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Synovial sarcoma is a soft tissue malignancy harboring t(X;18) resulting in fusion of two genes SS8 (at 18q11) and SSX (1, 2 or 4 at Xp11) forming the gene fusion product SS18-SSX. It affects adults in their 3rd-4th decades, most frequently in the para-articular regions of the extremities. Less than 10% of the cases occur within the head and neck region and of these, 60% occur in the neck and only 10% occur in the oral cavity. We report a synovial sarcoma of the tongue in a 14-year-old female patient with unusual histology. The patient presented with a mass occupying most of the tongue with extension into the floor of mouth and the lingual gingiva of the anterior mandibular teeth. The tumor was composed of a highly cellular proliferation of spindle cells in a herringbone pattern with many small vessels but without glandular structures, and with extensive calcifications throughout the tumor. Tumor cells were positive for epithelial membrane antigen and transducin-like enhancer of split-1, and fluorescence in situ hybridization studies identified SS18 gene rearrangement. The patient was managed with two debulking procedures followed by chemoradiation and is currently alive with disease.

Oral leukoplakia is common and may, in some cases, progress to carcinoma. Proliferative leukoplakia is a progressive, often multifocal subtype with a high rate of malignant transformation compared with the more common localized leukoplakia. We hypothesized that the immune microenvironment and gene expression patterns would be distinct for proliferative leukoplakia compared with localized leukoplakia. We summarize key clinicopathologic features among proliferative leukoplakia and localized leukoplakia and compare cancer-free survival (CFS) between subgroups. We analyze immunologic gene expression profiling in proliferative leukoplakia and localized leukoplakia tissue samples (NanoString PanCancer Immune Oncology Profiling). We integrate immune cell activation and spatial distribution patterns in tissue samples using multiplexed immunofluorescence and digital image capture to further define proliferative leukoplakia and localized leukoplakia. Among N = 58 patients (proliferative leukoplakia, n = 29; localized leukoplakia, n = 29), only the clinical diagnosis of proliferative leukoplakia was associated with significantly decreased CFS (HR, 11.25; P < 0.01; 5-year CFS 46.8% and 83.6% among patients with proliferative leukoplakia and localized leukoplakia, respectively). CD8+ T cells and T regulatory (Treg) were more abundant among proliferative leukoplakia samples (P < 0.01) regardless of degree of epithelial dysplasia, and often colocalized to the dysplasia–stromal interface. Gene set analysis identified granzyme M as the most differentially expressed gene favoring the proliferative leukoplakia subgroup (log2 fold change, 1.93; Padj < 0.001). Programmed death ligand 1 (PD-L1) was comparatively overexpressed among proliferative leukoplakia samples, with higher (>5) PD-L1 scores predicting worse CFS (Padj < 0.01). Proliferative leukoplakia predicts a high rate of malignant transformation within 5 years of diagnosis. A prominent CD8+ T-cell and Treg signature along with relative PD-L1 overexpression compared with localized leukoplakia provides strong rationale for PD-1/PD-L1 axis blockade using preventative immunotherapy. Significance: This is the first in-depth profiling effort to immunologically characterize high-risk proliferative leukoplakia as compared with the more common localized leukoplakia. We observed a notable cytotoxic T-cell and Treg signature with relative overexpression of PD-L1 in high-risk proliferative leukoplakia providing a strong preclinical rationale for investigating PD-1/PD-L1 axis blockade in this disease as preventative immunotherapy.

Biologic agents are rapidly emerging as an effective therapy to treat autoimmune and other chronic diseases. The use of these agents is poorly characterized, resulting in a lack of guidance for dental practitioners. Case reports of oral adverse events have begun to emerge. However, their scope and frequency have not been summarized and analysed to date. The objective of this review was to characterize the literature on oral adverse effects associated with biological therapy when used for autoimmune and inflammatory disorders.This review was developed in accordance with scoping review recommendations. Search strategies were developed and employed for six databases. Studies were selected using a systematic search process but with broad inclusion of study types given the paucity of information available. Reports of oral adverse events were analysed descriptively according to agent, mechanism of action, underlying disease, and oral adverse effect observed.Our search returned 2080 articles and 51 met our inclusion criteria, of which most were case reports. The most frequent adverse effects included angioedema, oral lichenoid lesions, osteonecrosis of the jaw, and oral infections. There were also cases of oral malignancies associated with use of biologic agents. Less common effects such as pigmentation were also described.Oral adverse events have been reported in patients on biologic therapy, albeit in small numbers to date. This limits the generalizability of these results, which should not be used to generate a clinical guideline as they are based primarily on case reports. However, this study presents the first review characterizing the adverse effects observed. Large multi-center studies will be necessary to further define the oral and dental complications caused by biologic agents.

Introduction Immunotherapy with immune checkpoint inhibitors (ICIs) has transformed cancer treatment over the past decade, improving survival rates in numerous advanced cancers. Immune-related adverse events (irAEs) are common and can affect any organ system, with many of these toxicities being well-characterized with clear grading criteria and management approaches. There has been less emphasis on oral manifestations of irAEs. Objective This review provides an overview of oral manifestations of irAEs, including mucosal and salivary gland toxicities, and proposes a grading system and management guidelines. Conclusion irAEs are common treatment-related toxicities in patients treated with ICIs. Oral irAEs can range from asymptomatic white reticulations to life-threatening mucocutaneous reactions requiring aggressive management with corticosteroids and/or permanent discontinuation of ICIs. Oral healthcare providers should be prepared to identify and manage oral irAEs in collaboration with oncologists and other specialists.

Objective Oral hairy leukoplakia (OHL) is a benign Epstein-Barr virus infection typically presenting as a white lesion on the lateral border of the tongue. Historically, OHL was described in patients who are severely immunocompromised, such as those with HIV/AIDS and organ transplant patients. OHL is increasingly seen in patients who are not severely immunocompromised. This study reviews 45 cases of OHL in a single institution and characterizes the clinical features of these relatively immunocompetent patients. Study Design Retrospective study. Results There were 45 cases with 23 male patients (51.1%) and a median age of 64 (range, 24-100 years). The lateral/ventral tongue was the affected site in 41 cases (91.1%), and 5 cases presented bilaterally. A review of the medical history and medications showed the most common conditions were hypertension (53.3%), hyperlipidemia (42.2%), and chronic respiratory conditions (33.3%); 8 patients (17.8%) had diabetes mellitus, and 1 had rheumatoid arthritis. Eleven cases (24.4%) reported no underlying medical conditions or history of medications. The most frequently reported medications included antihypertensive drugs (21.0%), steroid inhalers (14.6%), and cholesterol-lowering drugs (11.0%). Conclusions OHL is not exclusively seen in profoundly immunocompromised patients. Localized immunosuppression (from steroid inhalers) and immunosenescence (aging) are possible contributing factors.

The presence of epithelial dysplasia (ED) in oral leukoplakia is the single most important predictor of malignant transformation (MT). The majority of leukoplakias, however, do not show evidence of ED and yet MT of these lesions is well-recognized. These lesions have been referred to as "hyperkeratosis/hyperplasia, no dysplasia," "keratosis of unknown significance" and "hyperkeratosis, not reactive (HkNR)." This study evaluates the MT rate of such leukoplakias. A literature review was performed to identify cohort studies on leukoplakias where (1) there was a recorded histopathologic diagnosis, (2) cases of "hyperkeratosis/hyperplasia, no dysplasia" comprised part of the cohort, and (3) follow-up information was available. There were 9,358 leukoplakias, of which 28.5% exhibited ED while 37.7% consisted of HkNR. Follow-up ranged from 15 to 73 months. The incidence of MT in leukoplakia exhibiting HkNR was 4.9%, compared to 15.3% for ED. Among oral squamous cell carcinomas (SCC) with previously biopsied, site-specific precursor lesions, 55.7% arose from ED/carcinoma in situ and 28.0% arose from HkNR. Leukoplakia exhibiting HkNR has a substantial MT rate, similar to that of mild ED, and must be recognized and managed appropriately to reduce oral SCC incidence.

BACKGROUND: Irritant contact stomatitis (ICS) and contact hypersensitivity stomatitis (CHS) are often caused by alcohol, flavoring agents and additives in dentifrices and foods, and contactants with high or low pH. A well-recognized contactant for ICS is Listerine™ mouthwash, while that for CHS is cinnamic aldehyde. However, many other flavoring agents and even smokeless tobacco are contactants that cause mucosal lesions that are entirely reversible. The objective of this study is to 1) present cases of ICS and CHS with a clear history of a contactant at the site and the histopathologic features of the resulting lesion and 2) define the histopathologic features that characterize such lesions. METHODS: 12 cases of ICS and CHS with known contactants that exhibited distinct histopathologic patterns were identified. RESULTS: ICS are characterized by three patterns in increasing order of severity namely: 1) superficial desquamation, 2) superficial keratinocyte edema, and 3) keratinocyte coagulative necrosis with/out spongiosis and microabscesses. CHS is characterized by two patterns namely plasma cell stomatitis with an intense plasma cell infiltrate and a lymphohistiocytic infiltrate with or without non-necrotizing granulomatous inflammation. Three patterns of the latter are recognized: (1) lymphohistiocytic infiltrate at the interface with well-formed or loosely aggregated non-necrotizing granulomas; (2) lymphohistiocytic infiltrate at the interface with peri- and para-vascular lymphohistiocytic nodules; and (3) lymphohistiocytic infiltrate at the interface with peri- and para-vascular lymphohistiocytic nodules containing non-necrotizing granulomas. The same contactant may elicit ICS and CHS, while one histopathologic pattern may be brought on by various contactants. CONCLUSION: ICS and CHS have distinct histologic patterns. Recognizing that these patterns are caused by contactants would help clinicians manage such mucosal lesions.

Objective The aim of this study was to characterize clinical and histopathological features, and management outcomes of patients with oral immune-related adverse events (irAEs) secondary to programmed cell death-1 (PD-1) inhibitors. Methods This was a case series of cancer patients receiving PD-1 inhibitor therapy who were referred to oral medicine for the development of oral irAEs. Demographic, clinical, and histopathological data were collected from electronic medical records. Results There were 13 patients (7 males) with a median age of 68 years (range: 39-82) who were treated with nivolumab (n = 7) or pembrolizumab (n = 6). Oral irAEs included lichenoid lesions (n = 10), erythema multiforme (EM) (n = 2), and acute graft-versus-host disease reactivation (n = 1), with or without ulcerations (n = 8). Four patients (31%) presented with only oral irAEs. Oral biopsies showed lichenoid mucositis (n = 4). Management with topical and systemic steroids led to complete symptomatic response in most patients (n = 12). PD-1 inhibitor therapy was temporarily discontinued (n = 3) and discontinued indefinitely (n = 2) due to severe oral irAEs. Conclusion Patients receiving PD-1 inhibitors may develop oral irAEs characterized by lichenoid lesions, ulcers, or EM. Topical and systemic steroids appear to be effective in managing oral lesions although the severity of irAEs may necessitate PD-1 inhibitor therapy dose modification.

Objectives Oral and oropharyngeal squamous cell carcinoma (SCC) is the 10th most common cancer in the United States (8th in males, 13th in females), with an estimated 54,010 new cases expected in 2021, and is primarily associated with smoked tobacco, heavy alcohol consumption, areca nut use and persistent high-risk human papillomavirus (HPV). Family history of cancer (FHC) and family history of head and neck cancer (FHHNC) have been reported to play an important role in the development of OSCC. We aimed to investigate the role of FHC, FHHNC and personal history of cancer in first/second degree-relatives as co-risk factors for oral cancer. Methods This was a retrospective study of patients diagnosed with OSCC at the Division of Oral Medicine and Dentistry at Brigham and Women’s Hospital and at the Division of Head and Neck Oncology at Dana Farber Cancer Institute. Conditional logistic regressions were performed to examine whether OSCC was associated with FHC and FHHNC of FDRs and SDRs, personal history of cancer and secondary risk factors. Results Overall, we did not find an association between FHC, FHHNC and OSCC risk, whereas patients with a cancer history in one of their siblings were 1.6-times more likely to present with an OSCC. When secondary risk factors were considered, patients with a history of oral leukoplakia and dysplasia had a 16-times higher risk of having an OSCC. Conclusions Our study confirmed that a previous history of oral leukoplakia or dysplasia was an independent risk factor for OSCC. A positive family history of cancer in one or more siblings may be an additional risk factor for OSCC.

A Man with Painful Mouth Ulcers A 68-year-old man was admitted with painful mouth ulcers and weight loss of 6 weeks’ duration. The ulcers had worsened despite treatment with acyclovir, prednisone, ...

Oral lichen planus (OLP) is a chronic inflammatory disease affecting oral mucosa. Its pathogenesis includes T cell infiltration. T cells may be naïve or in response to antigen stimulation, progress through differentiation stages. The differentiated states of T cells in OLP mucosa have not previously been reported.Available OLP microarray gene expression data from Gene Expression Omnibus were analyzed for markers of T cell cytotoxicity. Immunohistochemical studies of T cell subset markers CD4 and CD8 and the T cell differentiation marker killer cell lectin-like receptor G1 (KLRG1) were performed on paraffin embedded formalin fixed oral mucosa biopsy samples from 10 patients with OLP.Gene expression analysis of OLP oral mucosa samples disclosed increased transcript expression of KLRG1, CD8A, and granzyme K (GZMK). By immunohistochemistry, prominent CD4 + and CD8 + T cell infiltration was seen in all patient samples. KLRG1 + T cells were abundant, constituting a mean of 51% (range 40-65%) of the number of CD8 + T cells. KLRG1 + T cells localized at the epithelium and lamina propria junction, infiltrating both basal and intraepithelial regions and adjacent to both basal and intraepithelial keratinocytes.OLP oral mucosa T cell infiltration includes KLRG1 + highly differentiated cytotoxic T cells, suggesting continued antigen exposure driving T cells to a highly differentiated phenotype. The known phenotype of these cells, together with microarray detected increases in cytotoxic molecules, suggests that highly differentiated cytotoxic T cells contribute to oral mucosa injury in OLP.

The aim of this multicenter retrospective study is to characterize the histopathologic features of initial/early biopsies of proliferative leukoplakia (PL; also known as proliferative verrucous leukoplakia), and to analyze the correlation between histopathologic features and malignant transformation (MT). Patients with a clinical diagnosis of PL who have at least one biopsy and one follow-up visit were included in this study. Initial/early biopsy specimens were reviewed. The biopsies were evaluated for the presence of squamous cell carcinoma (SCCa), oral epithelial dysplasia (OED), and atypical verrucous hyperplasia (AVH). Cases that lacked unequivocal features of dysplasia were termed "hyperkeratosis/parakeratosis not reactive (HkNR)". Pearson chi-square test and Wilcoxon test were used for statistical analysis. There were 86 early/initial biopsies from 59 patients; 74.6% were females. Most of the cases had a smooth/homogenous (34.8%) or fissured appearance (32.6%), and only 13.0% had a verrucous appearance. The most common biopsy site was the gingiva/alveolar mucosa (40.8%) and buccal mucosa (25.0%). The most common histologic diagnosis was OED (53.5%) followed by HkNR (31.4%). Of note, two-thirds of HkNR cases showed only hyperkeratosis and epithelial atrophy. A lymphocytic band was seen in 34.8% of OED cases and 29.6% of HkNR cases, mostly associated with epithelial atrophy. Twenty-eight patients (47.5%) developed carcinoma and 28.9% of early/initial biopsy sites underwent MT. The mortality rate was 11.9%. Our findings show that one-third of cases of PL do not show OED with most exhibiting hyperkeratosis and epithelial atrophy, but MT nevertheless occurred at such sites in 3.7% of cases.

Primordial odontogenic tumor (POT) is a rare, mixed odontogenic neoplasm composed of spindled and stellate-shaped cells in myxoid stroma resembling dental papilla, surfaced by cuboidal-to-columnar odontogenic epithelium. Most POTs present in the posterior mandible as a well-demarcated radiolucency associated with a developing tooth in children and adolescents. POT is treated conservatively with no recurrences documented to-date. To describe the clinicopathological features of a recurrent POT. A 19-year-old female presented with an asymptomatic swelling, and panoramic radiograph revealed a multiloculated radiolucency in the mandibular body and ramus, with buccal and lingual perforation. The tumor was composed of plump spindle and stellate cells in a delicately collagenous and myxoid stroma, surfaced by columnar epithelial cells with reverse nuclear polarization. There was extensive epithelial proliferation forming invaginations within the tumor mass and organoid/enamel organ-like structures with enameloid-like deposits, dentinoid, and dystrophic calcifications. This was similar to the POT that had been excised four years prior from the same location. The patient underwent hemi-mandibulectomy and currently is free of disease at a thirteen-month follow-up. This report describes the first recurrent POT exhibiting extensive epithelial proliferation.

The aim of this study was to report on the clinical indications and treatment outcomes of intralesional steroid therapy (IST) for oral ulcerative conditions in an oral medicine practice.This was a retrospective single-center study of patients with oral ulcerative conditions treated with IST. Demographic data, clinical diagnosis of the oral condition, size of the ulcer, and pain were abstracted from patients' electronic medical records.Ninety-three patients (51 females [54.8%]) were treated for persistent traumatic oral ulcers (n = 38 [40.8%]), ulcers in oral chronic graft-versus-host disease (n = 23 [24.7%]), oral lichen planus (n = 19 [20.4%]), and other conditions (14%). Complete resolution was achieved in 81.7% of patients in a median of 96 days (range 10-357 days), with 80% fully healed in a median of 84 days (range 10-140 days). Overall, patients received a median of 2 injections (range 1-5 injections) and a median dose of 12 mg per injection (range 2-36 mg). Nearly half the patients were also treated with concomitant topical steroid therapy. After the first injection, the median pain score reduced from 5 (range 1-10) to 1 (range 0-10; P.001) and the median size of ulcers reduced from 1 cm (range 0.1-5 cm) to 0.3 cm (range 0-2 cm; P.001).IST may be an effective treatment for inflammatory and immune-mediated oral ulcers.

OBJECTIVES Oral autoimmune bullous disorders show clinical overlap with diseases such as lichen planus and others that may cause desquamative gingivitis. As direct immunofluorescence is expensive, we sought to determine if routine histology alone would be sufficient to distinguish between oral autoimmune bullous disorders and mimics. METHODS We searched the records for patients with a suspected oral autoimmune bullous disorder who underwent biopsies for concurrent routine histologic evaluation and direct immunofluorescence and who had at least one follow-up visit. Cases were separated into high and low suspicion subgroups based on clinical findings. RESULTS Within 148 cases, the sensitivity of routine histology alone was 0.810, with a negative predictive value of 0.889. However, the specificity was 0.989 with a positive predictive value of 0.979. Of the high suspicion cases, 57 (47.1%) were found to be consistent with an oral autoimmune bullous disorder, with a total of 11 histologic false negatives. 8 cases, all in the high suspicion subgroup, showed indeterminate direct immunofluorescence results. There were no histologic false negatives or inconclusive direct immunofluorescence results in the low suspicion subgroup. CONCLUSIONS In patients with a low clinical suspicion for an oral autoimmune bullous disorder, it is reasonable and more cost-effective to evaluate the lesion with routine histology alone.

Objective. To assess the evidence for treatment of oral involvement of pemphigus and pemphigoid with biologics.Study Design. This systematic review used a comprehensive search strategy to identify literature describing oral involvement of pemphigus or pemphigoid treated with a biologic agent. The primary outcome measures were efficacy and safety of biologic therapy.Results. Inclusion criteria was met by 154 studies including over 1200 patients. Treatment of pemphigus with a total of 11 unique biologic agents and 3 unique combinations of agents is reported. Five randomized controlled trials (RCT) were included in the final analysis that investigated infliximab, IVIg, rituximab and autologous platelet-rich plasma therapy for pemphigus vulgaris. Three non-RCT studies reported on successful rituximab or IVIg therapy for mucous membrane pemphigoid. Studies demonstrated considerable heterogeneity in agent, methods, and quality.Conclusions. Evidence clearly describing oral tissue response to biologic therapy is sparse. Two RCTs support use of rituximab, one supports use of IVIg, and one pilot study suggests intralesional injection of autologous platelet-rich plasma aids healing of oral PV lesions. As oral lesions of pemphigus and pemphigoid can be refractory to systemic therapy, drug trials including biologic therapies should document details regarding response of the oral lesions to therapy.

Oral toxicities following radiation therapy (RT) for head and neck (HN) cancer can be profound and are associated with poor health outcomes. The Division of Oral Medicine and Dentistry at Brigham and Women’s Hospital and Dana-Farber Cancer Institute therefore implemented a dental evaluation program designed for community-based (CB) dentists to evaluate and treat patients scheduled for HN RT. The aim of this retrospective single-center cohort study was to assess the compliance of CB dentists with this pre-RT dental evaluation program. A retrospective analysis of dental evaluations completed by CB dentists from December 2013 to December 2015 was performed. Descriptive statistics were used to determine compliance. A total of 186 dental evaluations were received. Compliance with completion of dental treatment was as follows: scaling and prophylaxis: 94.5% (172/182); dental restorations: 78.7% (48/61); endodontic therapy: 76.9% (10/13); and dental extractions: 76.9% (30/39). Compliance of CB dentists with all requested components of the pre-RT evaluation and treatment was 77.4% (144/186). The median distance traveled by patients to the CB dentist and to the hospital was 5.2 miles (range 0.03–66.0) and 46.5 miles (range 0.8–1457; p

Bronchogenic cysts are foregut-derived developmental anomalies found along the developmental pathway of the foregut. The putative theory of pathogenesis is abnormal budding or branching of epithelial cells during the development of tracheobronchial tree. Over 99 % of cases occur in the mediastinum and lung while the head and neck area is affected in less than 1 % of cases with only rare cases reported in the oral cavity. This is a report of a case of a bronchogenic cyst arising in a 6-year-old male. The lesion presented as a painless swelling of the left underside of the tongue. Microscopically, the cyst was lined by pseudostratified columnar epithelium exhibiting many ciliated and mucous cells. A focus of cartilage and discontinuous bundles of smooth muscle were present adjacent to the lining. Where there was cyst rupture, there was granulation tissue associated with many foamy macrophages and acute and chronic inflammation. Four other cases, three in the tongue and one in the lower lip vestibule with cutaneous extension, all in the midline, have been reported in a 1 day-old male, 4 year-old male, 6 year-old female and 3 year-old male. There was no recurrence after excision and this is in keeping with the behavior in previous reports. Other developmental cysts including foregut cysts may be focally lined with respiratory epithelium but the presence of cartilage is the sine qua non for the diagnosis of a bronchogenic cyst.

The many diverse terms used to describe the wide spectrum of changes seen in proliferative verrucous leukoplakia (PVL) have resulted in disparate clinical management. The objective of this study was to produce an expert consensus guideline for standardized assessment and reporting by pathologists diagnosing PVL related lesions. 299 biopsies from 84 PVL patients from six institutions were selected from patients who had multifocal oral leukoplakic lesions identified over several years (a minimum follow-up period of 36 months). The lesions demonstrated the spectrum of histologic features described in PVL, and in some cases, patients developed oral cavity squamous cell carcinoma (SCC). An expert working group of oral and maxillofacial and head and neck pathologists reviewed microscopic features in a rigorous fashion, in combination with review of clinical photographs when available. The working group then selected 43 single slide biopsy cases for whole slide digital imaging (WSI) review by members of the consensus conference. The digital images were then reviewed in two surveys separated by a washout period of at least 90 days. Five non-PVL histologic mimics were included as controls. Cases were re-evaluated during a consensus conference with 19 members reporting on the cases. The best inter-observer diagnostic agreement relative to PVL lesions were classified as “corrugated ortho(para)hyperkeratotic lesion, not reactive” and “SCC” (chi-square p = 0.015). There was less than moderate agreement (kappa 0.41 kappa) for 35 of 48 cases. This expert consensus guideline has been developed with support and endorsement from the leadership of the American Academy of Oral and Maxillofacial Pathology and the North American Society of Head and Neck Pathologists to recommend the use of standardized histopathologic criteria and descriptive terminology to indicate three categories of lesions within PVL: (1) “corrugated ortho(para)hyperkeratotic lesion, not reactive;” (2) “bulky hyperkeratotic epithelial proliferation, not reactive;” and (3) “suspicious for,” or “squamous cell carcinoma.” Classification of PVL lesions based on a combination of clinical findings and these histologic descriptive categories is encouraged in order to standardize reporting, aid in future research and potentially guide clinical management.

Oral myeloid sarcoma (MS) is an extramedullary tumor that can occur in the setting of acute myeloid leukemia, either as the first sign of an underlying disease or later in the course of disease. The authors' aim was to present the clinical features of oral MS and review the literature.Case 1 was an 82-year-old woman with an asymptomatic erythematous swelling on the maxillary gingiva and no history of hematologic malignancy. Case 2, a 65-year-old man, and case 3, a 58-year-old woman, each had a history of acute myeloid leukemia and a painful ulcer on the palatal mucosa and an asymptomatic ulcer on the lower lip mucosa, respectively. Case 1 was treated with focal radiation then chemotherapy and achieved complete remission initially, but died of relapse 2 years after diagnosis. Case 2 received radiotherapy and immunotherapy and had a complete response. Case 3 received chemotherapy and achieved remission initially, but relapsed and is undergoing investigational targeted therapies.Oral MS can manifest as gingival or mucosal swelling or ulceration and can indicate onset or relapse of associated hematologic malignancies, which often have a poor prognosis. Because patients with oral findings are likely to seek treatment from their dentists first, oral clinicians should maintain a broad differential diagnosis list when evaluating oral lesions, especially if treatment prescribed for a more common diagnosis fails to resolve the lesion.

The current WHO histopathologic criteria for oral epithelial dysplasia (ED) are based on architectural and cytologic alterations, and do not address other histopathologic features of ED. Here we propose new diagnostic criteria including architectural, organizational, and cytologic features for oral ED. Cases of unifocal leukoplakia (UL) and proliferative leukoplakia (PL) with clinical photographs and follow-up information were identified. Only cases that showed minimal cytologic atypia or mild ED were used to demonstrate critical architectural changes as defined in this study. Eight biopsies from eight UL patients and 34 biopsies from four PL patients were included. The biopsies showed (a) corrugated, verrucous or papillary architecture, (b) hyperkeratosis with epithelial atrophy, (c) bulky squamous epithelial proliferation, and (d) demarcated hyperkeratosis and "skip" segments. The architectural alterations defined here are as important as the currently used criteria for the diagnosis of ED. Clinicopathologic correlation when diagnosing oral ED is also of the utmost importance in accurate diagnosis.

Keratocystic odontogenic tumors (KCOTs) are locally aggressive odontogenic neoplasms with recurrence rates of up to 60%. Approximately 5% of KCOTs are associated with nevoid basal cell carcinoma (Gorlin) syndrome and 90% of these show genomic inactivation of the PTCH1 gene encoding Patched 1. Sporadic KCOTs reportedly have PTCH1 mutations in 30% of cases, but previous genomic analyses have been limited by low tumor DNA yield. The aim of this study was to identify recurrent genomic aberrations in sporadic KCOTs using a next-generation sequencing panel with complete exonic coverage of sonic hedgehog (SHH) pathway members PTCH1, SMO, SUFU, GLI1, and GLI2. Included were 44 sporadic KCOTs from 23 female and 21 male patients with a median age of 50 years (range, 10 to 82 y) and located in the mandible (N = 33) or maxilla (N = 11). Sequencing identified PTCH1 inactivating mutations in 41/44 (93%) cases, with biallelic inactivation in 35 (80%) cases; 9q copy neutral loss of heterozygosity targeting the PTCH1 locus was identified in 15 (34%) cases. No genomic aberrations were identified in other sequenced SHH pathway members. In summary, we demonstrate PTCH1 inactivating mutations in 93% of sporadic KCOTs, indicating that SHH pathway alterations are a near-universal event in these benign but locally aggressive neoplasms. The high frequency of complete PTCH1 loss of function may provide a rational target for SHH pathway inhibitors to be explored in future studies.

Benign alveolar ridge keratosis (BARK), the intraoral counterpart of cutaneous lichen simplex chronicus, is a reactive hyperkeratosis caused by trauma or friction that presents as a poorly demarcated white papule or plaque on the keratinized mucosa of the retromolar pad or alveolar ridge mucosa (often edentulous). This is a clinical and histopathologic analysis of BARK including evaluation of p53 expression in selected cases. One hundred and sixty-seven cases of BARK were identified from 2016 to 2017 and 112 (67.1%) occurred in males with a median age of 56 years (range 15–86). The retromolar pad was affected in 107 (64.1%) cases and the edentulous alveolar mucosa in 60 (35.9%) cases, with 17.4% of the cases presenting bilaterally. BARK showed hyperkeratosis often with wedge-shaped hypergranulosis and occasional focal parakeratosis. The epithelium exhibited acanthosis and surface corrugation with tapered rete ridges often interconnected at the tips. The study for p53 performed in 12 cases showed less than 25% nuclear positivity. BARK is a distinct benign clinicopathologic entity caused by friction, which should be clearly distinguished from true leukoplakia, a potentially malignant disorder.

Young patients with oral cavity squamous cell carcinoma (OCSCC) are often recognized as a distinct epidemiological cohort. In this study, genomic and immune-based metrics were correlated with long-term outcomes for a young patient population treated at a single institution. A fully clinically annotated, retrospective cohort of 81 patients aged ≤45 years with OCSCC is described, and the impact of clinicopathological features on long-term survival outcomes is reported. Genomic and immune parameters were integrated utilizing a whole-exome sequencing and immunohistochemical approach among females in the cohort. It was found that young OCSCC patients had favorable outcomes (10-year disease-free survival 79.1%, overall survival 80.0%) regardless of sex, particularly if they presented with oral tongue primaries and early stage disease. While mutational analysis appeared similar to that of older patients with OCSCC who lack a smoking history, a comparatively high degree of PD-L1 expression and PD-1/L1 concordance (P=0.001) was found among young female OCSCC patients. Subjects with greater membranous PD-L1 positivity and the presence of tumor-infiltrating lymphocytes had a decreased risk of recurrence (P=0.01 and P=0.01, respectively) and improved survival (P=0.04 and P=0.03, respectively). These findings warrant further validation and support the investigation of immunotherapeutic approaches targeting PD-1/L1 interactions in young OCSCC patients.

Aims Primordial odontogenic tumour (POT) is a rare mixed odontogenic neoplasm that is composed of primitive ectomesenchyme resembling dental papilla, surfaced by odontogenic epithelium resembling inner enamel epithelium, without hard tissue formation. Most reported cases have presented in the posterior mandible as a well-demarcated radiolucency associated with an unerupted tooth in the first two decades of life. The aim of this report is to describe the clinicopathological features of two more cases of POT. Methods and results Each presented as an asymptomatic well-delineated radiolucency in the mandible in a 15-year-old female and an 18-year-old male, respectively. Both tumours were composed of a proliferation of plump spindle and stellate cells in delicately collagenous and myxoid stroma, surfaced by columnar-squamous epithelial cells with reverse nuclear polarisation at the tumour periphery. In one case, the formation of abortive tooth germ-like structures was noted. This has not been reported previously and supports the hypothesis of the primordial nature of this tumour. Both patients showed no recurrence at 3- and 20-month follow-up, respectively. Conclusion This report describes two additional cases of POT for a total of 11 cases reported in the English language literature.

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.

Objectives The aim of this study was to evaluate the impact of oral health status on bacteremia risk in a cohort of patients with acute myeloid leukemia (AML) who underwent chemotherapy followed by myeloablative allogeneic hematopoietic cell transplantation (allo-HCT). Study Design A retrospective study was conducted in patients with AML from 2007 to 2011. Oral health status was determined from a pre–allo-HCT dental evaluation. Positive blood cultures were recorded from AML induction to post–allo-HCT day +60. Organisms that caused bacteremia were classified as “of possible oral source” by a blinded microbiologist. Two-sided Fisher's exact test was used to compare the oral health status of the entire cohort with that of patients with blood cultures of potential oral source. Results Pre–allo-HCT dental evaluations were completed in 91 (99%) of 92 patients. Of these 91 patients, 13 (14%) with dental pathology (13 of 13 [100%]) completed all required dental treatment before allo-HCT. Bacteremias occurred in 63 of 92 patients (68%), and 12 (19%) of 63 patients had positive blood cultures of potential oral source. Of these, 1 of 12 patients developed bacteremia during AML induction, and 11 of 12 developed bacteremia during allo-HCT. Conclusions Oral health status was not associated with risk of bacteremia of potential oral source either at AML induction or consolidation or at allo-HCT.

Objectives The aim of the study was to determine the absolute and relative safety of treatment with 2 concentrations of topical clonazepam solution (0.1 mg/mL, 0.5 mg/mL) for management of oral dysesthesia. Study Design The study was a retrospective chart review of patients diagnosed with oral dysesthesia and managed with topical clonazepam solution (swish and spit) between 2008 and 2015. The relative safety of the 2 concentrations was evaluated in terms of occurrence of adverse drug reactions (ADRs) and occurrence of change to treatment plan secondary to ADRs. Results For the study, 162 patients were included—84 patients in the 0.1 mg/mL cohort and 78 in the 0.5 mg/mL cohort, who were evaluated for a median follow-up period of 6 weeks. Thirty-eight (23%) patients developed ADRs. The most frequently reported ADR was sedation (62% of ADRs), followed by altered mental status and dizziness (7% each). Dose adjustments were required in 9 patients (6%) and treatment discontinuation in 13 (8%). ADRs were more frequently reported in the 0.5 mg/mL cohort, but no significant difference was found in terms of occurrence of ADRs, change to treatment plan secondary to ADRs, or types of ADRs ( P > .05). Conclusions Treatment with topical clonazepam solution in either 0.5 mg/mL or 0.1 mg/mL concentration appears to be safe and well-tolerated. Future prospective studies are needed to confirm this finding.