocation by fluorescence in-situ hybridization on seven archived formalin-fixed paraffin-embedded tissues of AdCC of Nigerian patients and its clinicopathologic features. Only 3 of the 7 cases were successfully hybridized, all featuring MYB-NFIB translocations with a range of 14.7-83.3% of translocated cells in 60 cells examined. The 3 translocation positive cases were located in the maxillary sinus, buccal mucosa and parotid. Their morphologic appearances were cribriform-solid (1) & cribriform (2) and classified as grades III (1) & I (2), respectively. These patients may potentially benefit from MYB-targeted anti-neoplastic therapy.

BRAF V600E mutation-specific immunohistochemical analysis in ameloblastomas: a 44-patient cohort study from a single institution.

PURPOSE: The aim of this study is to investigate the presence and prevalence of BRAF V600E mutation in ameloblastomas using anti-BRAF V600E monoclonal antibody (VE1 clone) and to identify any clinicopathologic correlation with BRAF V600E mutation in ameloblastoma. MATERIALS AND METHODS: The pathology files of the Department of Oral Pathology and Oral Medicine, Faculty of Dentistry, Lagos State University College of Medicine, Lagos, Nigeria, were searched for the diagnosis of ameloblastoma from 2016 to 2020. Archived non-decalcified formalin-fixed paraffin-embedded tissue underwent immunohistochemistry using anti-BRAF V600E antibody at the University of Pittsburgh, Pennsylvania. Clinicopathologic data such as age at diagnosis, gender, jaw bone involved (mandible or maxilla), tumor location (anterior or posterior) and histologic subtype were collected. The clinicopathologic parameters were analyzed using Chi-square test and Fisher's exact test according to the BRAF status. RESULTS: Forty-four cases of ameloblastoma were retrieved. The male to female ratio was 1.32:1. The average age of patients at diagnosis was 33.3 years. Thirty-nine cases were located in the mandible and 5 cases in the maxilla. Only cases in the mandible were positive for anti-BRAF V600E antibody (n = 15/39; 38.5%). There was a significant correlation between BRAF V600E expression in mandibular tumors and histologic subtype (p = 0.02); however, no significance was observed for gender, age and tumor location. CONCLUSION: BRAF V600E mutation preferentially occurs in mandibular ameloblastomas, especially in non-plexiform ameloblastomas. These patients may benefit therapeutically from the use of BRAF inhibitors.

Intraoral Herniation of a Sinonasal Polyp: An Underreported Complication of Maxillary Extraction?

PURPOSE: The aim of the present study was to increase awareness of an underreported surgical complication by presenting the relevant findings of cases of herniated oroantral sinonasal polyp (OASNP) identified from our biopsy service and from previously reported cases. MATERIALS AND METHODS: The present study was a retrospective descriptive case series with a review of the reported data. Cases of OASNP were identified from our biopsy service, and the clinical, radiographic, surgical, and demographic information was retrieved. Previously reported cases of OASNP were also reviewed. RESULTS: We identified 14 cases of OASNP in our biopsy service and an additional 10 reported cases. Overall, OASNP was more prevalent in males (71%). The age range was 19 to 85 years (overall mean, 46.6 years; median, 43.5 years). OASNP typically presented as a red polypoid mass that was frequently pedunculated with a smooth or granular surface. The lesions were located on the maxillary alveolus in the molar region. The most commonly implicated tooth was a maxillary first molar (74%). In some cases, the OASNP had been mistaken for a tumor or pyogenic granuloma. Almost all were at least 1 cm in the greatest dimension, with 43% measuring at least 2 cm in size, and 1 lesion reaching 5 cm in diameter. The reported period for development of the lesion ranged from 2 days to 5 years, with 60% developing within 2 months of the extraction. All lesions had undergone surgical excision. Antibiotic use and surgical closure of the oroantral communication had been described for some of the cases. CONCLUSIONS: The results from our study suggest that herniation of a sinonasal polyp through an oroantral defect could be an underreported complication of maxillary exodontia. Additional research would help to enhance our knowledge and understanding of this interesting condition.

Inhibition of Pro-inflammatory and Anti-apoptotic Biomarkers during Experimental Oral Cancer Chemoprevention by Dietary Black Raspberries.

Oral cancer continues to be a significant public health problem worldwide. Recently conducted clinical trials demonstrate the ability of black raspberries (BRBs) to modulate biomarkers of molecular efficacy that supports a chemopreventive strategy against oral cancer. However, it is essential that a preclinical animal model of black raspberry (BRB) chemoprevention which recapitulates human oral carcinogenesis be developed, so that we can validate biomarkers and evaluate potential mechanisms of action. We therefore established the ability of BRBs to inhibit oral lesion formation in a carcinogen-induced rat oral cancer model and examined potential mechanisms. F344 rats were administered 4-nitroquinoline 1-oxide (4NQO) (20 µg/ml) in drinking water for 14 weeks followed by regular drinking water for 6 weeks. At week 14, rats were fed a diet containing either 5 or 10% BRB, or 0.4% ellagic acid (EA), a BRB phytochemical. Dietary administration of 5 and 10% BRB reduced oral lesion incidence and multiplicity by 39.3 and 28.6%, respectively. Histopathological analyses demonstrate the ability of BRBs and, to a lesser extent EA, to inhibit the progression of oral cancer. Oral lesion inhibition by BRBs was associated with a reduction in the mRNA expression of pro-inflammatory biomarkers Cxcl1, Mif, and Nfe2l2 as well as the anti-apoptotic and cell cycle associated markers Birc5, Aurka, Ccna1, and Ccna2. Cellular proliferation (Ki-67 staining) in tongue lesions was inhibited by BRBs and EA. Our study demonstrates that, in the rat 4NQO oral cancer model, dietary administration of BRBs inhibits oral carcinogenesis via inhibition of pro-inflammatory and anti-apoptotic pathways.

Seven Cases of Proliferative Verrucous Leukoplakia: The Need for a High Clinical Suspicion Among Dental Practitioners.

Proliferative verrucous leukoplakia is a distinct precancerous condition with a high rate of recurrence and malignant transformation over time. Proliferative verrucous leukoplakia has no specific histopathologic presentation; therefore, emphases must be on clinical presentation and history to make a diagnosis giving the need for a high clinical suspicion. This condition is very important for the general dentist to recognize. Here we describe the clinical and microscopic features of seven cases of proliferative verrucous leukoplakia, with two cases which demonstrated malignant transformation (hybrid carcinoma and squamous cell carcinoma).

7 Cases of Proliferative Verrucous Leukoplakia: The Need for a High Clinical Suspicion Among Dental Practitioners. .

Proliferative verrucous leukoplakia is a distinct precancerous condition with a high rate of recurrence and malignant transformation over time. Proliferative verrucous leukoplakia has no specific histopathologic presentation; therefore, emphases must be on clinical presentation and history to make a diagnosis; giving the need for a high clinical suspicion. This condition is very important for the general dentist to recognize. Here we describe the clinical and microscopic features of seven cases of proliferative verrucous leukoplakia, with two cases which demonstrated malignant transformation (hybrid carcinoma and squamous cell carcinoma).

Orofacial dermal fillers: foreign body reactions, histopathologic features, and spectrometric studies.

OBJECTIVE: The aim of this study is to assess the different histopathologic presentations of dermal filler materials-induced foreign body reactions by spectrometric analyses. STUDY DESIGN: Sixteen cases of dermal filler foreign body reactions in the orofacial region were retrieved from the 2006-2013 period. The histologic features were evaluated and categorized into 5 groups (I to V). Unstained deparaffinized sections of representative tissue from one case in each of groups I to IV were sent for spectrometric analysis, along with samples of 2 popular dermal fillers (Juvéderm and Radiesse). RESULTS: With the help of spectrometric analysis, we were able to correlate the histopathologic presentations with the specific type of dermal filler used.

Human papillomavirus in oral exfoliated cells and risk of head and neck cancer.

BACKGROUND: Human papillomavirus (HPV) has been associated with the development of head and neck cancers. In this study, we investigated whether the risk factors for head and neck cancer in relation to HPV infection are different from those in the absence of HPV infection and whether HPV detected in oral exfoliated cells is an independent predictor of head and neck cancer risk. METHODS: We conducted a case-control study in 201 head and neck cancer case patients and 333 control subjects, frequency matched for age and sex. Oral exfoliated cells and tumor tissue were evaluated for HPV using polymerase chain reaction and DNA sequencing to type HPV. Logistic regression was used to calculate odds ratios (ORs) for head and neck cancer with HPV infection and 95% confidence intervals (CIs), adjusted for age, tobacco use, and alcohol consumption. RESULTS: Oncogenic, or high-risk (HR), HPV types were detected in oral cells from 22.9% of case patients and 10.8% of control subjects. HPV16 was the most frequently detected type (19% versus 10% of case patients and control subjects, respectively). After adjusting for age, tobacco use, and alcohol consumption, the risk of head and neck cancer was statistically significantly greater in individuals with HPV-HR types (adjusted OR = 2.6, 95% CI = 1.5 to 4.2) but not in individuals with nononcogenic HPV types (adjusted OR = 0.8, 95% CI = 0.4 to 1.7) compared with HPV-negative individuals. Compared with individuals who were HPV-negative and did not use alcohol or tobacco, there was a statistically significant synergistic effect between detection of HPV-HR and heavy alcohol consumption (OR = 18.8, 95% CI = 5.1 to 69.5) but an additive effect between detection of HPV-HR and tobacco use (OR = 5.5, 95% CI = 2.1 to 14.1). HPV-HR types detected in oral exfoliated cells were predictive of HPV-HR types in tumor tissue. CONCLUSION: Infection of oral exfoliated cells with HPV-HR types is a risk factor for head and neck cancer, independent of alcohol and tobacco use, and acts synergistically with alcohol consumption. HPV testing of an oral rinse may be predictive of an HPV-related head and neck cancer.