Faculty Bibliography

Oral leiomyomatous hamartoma (OLH) is a rare lesion, with only 40 cases reported in the literature. It typically presents early in life as a nodule on the anterior maxillary alveolar tissues or the tongue. Its growth potential is limited, with few cases reaching dimensions >2.0 cm, and its microscopic composition includes an intact surface mucosa with an underlying fibrovascular stroma possessing an unencapsulated proliferation of smooth muscle fascicles. Excision is considered the definitive treatment. Here we describe the clinical, microscopic, histochemical, and immunohistochemical features and management of 3 cases of OLH and review the literature. The findings we present here can assist in performing differential diagnosis, particularly in discriminating between OLH and similar yet non-hamartomatous processes and in selecting appropriate management.

OBJECTIVES/OBJECTIVE:knockout mice were included to evaluate the effects of the conditional E-cadherin ablation onto tooth development. MATERIAL AND METHODS/METHODS:littermate controls. These litters were euthanized at postnatal day P2 to study the effects of conditional E-cadherin ablation in vivo. RESULTS:mice also displayed a smaller overall stature compared with heterozygotes and wild-type littermates. CONCLUSIONS:E-cadherin is important in tooth development, including the formation of enamel, the crown, pulp space, and the roots.

Oral cavity cancer has a low 5-y survival rate, but outcomes improve when the disease is detected early. Cytology is a less invasive method to assess oral potentially malignant disorders relative to the gold-standard scalpel biopsy and histopathology. In this report, we aimed to determine the utility of cytological signatures, including nuclear F-actin cell phenotypes, for classifying the entire spectrum of oral epithelial dysplasia and oral squamous cell carcinoma. We enrolled subjects with oral potentially malignant disorders, subjects with previously diagnosed malignant lesions, and healthy volunteers without lesions and obtained brush cytology specimens and matched scalpel biopsies from 486 subjects. Histopathological assessment of the scalpel biopsy specimens classified lesions into 6 categories. Brush cytology specimens were analyzed by machine learning classifiers trained to identify relevant cytological features. Multimodal diagnostic models were developed using cytology results, lesion characteristics, and risk factors. Squamous cells with nuclear F-actin staining were associated with early disease (i.e., lower proportions in benign lesions than in more severe lesions), whereas small round parabasal-like cells and leukocytes were associated with late disease (i.e., higher proportions in severe dysplasia and carcinoma than in less severe lesions). Lesions with the impression of oral lichen planus were unlikely to be either dysplastic or malignant. Cytological features substantially improved upon lesion appearance and risk factors in predicting squamous cell carcinoma. Diagnostic models accurately discriminated early and late disease with AUCs (95% CI) of 0.82 (0.77 to 0.87) and 0.93 (0.88 to 0.97), respectively. The cytological features identified here have the potential to improve screening and surveillance of the entire spectrum of oral potentially malignant disorders in multiple care settings.

BACKGROUND:The effective detection and monitoring of potentially malignant oral lesions (PMOL) are critical to identifying early-stage cancer and improving outcomes. In the current study, the authors described cytopathology tools, including machine learning algorithms, clinical algorithms, and test reports developed to assist pathologists and clinicians with PMOL evaluation. METHODS:Data were acquired from a multisite clinical validation study of 999 subjects with PMOLs and oral squamous cell carcinoma (OSCC) using a cytology-on-a-chip approach. A machine learning model was trained to recognize and quantify the distributions of 4 cell phenotypes. A least absolute shrinkage and selection operator (lasso) logistic regression model was trained to distinguish PMOLs and cancer across a spectrum of histopathologic diagnoses ranging from benign, to increasing grades of oral epithelial dysplasia (OED), to OSCC using demographics, lesion characteristics, and cell phenotypes. Cytopathology software was developed to assist pathologists in reviewing brush cytology test results, including high-content cell analyses, data visualization tools, and results reporting. RESULTS:Cell phenotypes were determined accurately through an automated cytological assay and machine learning approach (99.3% accuracy). Significant differences in cell phenotype distributions across diagnostic categories were found in 3 phenotypes (type 1 ["mature squamous"], type 2 ["small round"], and type 3 ["leukocytes"]). The clinical algorithms resulted in acceptable performance characteristics (area under the curve of 0.81 for benign vs mild dysplasia and 0.95 for benign vs malignancy). CONCLUSIONS:These new cytopathology tools represent a practical solution for rapid PMOL assessment, with the potential to facilitate screening and longitudinal monitoring in primary, secondary, and tertiary clinical care settings.

AIMS: Ectomesenchymal chondromyxoid tumor (ECT) is a rare, benign intraoral neoplasm showing predilection for the anterior dorsum of the tongue. The World Health Organization (W.H.O.) includes ECT in the pathologic spectrum of soft tissue myoepithelioma. EWSR1 rearrangement is identified in 45% of cutaneous, soft tissue and bone myoepithelial neoplasms, while PLAG1 aberrations are found in 37% of EWSR1-negative soft tissue myoepitheliomas. The aim of this study was to evaluate the presence of EWSR1 and PLAG1 rearrangements in ECTs. METHODS AND RESULTS: Eleven formalin-fixed, paraffin-embedded ECTs were evaluated using FISH probes to EWSR1 (22q12) and PLAG1 (8q12). Among the 11 ECT cases tested, 3 (27.3%) showed EWSR1 rearrangement in >15% of tumor cells, while 8 (72.7%) cases did not show EWSR1 rearrangement. Eight of 9 (89%) ECTs demonstrated gain of EWSR1, likely representing gain of all or part of chromosome 22, in a varying proportion of neoplastic cells ranging between 1.4-27.9%. PLAG1 rearrangement was not detected in the successfully hybridized tissue sections (7/11). No correlation was observed between the molecular and histopathologic findings such as morphology of the neoplastic cells, presence of atypia, and matrical type. CONCLUSIONS: We identified EWSR1 rearrangement in > 25% of ECTs. These results suggest that some ECTs are at least genetically related to myoepithelioma of the soft parts. Finally, PLAG1 aberrations do not appear to be critical in the pathogenesis of ECT of the tongue

OBJECTIVE: Heightened levels of sEcad are found in the serum of patients with cancer and correlate with an unfavorable prognosis and later-stages of disease. In this study, we explored whether sEcad is elevated in human OPSCC specimens and FaDu cells. Additionally, we investigated sEcad-EGFR and sEcad-IGF-1R interactions and performed a functional analysis of sEcad in OPSCC cancers. MATERIALS AND METHODS: sEcad, EGFR, and IGF-1R levels were examined in human OPSCC specimens and cells by immunoblotting. sEcad-EGFR and sEcad-IGF-1R interactions were examined by immunoprecipitation and immunoblot assays. Levels of sEcad on EGFR and IGF-1R pathway components were evaluated by IB. The effects of sEcad on OPSCC proliferation, migration, and invasion were assessed using standard cellular assays. RESULTS: Statistical analysis demonstrated that sEcad levels were significantly higher in OPSCC primary tumors and cells compared with normal controls. IP studies indicated that sEcad associated with EGFR and IGF-1R, and addition of sEcad resulted in a statistically significant increase in downstream signaling. Finally, cell-based assays demonstrated enhanced sEcad-induced proliferation, migration, and invasion, which was blocked by EGFR and IGF-1R inhibitors. CONCLUSIONS: These findings suggest that sEcad may play an important role in OPSCC oncogenicity via its interaction and activation of EGFR and IGF-1R.

Tumor cell survival consists of an intricate balance between cell growth and cell death pathways involving receptor tyrosine kinases [RTK; i.e., HER1-4, insulin-like growth factor-1 receptor (IGF-1R), etc.], MDM2, and the tumor suppressor proteins phosphatase and tensin homolog deleted on chromosome ten (PTEN) and p53. We recently demonstrated that shedded E-cadherin extracellular domain fragment (sEcad) is a valid oncogenic target that is significantly increased in human clinical skin squamous cell cancers (SCC) samples, UV-induced mouse tumors, and cells and promotes tumor cell proliferation, migration, and invasion by interacting and activating with the HER-phosphatidylinositol 3-kinase (PI3K)-Akt-mammalian target of rapamycin (mTOR) and mitogen-activated protein kinase (MAPK) axis. In resected human SCC tumors, we reported enhanced sEcad-HER1, sEcad-HER2, and sEcad-IGF-1R, but not FL-Ecad-RTK interactions. Here, we demonstrate that a sEcad antibody against the ectodomain of E-cadherin suppressed SCC growth and increased tumor differentiation in orthotopic cutaneous SCC xenografts by inhibiting proliferation and inducing apoptosis. A similar anti-sEcad antibody-induced inhibition of proliferation and induction of cell death was evident in PAM212 cells in vitro. Mechanistically, anti-sEcad administration upregulated an array of cell death pathways (i.e., Bad, active caspase-3, and cleaved PARP) and inhibited inhibitors of apoptosis (IAP; survivin, livin, etc.), RTKs (HER1, HER2, p95HER2, and IGF-1R), MAPK and PI3K/mTOR prosurvival signaling. Interestingly, in anti-sEcad mAb-treated tumors and PAM212 cells, this effect was associated with a profound increase in membrane, cytosolic, and nuclear levels of PTEN; enhanced cytosolic p53; and a decrease in MDM2 levels. Overall, our studies suggest that an antibody-based therapy against sEcad may be a novel therapeutic platform for cutaneous SCCs by hampering key proto-oncogenes (RTKs, IAPs, and MDM2) and activating potent tumor suppressor proteins (PTEN and p53) intricately linked to tumor growth and survival.

UNLABELLED: Identification of unknown individuals using dental comparison is well established in the forensic setting. The identification technique can be time and resource consuming if many individuals need to be identified at once. Medical CT (MDCT) for dental profiling has had limited success, mostly due to artifact from metal-containing dental restorations and implants. DESCRIPTION: The authors describe a CBCT reformatting technique that creates images, which closely approximate conventional dental images. METHOD: Using a i-CAT Platinum CBCT unit and standard issue i-CAT Vision software, a protocol is developed to reproducibly and reliably reformat CBCT volumes. The reformatted images are presented with conventional digital images from the same anatomic area for comparison. CONCLUSION: The authors conclude that images derived from CBCT volumes following this protocol are similar enough to conventional dental radiographs to allow for dental forensic comparison/identification and that CBCT offers a superior option over MDCT for this purpose.