Impact of depth of invasion on local recurrence in R0 resected node-negative oral tongue squamous cell carcinoma.

BACKGROUND: This study evaluates the impact of depth of invasion (DOI) on local recurrence (LR) in node-negative oral tongue squamous cell carcinoma (SCC). METHODS: Fifty-one patients were retrospectively reviewed from an institutional database. Patients were evaluated for local control (LC). Cox-proportional hazards modeling was used to calculate hazard ratios. RESULTS: There were 84.3% T1/2 and 15.7% T3/4 classification tumors. The 3-year overall survival rate was 97.9%. Local failure rate was 5.7% with a 3-year LC of 93.6%. On Univariate analysis, increased hazard of LR was noted with each unit increase in DOI (HR 1.40, 95% CI 1.07-1.83, p = 0.014). Age, sex, T classification, margins ≥5 mm, lymphovascular invasion (LVI) and perineural invasion (PNI), and adjuvant treatment were not associated with LR. On Multivariate analysis, adjusting for age and adjuvant treatment, results for DOI remained significant (aHR 1.46, 95% CI 1.08-1.98, p = 0.013). CONCLUSION: On evaluation of our institutional dataset increasing DOI was associated with increased hazard of local recurrence with oral tongue SCC.

ß-catenin/CBP activation of mTORC1 signaling promotes partial epithelial-mesenchymal states in head and neck cancer.

Head and neck cancers, which include oral squamous cell carcinoma (OSCC) as a major subsite, exhibit cellular plasticity that includes features of an epithelial-mesenchymal transition (EMT), referred to as partial-EMT (p-EMT). To identify molecular mechanisms contributing to OSCC plasticity, we performed a multiphase analysis of single cell RNA sequencing (scRNAseq) data from human OSCC. This included a multiresolution characterization of cancer cell subgroups to identify pathways and cell states that are heterogeneously represented, followed by casual inference analysis to elucidate activating and inhibitory relationships between these pathways and cell states. This approach revealed signaling networks associated with hierarchical cell state transitions, which notably included an association between ß-catenin-driven CREB-binding protein (CBP) activity and mTORC1 signaling. This network was associated with subpopulations of cancer cells that were enriched for markers of the p-EMT state and poor patient survival. Functional analyses revealed that ß-catenin/CBP induced mTORC1 activity in part through the transcriptional regulation of a raptor-interacting protein, chaperonin containing TCP1 subunit 5 (CCT5). Inhibition of ß-catenin-CBP activity through the use of the orally active small molecule, E7386, reduced the expression of CCT5 and mTORC1 activity in vitro, and inhibited p-EMT-associated markers and tumor development in a murine model of OSCC. Our study highlights the use of multiresolution network analyses of scRNAseq data to identify targetable signals for therapeutic benefit, thus defining an underappreciated association between ß-catenin/CBP and mTORC1 signaling in head and neck cancer plasticity.

Treatment of tophaceous pseudogout in the temporomandibular joint with resection and alloplastic reconstruction: a single-staged approach.

Tophaceous pseudogout is a rare variant of the calcium pyrophosphate dihydrate (CPPD) disorder, with predilection for the TMJ. It is characterized by calcific deposits composed of rhomboid- or rectangular-shaped crystals that exhibit birefringence when examined under polarized light. We hereby present a case of a 65-year-old man with left pre-auricular tenderness and malocclusion. CT imaging was notable for a left TMJ mineralized mass with erosion of the condylar head. Treatment involved excision of the mass with eminectomy, condylectomy, and a stock total TMJ reconstruction. In this report, important considerations for diagnosis, biopsy, and surgical treatment with emphasis on reconstruction for tophaceous pseudogout of the TMJ have been highlighted by the authors.

Inhibition of LSD1 Attenuates Oral Cancer Development and Promotes Therapeutic Efficacy of Immune Checkpoint Blockade and YAP/TAZ Inhibition.

Lysine-specific demethylase 1 (LSD1) is a histone demethylase that contributes to the etiology of oral squamous cell carcinoma (OSCC) in part by promoting cancer stem cell phenotypes. The molecular signals regulated by LSD1, or acting with LSD1, are poorly understood, particularly in the development of OSSC. In this study, we show that conditional deletion of the Lsd1 gene or pharmacologic inhibition of LSD1 in the tongue epithelium leads to reduced development of OSCC following exposure to the tobacco carcinogen 4NQO. LSD1 inhibition attenuated proliferation and clonogenic survival and showed an additive effect when combined with the YAP inhibitor Verteporfin. Interestingly, LSD1 inhibition upregulated the expression of PD-L1, leading to immune checkpoint inhibitor therapy responses. IMPLICATIONS: Collectively, our studies reveal a critical role for LSD1 in OSCC development and identification of tumor growth targeting strategies that can be combined with LSD1 inhibition for improved therapeutic application.

Oral hairy leukoplakia: a series of 45 cases in immunocompetent patients.

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.

Diatoms: A novel cause of granulomatous inflammation of the head and neck.

OBJECTIVE: We report the first 4 cases of intraoral nonnecrotizing granulomatous foreign body reactions to diatoms, plausibly as a result of exogenous material introduced following iatrogenic or traumatic injury. STUDY DESIGN: Clinical and histopathologic findings of 4 intraoral cases of nonnecrotizing granulomatous foreign body reaction to diatoms, single-celled algae belonging to the taxonomic phylum Bacillariophyta, are reported. RESULTS: The lesions presented either in the jaws or in the soft tissue overlying the alveolar bone, in some instances mimicking an inflammatory lesion of odontogenic etiology. Microscopically, the lesions presented as nonnecrotizing granulomatous inflammation associated with either spherical and radially symmetric or rectangular and bilaterally symmetric diatomaceous foreign material. CONCLUSION: The diagnosis of a diatom-associated foreign body reaction necessitates familiarization with the histopathologic features of these organisms to accurately characterize the nature of such lesions.

Mechanism for oral tumor cell lysyl oxidase like-2 in cancer development: synergy with PDGF-AB.

Extracellular lysyl oxidases (LOX and LOXL1-LOXL4) are critical for collagen biosynthesis. LOXL2 is a marker of poor survival in oral squamous cell cancer. We investigated mechanisms by which tumor cell secreted LOXL2 targets proximal mesenchymal cells to enhance tumor growth and metastasis. This study identified the first molecular mechanism for LOXL2 in the promotion of cancer via its enzymatic modification of a non-collagenous substrate in the context of paracrine signaling between tumor cells and resident fibroblasts. The role and mechanism of active LOXL2 in promoting oral cancer was evaluated and employed a novel LOXL2 small molecule inhibitor, PSX-S1C, administered to immunodeficient, and syngeneic immunocompetent orthotopic oral cancer mouse models. Tumor growth, histopathology, and metastases were monitored. In vitro mechanistic studies with conditioned tumor cell medium treatment of normal human oral fibroblasts were carried out in the presence and absence of the LOXL2 inhibitor to identify signaling mechanisms promoted by LOXL2 activity. Inhibition of LOXL2 attenuated cancer growth and lymph node metastases in the orthotopic tongue mouse models. Immunohistochemistry data indicated that LOXL2 expression in and around tumors was decreased in mice treated with the inhibitor. Inhibition of LOXL2 activity by administration of PXS-S1C to mice reduced tumor cell proliferation, accompanied by changes in morphology and in the expression of epithelial to mesenchymal transition markers. In vitro studies identified PDGFRß as a direct substrate for LOXL2, and indicated that LOXL2 and PDGF-AB together secreted by tumor cells optimally activated PDGFRß in fibroblasts to promote proliferation and the tendency toward fibrosis via ERK activation, but not AKT. Optimal fibroblast proliferation in vitro required LOXL2 activity, while tumor cell proliferation did not. Thus, tumor cell-derived LOXL2 in the microenvironment directly targets neighboring resident cells to promote a permissive local niche, in addition to its known role in collagen maturation.