Unusual case of extramammary Paget disease of the oral mucosa: A case report and literature review.

Paget disease is an intraepithelial neoplastic proliferation, commonly occurring in the breast and apocrine-rich areas, often associated with an underlying internal malignancy. Extramammary Paget disease (EMPD) of the oral cavity is exceedingly rare, with only eight reported cases, four of which were associated with an underlying internal malignancy. Here, we report a case of oral EMPD involving the buccal mucosa and gingiva of an 81-year-old male with no known underlying internal malignancy. The Paget cells were positive for CK7, CK20, CAM5.2, and androgen receptor, but negative for SOX10 and p63. The immunophenotype, association with internal malignancies, and treatment approaches for oral EMPD are reviewed.

Bizarre Parosteal Osteochondromatous Proliferation (Nora's Lesion) of Mandible With Recurrence: Case Report and Review of Literature.

Bizarre parosteal osteochondromatous proliferation (BPOP) is a rare benign lesion exhibiting radiographic and histologic features that can be mistaken for malignancy. Most cases have been reported in the small tubular bones of the hands and feet, but involvement of the skull and jaws is extremely rare. Here, we present a case of BPOP involving the mandible in a 23-year-old male that, after initial excision, recurred within 18 months. To the best of our knowledge, this is only the third published case of BPOP arising in the mandible.

Neuropathic Pain in the Eyes, Body, and Mouth: Insights from the Sjögren's International Collaborative Clinical Alliance.

OBJECTIVE: To evaluate how ocular, oral, and bodily neuropathic pain symptoms, which characterize small fiber neuropathies, are associated with Sjögren's syndrome (SS) classification based on the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) criteria. METHODS: Participants enrolled in the Sjögren's International Collaborative Clinical Alliance (SICCA) registry had ocular, rheumatologic, oral, and labial salivary gland (LSG) biopsy examinations, blood and saliva samples collected, and completed questionnaires at baseline. We used mixed effects modeling with age, country, gender, and depression being fixed effects and study site, a random effect, to determine if neuropathic pain indicators (assessed via questionnaires) were associated with being classified as SS. RESULTS: A total of 3,514 participants were enrolled into SICCA, with 1,541 (52.9%) meeting the 2016 ACR/EULAR classification criteria for SS. There was a negative association between being classified as SS and experiencing bodily neuropathic pain features of needle-like pain, prickling/tingling sensation, ocular neuropathic pain of constant burning, and constant light sensitivity, and having a presumptive diagnosis of neuropathic oral pain. CONCLUSIONS: We found that those classified as SS had lower scores/reports of painful neuropathies compared with those classified as non-SS. Non-SS patients with dry eye disease or symptoms could benefit from pain assessment as they may experience painful small-fiber neuropathies (SFNs). Pain questionnaires may help identify pain associated with SFNs in patients with SS and non-SS dry eye. Future studies would be helpful to correlate self-reports of pain to objective measures of SFNs in those with SS, non-SS dry eye, and healthy controls.

Localized juvenile spongiotic gingival hyperplasia: A report of 27 cases.

BACKGROUND: Localized juvenile spongiotic gingival hyperplasia (LJSGH) is a poorly understood but distinctive inflammatory hyperplasia occurring in children and young adults. Fewer than 100 cases have been reported since its initial description. METHODS: During the period of 2015 to 2018, cases of LJSGH were identified, retrieved and their clinical and histopathological data reviewed. RESULTS: There were 27 cases, with a median age of 13 years (range 7-72 years). Twenty-four of 27 patients were less than 20 years old, and in three cases the patients were over 60 years of age. The most commonly affected site was the anterior maxillary gingiva presenting as a solitary, red, and papillated lesion. Typical microscopic findings included elevated areas of variably acanthotic, spongiotic nonkeratinized epithelium with elongated rete ridges, accompanied by a neutrophilic-rich infiltrate. An abrupt transition between epithelium affected by LJSGH and normal mucosa was characteristic. LJSGH typically exhibited full-thickness epithelial expression of CK19 without expression of estrogen and progesterone receptors. CONCLUSIONS: The clinical and histopathologic characteristics of LJSGH are unique and consistent. Despite the name, the condition is not limited to juveniles and can occur in adults. LJSGH in adults and juveniles shares the same spectrum of histopathologic and immunohistochemical findings.

PHACES syndrome and multi-regional odontodysplasia: a case report.

PHACES syndrome is an acronym for the syndromic presentation of Posterior fossa malformation, Hemangioma, Arterial anomalies, Coarctation of aorta/cardiac defects, Eye abnormalities and Sternal malformations. Infantile hemangiomas are the most common tumors of infancy. Regional odontodysplasia, commonly referred to as "ghost teeth", is a rare localized developmental malformation of enamel and dentin with varying levels of severity that results in unusual clinical and radiographic appearances of affected teeth. This report describes a rare case of a two-year-old Caucasian male diagnosed with PHACES syndrome also presenting with multi-regional odontodysplasia. Ten of twenty teeth were dysplastic. The patient was treated under general anesthesia in a hospital setting. All affected primary teeth were extracted due to sensitivity, abscess and extremely poor long-term prognosis. Moving forward, a long-term interdisciplinary approach will be necessary to address this child's dentition as it develops.

Giant cell lesions of the jaws: does the level of vascularity and angiogenesis correlate with behavior?

PURPOSE: To compare vascularity and angiogenic activity in aggressive and nonaggressive giant cell lesions (GCLs) of the jaws. MATERIALS AND METHODS: This is a retrospective study of 14 GCLs treated at the University of California, San Francisco. Immunohistochemistry was used to determine of the expression of vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), CD34, and CD31. VEGF and bFGF expression in giant cells (GCs) and surrounding mononuclear stroma was classified into 1) high immunoreactivity (>50% staining) and 2) low immunoreactivity (<50% staining). CD31- and CD34-stained vessels were counted at 200× magnification. Clinical and radiographic records were reviewed to classify lesions as aggressive or nonaggressive. RESULTS: Of the lesions, 8 were aggressive and 6 were nonaggressive. High VEGF expression was found within the GCs in 4 of 8 aggressive lesions compared with 1 of 6 nonaggressive lesions. The stroma in both groups had low staining. High staining of the GCs for bFGF was found in 6 of 8 aggressive lesions compared with 3 of 6 nonaggressive lesions. The stroma of all aggressive cases showed high expression of bFGF compared with 3 of 6 nonaggressive cases. The aggressive group had a mean of 20.1 ± 5.4 vessels/high-powered field (hpf) stained for CD31 compared with 11.5 ± 5.6 vessels/hpf in the nonaggressive group. The aggressive group had 24.6 ± 7.0 vessels/hpf stained with CD34 compared with 18.5 ± 4.0 vessels/hpf in the nonaggressive group. CONCLUSIONS: The vascularity and level of angiogenesis within aggressive GCLs are higher than those in nonaggressive lesions.

Gene Expression Profiling of Head and Neck Tumors Identifies FOXP1 and SOX10 Expression as Useful for Distinguishing Ameloblastoma From Basaloid Salivary Gland Tumors.

Odontogenic tumors show considerable morphologic heterogeneity and at times the diagnosis can be challenging. Ameloblastoma, the most common odontogenic tumor, can have morphologic similarity to some salivary gland tumors and therefore we sought to identify biomarkers that might aid in the diagnosis by performing transcriptome wide gene expression profiling of 80 odontogenic and salivary gland neoplasms. These data identified the FOXP1/SOX10 expression profile as characteristic of many odontogenic tumors including ameloblastoma but largely absent in salivary gland tumors. We then assessed 173 salivary gland tumors and 108 odontogenic tumors by immunohistochemistry for FOXP1 and SOX10 expression and found that 34/35 (97%) cases of ameloblastomas were diffusely positive for FOXP1 but completely negative for SOX10. None of the basaloid salivary neoplasms (basal cell adenoma, adenoid cystic carcinoma, polymorphous adenocarcinoma, and myoepitheloma) demonstrated FOXP1/SOX10 expression pattern. Taken together, the results of this study suggest that the FOXP1/SOX10 immunophenotype is common in odontogenic tumors including ameloblastoma and might be useful distinguishing these from similar appearing basaloid salivary gland tumors.

Elevated salivary endothelin levels in oral cancer patients--a pilot study.

The analysis of saliva has been proposed as a potentially rapid, non-invasive method to monitor and diagnose patients with oral disease. In this study we measured salivary endothelin-1 (ET-1) levels in patients diagnosed with oral squamous cell carcinoma (SCC) prior to treatment. We demonstrate significantly elevated salivary ET-1 levels in the oral SCC group (4.37+/-1.35pg/ml), relative to the control group (1.16+/-0.29pg/ml). ET-1 and ET-1 mRNA were also measured in oral SCC tissue specimens and compared to normal oral epithelial controls. The concentration of ET-1 in the oral SCC specimens was 17.87+/-4.0pg/ml and in the normal epithelial controls the concentration of ET-1 was 5.43+/-2.5pg/ml. ET-1 mRNA was significantly overexpressed in 80% (8/10) of the oral SCC specimens. Our results demonstrate the potential utility of salivary analysis for ET-1 levels to monitor patients at risk for oral SCC.

Racial disparity in stage at diagnosis and survival among adults with oral cancer in the US.

OBJECTIVES: To explore distribution of stage at diagnosis and relative survival rates among US adults with oral cavity cancer in relation to race, and over time. METHODS: We obtained 1973-2002 oral cancer incidence data from the Surveillance, Epidemiology, and End Results (SEER) Program, and computed proportions for each oral cavity site by stage at diagnosis, tumor size, and 5-year relative survival rates among Whites and Blacks. RESULTS: A total of 46 855 cases of oral cavity cancer were reported to the SEER registry among adults > or =20 years between 1973 and 2002. African-Americans had a significantly higher proportion of cancer, mainly in the tongue, that had spread to a regional node or to a distant site at diagnosis than Whites: 67% versus 49% of tongue cancers reported from 1973 to 1987 (P < 0.001), and 70% versus 53% of those reported from 1988 to 2002 (P < 0.001). They had a significantly higher proportion of tongue cancer that were >4 cm in diameter at time of diagnosis (59% versus 44%; P < 0.001), and black men in particular experienced lower 5-year relative survival rates than white men, in particular, for tongue cancer (25% versus 43% from 1973 to 1987, and 31% versus 53% from 1988 to 2002). CONCLUSION: There are significant racial disparities with respect to stage at diagnosis and survival among adults with oral cancer reported to the SEER registry from 1973 to 2002. One possible explanation for the lower survival among Blacks may be a difference in access to, and utilization of, healthcare services.

DNA promoter hypermethylation in saliva for the early diagnosis of oral cancer.

Oral health care professionals could drastically improve the quality of life for patients with potentially malignant oral lesions by using a noninvasive test that could be used to detect cancer using saliva. Promoter DNA hypermethylation is a critical step in oral carcinogenesis and has a number of significant advantages over genetic and protein diagnostic markers. Methylight is a recently developed assay that rapidly quantifies promoter hypermethylation and could potentially be applied into a clinical setting.

Gingival pustules and sterile diffuse sclerosing osteomyelitis as a feature of synovitis, acne, pustulosis, hyperostosis, osteitis (SAPHO) syndrome.

Synovitis, acne, pustulosis, hyperostosis, osteitis (SAPHO) syndrome represents the rare co-occurrence of sterile inflammatory osteoarticular disease in association with a variety of cutaneous manifestations. Oral involvement is uncommon. The etiology of SAPHO is complex and is likely the combined result of infectious, genetic, and immunologic factors. Due to diverse clinical presentations, SAPHO is difficult to diagnose. Here, we describe the case of a 74-year-old man, who had a history of SAPHO syndrome and presented with gingival pustules and sterile diffuse sclerosing osteomyelitis of the mandible. This is the first case report describing neutrophilic mucositis as a feature of SAPHO.

Salivary transcriptome diagnostics for oral cancer detection.

PURPOSE: Oral fluid (saliva) meets the demand for noninvasive, accessible, and highly efficient diagnostic medium. Recent discovery that a large panel of human RNA can be reliably detected in saliva gives rise to a novel clinical approach, salivary transcriptome diagnostics. The purpose of this study is to evaluate the diagnostic value of this new approach by using oral squamous cell carcinoma (OSCC) as the proof-of-principle disease. EXPERIMENTAL DESIGN: Unstimulated saliva was collected from patients (n = 32) with primary T1/T2 OSCC and normal subjects (n = 32) with matched age, gender, and smoking history. RNA isolation was done from the saliva supernatant, followed by two-round linear amplification with T7 RNA polymerase. Human Genome U133A microarrays were applied for profiling human salivary transcriptome. The different gene expression patterns were analyzed by combining a t test comparison and a fold-change analysis on 10 matched cancer patients and controls. Quantitative polymerase chain reaction (qPCR) was used to validate the selected genes that showed significant difference (P < 0.01) by microarray. The predictive power of these salivary mRNA biomarkers was analyzed by receiver operating characteristic curve and classification models. RESULTS: Microarray analysis showed there are 1,679 genes exhibited significantly different expression level in saliva between cancer patients and controls (P < 0.05). Seven cancer-related mRNA biomarkers that exhibited at least a 3.5-fold elevation in OSCC saliva (P < 0.01) were consistently validated by qPCR on saliva samples from OSCC patients (n = 32) and controls (n = 32). These potential salivary RNA biomarkers are transcripts of IL8, IL1B, DUSP1, HA3, OAZ1, S100P, and SAT. The combinations of these biomarkers yielded sensitivity (91%) and specificity (91%) in distinguishing OSCC from the controls. CONCLUSIONS: The utility of salivary transcriptome diagnostics is successfully demonstrated in this study for oral cancer detection. This novel clinical approach could be exploited to a robust, high-throughput, and reproducible tool for early cancer detection. Salivary transcriptome profiling can be applied to evaluate its usefulness for other major disease applications as well as for normal health surveillance.

Tenascin and beta 6 integrin are overexpressed in floor of mouth in situ carcinomas and invasive squamous cell carcinomas.

Floor of the mouth squamous cell carcinomas exhibit many characteristics that suggest they represent a distinct biological subset within head and neck tumors. The features of preinvasive lateral intraepithelial spread, high rate of conversion of intraepithelial neoplasia to invasive carcinoma, and high incidence of occult metastases, suggest the importance of motility-associated proteins in the pathogenesis of these lesions. Two such proteins, tenascin and beta 6 integrin, are generally overexpressed in squamous carcinomas, and may play a central role in the invasive process of floor of the mouth lesions. The purpose of this study was to evaluate in situ and invasive squamous cell carcinomas from the floor of the mouth for the expression of tenascin and beta 6 integrin. Twenty lesions each of floor of the mouth in situ carcinomas and squamous cell carcinomas, and 10 normal controls were stained for tenascin and beta 6 using a standard immunohistochemical protocol for formalin-fixed specimens. Sections were assessed for staining intensity, pattern, and co-localization. Tenascin was highly expressed at the keratinocyte-connective tissue interface of both in situ and invasive carcinomas. beta 6 was expressed in basal keratinocytes of all in situ and invasive lesions, but was not evident in any of the control epithelia. There was no significant difference in staining of in situ and invasive carcinomas, but there was a significant difference in staining between these lesions and controls. Staining was colocalized in serial sections, supporting a receptor-ligand relationship. Both tenascin and beta 6 were weakly expressed in dysplastic areas adjacent to carcinomas suggesting that changes in the expression of these proteins occurs prior to the invasive phenotype. We conclude that tenascin and beta 6 are overexpressed in in situ and invasive floor of the mouth carcinomas, but that transgression of the basement membrane by neoplastic epithelial cells requires additional changes to the keratinocyte molecular profile.

Advanced diagnostic methods in oral and maxillofacial pathology. Part II: immunohistochemical and immunofluorescent methods.

The practice of pathology is currently undergoing significant change, in large part due to advances in the analysis of DNA, RNA, and proteins in tissues. These advances have permitted improved biologic insights into many developmental, inflammatory, metabolic, infectious, and neoplastic diseases. Moreover, molecular analysis has also led to improvements in the accuracy of disease diagnosis and classification. It is likely that, in the future, these methods will increasingly enter into the day-to-day diagnosis and management of patients. The pathologist will continue to play a fundamental role in diagnosis and will likely be in a pivotal position to guide the implementation and interpretation of these tests as they move from the research laboratory into diagnostic pathology. The purpose of this 2-part series is to provide an overview of the principles and applications of current molecular biologic and immunologic tests. In Part I, the biologic fundamentals of DNA, RNA, and proteins and methods that are currently available or likely to become available to the pathologist in the next several years for their isolation and analysis in tissue biopsies were discussed. In Part II, advances in immunohistochemistry and immunofluorescence methods and their application to modern diagnostic pathology are reviewed.

Low etiologic fraction for high-risk human papillomavirus in oral cavity squamous cell carcinomas.

BACKGROUND: Human papillomavirus (HPV) is a cause of oropharyngeal cancer, but a role for HPV in the etiology of oral cavity squamous cell carcinomas (OCSCC) remains uncertain. METHODS: We sought to estimate the etiologic fraction for HPV among consecutive, incident OCSCC diagnosed from 2005 to 2011 at four North American hospitals. DNA and RNA purified from paraffin-embedded tumors were considered evaluable if positive for DNA and mRNA control genes by quantitative PCR. Fifteen high-risk (HR) HPV types were detected in tumors by consensus PCR followed by type-specific HR-HPV E6/7 oncogene expression by quantitative reverse-transcriptase PCR. P16 expression was evaluated by immunohistochemistry (IHC). A study of 400 cases allowed for precision to estimate an etiologic fraction of as low as 0% (97.5% confidence interval, 0-0.92%). RESULTS: Of 409 evaluable OCSCC, 24 (5.9%, 95%CI 3.6-8.2) were HR-HPV E6/7 expression positive; 3.7% (95%CI 1.8-5.5) for HPV16 and 2.2% (95%CI 0.8-3.6) for other HR-HPV types. HPV-positive tumors arose from throughout the oral cavity (floor of mouth [n=9], anterior tongue [6], alveolar process [4], hard palate [3], gingiva [1] and lip [1]) and were significantly associated with male gender, small tumor stage, poor tumor differentiation, and basaloid histopathology. P16 IHC had very good-to-excellent sensitivity (79.2%, 95%CI 57.9-92.9), specificity (93.0%, 95%CI 90.0-95.3), and negative-predictive value (98.6%, 95%CI 96.8-99.6), but poor positive-predictive value (41.3%, 95%CI 27.0-56.8) for HR-HPV E6/7 expression in OCSCC. CONCLUSION: The etiologic fraction for HR-HPV in OCSCC was 5.9%. p16 IHC had poor positive predictive value for detection of HPV in these cancers.

Clinical signs and histologic findings in dogs with odontogenic cysts: 41 cases (1995-2010).

OBJECTIVE: To characterize clinical signs and histologic findings in dogs with odontogenic cysts and determine whether histologic findings were associated with clinical features. DESIGN: Retrospective case series. ANIMALS: 41 dogs. PROCEDURES: Medical records were reviewed to obtain clinical data, including breed, age, sex, and lesion location. Microscopic sections and results of diagnostic imaging were reviewed. RESULTS: Odontogenic cysts were identified in 41 dogs between 1995 and 2010. There were 29 dogs with dentigerous cysts, 1 with a radicular cyst, 1 with a lateral periodontal cyst, and 1 with a gingival inclusion cyst. In addition, 9 dogs with odontogenic cysts that had clinical and histologic features suggestive of, but not diagnostic for, odontogenic keratocysts seen in people were identified. In all 9 dogs, these cysts were located in the maxilla and surrounded the roots of normally erupted teeth. Of the 29 dogs with dentigerous cysts, 23 had a single cyst, 5 had 2 cysts, and 1 had 3 cysts. Six cysts were associated with an unerupted canine tooth, and 30 were associated with an unerupted first premolar tooth (1 cyst was associated both with an unerupted canine tooth and with an unerupted first premolar tooth). Dentigerous cysts were identified in a variety of breeds, but several brachycephalic breeds were overrepresented, compared with the hospital population during the study period. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that a variety of odontogenic cysts can occur in dogs. In addition, cysts that resembled odontogenic keratocysts reported in people were identified. We propose the term canine odontogenic parakeratinized cyst for this condition.

Patterns of second-opinion diagnosis in oral and maxillofacial pathology.

OBJECTIVES: Several studies have documented the beneficial effect of second opinions in diagnostic pathology. Among disease sites, the head and neck can be a particularly problematic area for pathologists, prompting frequent second opinions. However, the effect of second opinion requests made by physician pathologists (PPs) to oral and maxillofacial pathologists (OMPs) has not been well studied and might identify disease and subsites that pose diagnostic challenges. The objectives of this study were to study the referral patterns of PPs to a referral center for oral and maxillofacial pathology and to assess changes in diagnosis following second opinion. STUDY DESIGN: We retrospectively reviewed 142 consecutive pathology consultation requests over a 2-year period. The submitted report and matched second opinion report were reviewed to extract predetermined demographic, clinical, and pathologic data. Each diagnosis was reviewed to determine if there was agreement, minor disagreement, or major disagreement between the original and the second opinion. RESULTS: The most common diagnostic categories sent for second opinion were dysplasia/carcinoma, odontogenic cysts, and odontogenic tumors. In the 135 cases where agreement could be assessed, there were a total of 46 cases (34.1%) with differences in diagnostic opinion. Minor disagreements occurred in 24 cases (17.8%) and major disagreements in 22 cases (16.3%). Importantly, major disagreements identified here would have resulted in significant differences in patient evaluation and management. CONCLUSIONS: This study supports the positive impact of second-opinion surgical pathology for lesions in the maxillofacial complex and supports the role of OMPs in subspecialty diagnostic pathology.

Rare oral cavity presentation of a B-cell lymphoblastic lymphoma. A case report and review of the literature.

Lymphoblastic lymphoma is an uncommon malignancy, with most cases showing a T-cell phenotype and presenting as a mediastinal mass. By contrast, B-cell lymphoblastic lymphoma/leukemia is a rare high-grade malignancy that comprises approximately 10% of all lymphoblastic lymphomas. Lymphomas of the oral cavity are rare and typically present as intraosseous lesions that are most commonly diffuse large B-cell type. Here we present what we believe is the first B-cell lymphoblastic lymphoma initially presenting in the oral cavity. The case involves a 46-year-old white woman who presented with a mass in the right mandible. This report discusses this rare malignancy, including clinical presentation, histopathologic features, immunologic profile, treatment, and prognosis. This case emphasizes the importance of recognizing rare entities that may present in the oral cavity and the impact of the disease and its management.