Aligning Small Datasets Using Domain Adversarial Learning: Applications in Automated in Vivo Oral Cancer Diagnosis.

Deep learning approaches for medical image analysis are limited by small data set size due to factors such as patient privacy and difficulties in obtaining expert labelling for each image. In medical imaging system development pipelines, phases for system development and classification algorithms often overlap with data collection, creating small disjoint data sets collected at numerous locations with differing protocols. In this setting, merging data from different data collection centers increases the amount of training data. However, a direct combination of datasets will likely fail due to domain shifts between imaging centers. In contrast to previous approaches that focus on a single data set, we add a domain adaptation module to a neural network and train using multiple data sets. Our approach encourages domain invariance between two multispectral autofluorescence imaging (maFLIM) data sets of in vivo oral lesions collected with an imaging system currently in development. The two data sets have differences in the sub-populations imaged and in the calibration procedures used during data collection. We mitigate these differences using a gradient reversal layer and domain classifier. Our final model trained with two data sets substantially increases performance, including a significant increase in specificity. We also achieve a significant increase in average performance over the best baseline model train with two domains (p = 0.0341). Our approach lays the foundation for faster development of computer-aided diagnostic systems and presents a feasible approach for creating a robust classifier that aligns images from multiple data centers in the presence of domain shifts.

Cone-beam computed tomographic imaging of central giant cell granuloma: A comprehensive review.

Purpose: The aim of this study was to characterize the cone-beam computed tomographic (CBCT) imaging features of central giant cell granuloma (CGCG) of the jawbone. Materials and Methods: This study retrospectively reviewed 26 CBCT studies of histologically proven cases of CGCG during a period of 20 years, from 1999 to 2019. Patients' demographic data were recorded, and radiographic features were assessed (location, border, cortication, appearance of the internal structure, locularity, septation, expansion, cortical perforation, effects on surrounding tissue, whether the lesion crossed the midline, and lesion volume). Results: In this study, CGCGs were seen almost twice as often in the mandible than in the maxilla, and 64.7% of mandibular lesions involved the anterior region. Only 26.9% of lesions crossed the midline, a feature that was considered characteristic of CGCG. Furthermore, 65.4% of lesions were unilocular and 34.6% were multilocular. The correlation between a lesion's size and its locularity was statistically significant, and larger lesions showed a multilocular appearance. The mean volume of multilocular lesions was greater than that of unilocular lesions. Conclusion: CGCGs showed variable radiographic features on CBCT, and this imaging modality is highly effective at demonstrating the radiographic spectrum and lesional extent of CGCGs in the jawbone.

Adenomatoid odontogenic tumor: evidence for a mixed odontogenic tumor.

OBJECTIVE: Adenomatoid odontogenic tumor (AOT) was classified by the World Health Organization as a mixed odontogenic tumor in 1992 and reclassified without a clear rationale as an epithelium-only tumor in 2005. The purpose of this study was to investigate if there was any evidence to suggest AOT might be a mixed odontogenic tumor. STUDY DESIGN: Immunohistochemical studies with nestin, dentin sialophosphoprotein (DSPP), cytokeratin, and vimentin were performed using 21 cases of AOT, and the staining results were analyzed according to the various morphologic patterns seen in AOT. Sirius red stain was used to detect the presence of collagen types I and III in AOT products. RESULTS: Our results showed that 20 of 21 (95.23%), 0 of 21 (0%), 21 of 21 (100%), and 20 of 21 (95.23%) cases expressed nestin, DSPP, cytokeratin, and vimentin, respectively. Some cells in rosette/duct-like structures (RDSs) expressed nestin, vimentin, or both, without cytokeratin. Coexpression of vimentin and cytokeratin or of nestin, cytokeratin, and vimentin was noted in some cells. Sirius red staining was positive in eosinophilic products in RDSs, double-layered spheres, and dentinoids. CONCLUSION: Although most AOT cells appear epithelial, there is a small population of cells expressing mesenchymal proteins and secreting collagen types I and III. This evidence suggests that AOT is a mixed odontogenic tumor.

LED-based Hyperspectral Endoscopic Imaging.

Hyperspectral endoscopy can offer multiple advantages as compared to conventional endoscopy. Our goal is to design and develop a real-time hyperspectral endoscopic imaging system for the diagnosis of gastrointestinal (GI) tract cancers using a micro-LED array as an in-situ illumination source. The wavelengths of the system range from ultraviolet to visible and near infrared. To evaluate the use of the LED array for hyperspectral imaging, we designed a prototype system and conducted ex vivo experiments using normal and cancerous tissues of mice, chicken, and sheep. We compared the results of our LED-based approach with our reference hyperspectral camera system. The results confirm the similarity between the LED-based hyperspectral imaging system and the reference HSI camera. Our LED-based hyperspectral imaging system can be used not only as an endoscope but also as a laparoscopic or handheld devices for cancer detection and surgery.

Machine-Learning Assisted Discrimination of Precancerous and Cancerous from Healthy Oral Tissue Based on Multispectral Autofluorescence Lifetime Imaging Endoscopy.

Multispectral autofluorescence lifetime imaging (maFLIM) can be used to clinically image a plurality of metabolic and biochemical autofluorescence biomarkers of oral epithelial dysplasia and cancer. This study tested the hypothesis that maFLIM-derived autofluorescence biomarkers can be used in machine-learning (ML) models to discriminate dysplastic and cancerous from healthy oral tissue. Clinical widefield maFLIM endoscopy imaging of cancerous and dysplastic oral lesions was performed at two clinical centers. Endoscopic maFLIM images from 34 patients acquired at one of the clinical centers were used to optimize ML models for automated discrimination of dysplastic and cancerous from healthy oral tissue. A computer-aided detection system was developed and applied to a set of endoscopic maFLIM images from 23 patients acquired at the other clinical center, and its performance was quantified in terms of the area under the receiver operating characteristic curve (ROC-AUC). Discrimination of dysplastic and cancerous from healthy oral tissue was achieved with an ROC-AUC of 0.81. This study demonstrates the capabilities of widefield maFLIM endoscopy to clinically image autofluorescence biomarkers that can be used in ML models to discriminate dysplastic and cancerous from healthy oral tissue. Widefield maFLIM endoscopy thus holds potential for automated in situ detection of oral dysplasia and cancer.

Interobserver Variation in Evaluating Perineural Invasion for Oral Squamous Cell Carcinoma: Phase 2 Survey Study.

In a previous study, we found interobserver agreement among 88 board-certified pathologists evaluating perineural invasion (PNI) in oral squamous cell carcinoma (OSCC) was fair, and participants most often used the following criteria: (1) tumor invading the perineurium, (2) tumor surrounding a nerve. In this study, we aimed to determine whether application of these most commonly used criteria may improve interobserver agreement. 512 pathologists were invited to participate in a web-based survey. Participants were asked to assess the presence/absence of PNI in a set of OSCC photomicrographs by applying each of the two criteria above. The survey was completed by 84 board-certified pathologists [mean age: 52 years (range 31-81), mean years in practice: 19 (range 1-56)]. Interobserver agreement was moderate (k = 0.46, 95% CI 0.45-0.46) when using definition #1 (tumor invading the perineurium) and fair (k = 0.24, 95% CI 0.23-0.25) when using definition #2 (tumor surrounding a nerve). By comparison, interobserver agreement was fair (k = 0.36, 95% CI 0.35-0.37) among phase 1 participants asked to evaluate these photomicrographs as they would in their pathology practice. Differences in kappa between definition #1 and phase 1, definition #2 and phase 2, and definition #1 and #2 were statistically significant (p < 0.001). Compared to our prior study based on pathologists' personal views, the current study shows improved interobserver agreement with application of the criterion, "tumor invading the perineurium." However, further work is needed to delineate concise, objective, and more reproducible criteria for histopathologic assessment of PNI.

Down-regulation of the tumor suppressor miR-34a contributes to head and neck cancer by up-regulating the MET oncogene and modulating tumor immune evasion.

BACKGROUND: MicroRNAs (miRs) have been shown to play an important role in tumorigenesis, including in head and neck squamous cell carcinoma (HNSCC). The miR-34 family is thought to play a role in tumor suppression, but the exact mechanism of their action in HNSCC is not well understood. Moreover, the impact of chromosomal changes and mutation status on miR-34a expression remains unknown. METHODS: Differential expression of miR-34a, MET, and genomic alterations were assessed in the Cancer Genome Atlas (TCGA) datasets as well as in primary HNSCC and adjacent normal tissue. The biological functions of miR-34a in HNSCC were investigated in samples derived from primary human tumors and HNSCC cell lines. The expression of MET was evaluated using immunohistochemistry, and the molecular interaction of miR-34a and MET were demonstrated by RNA pulldown, RNA immunoprecipitation, luciferase reporter assay, and rescue experiments. Lastly, locked nucleic acid (LNA) miRs in mouse xenograft models were used to evaluate the clinical relevance of miR-34a in HNSCC tumor growth and modulation of the tumor microenvironment in vivo. RESULTS: Chromosome arm 1p loss and P53 mutations are both associated with lower levels of miR-34a. In HNSCC, miR-34a acts as a tumor suppressor and physically interacts with and functionally targets the proto-oncogene MET. Our studies found that miR-34a suppresses HNSCC carcinogenesis, at least in part, by downregulating MET, consequently inhibiting HNSCC proliferation. Consistent with these findings, administration of LNA-miR-34a in an in vivo model of HNSCC leads to diminished HNSCC cell proliferation and tumor burden in vitro and in vivo, represses expression of genes involved in epithelial-mesenchymal transition, and negates the oncogenic effect of MET in mouse tumors. Consistently, LNA-miR-34a induced a decreased number of immunosuppressive PDL1-expressing tumor-associated macrophages in the tumor microenvironment. In HNSCC patient samples, higher levels of miR-34a are significantly associated with a higher frequency of Th1 cells and CD8 naïve T cells. CONCLUSIONS: Our results demonstrate that miR-34a directly targets MET and maintains anti-tumor immune activity. We propose miR-34a as a potential new therapeutic approach for HNSCC.

Non-calcifying Langerhans Cell Rich Variant of Calcifying Epithelial Odontogenic Tumor and Amyloid Rich Variant of Central Odontogenic Fibroma: A Unique Entity or a Spectrum?

Overlapping clinicopathological features of non-calcifying Langerhans cell rich variant of calcifying epithelial odontogenic tumor (NCLC-CEOT) and the amyloid rich variant of the central odontogenic fibroma (AR-COF) have been recognized recently. It is still under debate whether these two diseases are indeed one unique disease entity or belong to CEOT and COF, respectively. To clarify this issue, we have performed a literature review to compare the similarities and differences in clinicopathological features among NCLC-CEOT, AR-COF, classic CEOT, and classic COF. We aimed to investigate whether NCLC-CEOT and AR-COF might be the same and one distinctive disease entity, or a variant (or variants) of either CEOT or COF; or whether COF, NCLC-CEOT/AR-COF, and CEOT represented a histopathological spectrum of one disease. Our results indicate that NCLC-CEOT and AR-COF cases share many similar clinicopathological features. Thus, we suggest that they are the same disease entity. Due to nearly no reported recurrence of NCLC-CEOT/AR-COF cases, the conservative surgical treatment is appropriate. The NCLC-CEOT/AR-COF cases show some overlapping clinicopathological features with COF rather than the CEOT cases. However, differences in the clinicopathological features are still recognized among the NCLC-CEOT/AR-COF, COF, and CEOT cases. Future research, particularly molecular biological studies, may further elucidate their relationships and assist proper classification of the NCLC-CEOT/AR-COF cases.

Dysbiosis of saliva microbiome in patients with oral lichen planus.

BACKGROUND: Oral microbiota is not only important for maintaining oral health but also plays a role in various oral diseases. However, studies regarding microbiome changes in oral lichen planus (OLP) are very limited. To the best of our knowledge, there has been only two studies investigating salivary microbiome changes in OLP. Therefore, the purpose of this study was to identify the characteristic microbial profile in the saliva of OLP patients, with or without erosive lesions, and compare that with recurrent aphthous ulcer (RAU), a common oral immunological disorder that also shows multiple erosive/ulcerative lesions. Whole saliva samples were collected from 20 patients with OLP (erosive E, n = 10 and non-erosive NE, n = 10), 10 patients with RAU (U) and 10 healthy controls (C). DNA was extracted from the saliva samples, and the 16S rDNA gene V4 hypervariable region was analyzed using Illumina sequencing. RESULTS: We obtained 4949 operational taxonomic units (OTUs) from the V4 region in all saliva samples. Community composition analysis showed a clear decreased relative abundance of genera Streptococcus and Sphingomonas in saliva from RAU patients when compared to the other three groups. Relative abundance of Lautropia and Gemella were higher in E group, whereas relative abundance of Haemophilus and Neisseria were higher in NE group when compared to C group. Abiotrophia and Oribacterium were higher in OLP (combining E and NE groups), while Eikenella and Aggregatibacter were lower when compared to C group. There was statistically significance in α-diversity between E and RAU groups(p < 0.05). Significant differences in ß-diversity were detected in bacteria between E and C; NE and C; as well as E and NE groups. The LDA effect size algorithm identified the g_Haemophilus might be the potential biomarker in NE group. CONCLUSIONS: We found that salivary microbiome in erosive OLP was significantly different from that found in RAU; and these changes may be related to the underlying disease process rather than presence of ulcerative/erosive lesions clinically. In addition, our findings in bacterial relative abundance in OLP were significantly different from the previously reported findings, which points to the need for further research in salivary microbiome of OLP.

Salivary Sialadenoma Papilliferum Consists of Two Morphologically, Immunophenotypically, and Genetically Distinct Subtypes.

Papillary salivary gland neoplasms are rare tumors usually arising in the minor salivary glands of the oral cavity. Their classification has been historically confusing due to overlapping histologic features, but molecular analysis may clarify these entities. Sialadenoma papilliferum (SP) is a peculiar member of this group that demonstrates both an endophytic ductal and an exophytic squamous component. SP closely resembles syringocystadenoma papilliferum of the skin, a tumor which has recently been shown to harbor BRAF V600E or HRAS mutations. We sought to perform histologic and immunophenotypic analysis of a group of SP, along with BRAF and HRAS mutational analysis. We collected 13 SP cases from 7 females and 6 males ranging from 2 to 91 years (mean 62.8). Five exophytic ductal papillomas were also analyzed as controls. Histological analysis was performed along with immunohistochemistry for CK7, p63, and SOX10. BRAF VE1 immunohistochemistry was done in all tumors, and BRAF V600E and HRAS Sanger sequencing was successfully performed in all but two cases. Histologic analysis revealed that SP consisted not only of classic SP (9 of 13 cases) but also an oncocytic variant (4 of 13 cases) characterized by a glandular component that uniformly exhibited abundant granular cytoplasm and prominent nucleoli. By immunohistochemistry, all SP demonstrated luminal CK7 and basal p63 expression, but SOX10 was expressed only in conventional SP (9 of 9 cases). BRAF VE1 immunohistochemistry was positive in 9 of 9 conventional SP but 0 of 4 oncocytic SP; staining was present in both the exophytic and endophytic components. BRAF V600E mutational status was confirmed by Sanger sequencing in 11 cases (7 conventional and 4 oncocytic). The exophytic ductal papillomas were negative for BRAF mutations, and all tumors tested were negative for HRAS mutations. In summary, we demonstrated that SP consists of two variants: (1) conventional SP which is SOX10-positive and harbors BRAF V600E mutations similar to syringocystadenoma papilliferum of the skin; and (2) an oncocytic variant which is SOX10-negative and negative for BRAF mutations. We also demonstrated that both the endophytic glandular component and exophytic squamous components of conventional SP harbor BRAF V600E mutations and are therefore neoplastic.

Radiographic manifestations of fibroblastic osteosarcoma: A diagnostic challenge.

Osteosarcoma is the most common primary bone tumor after plasma cell neoplasms. Osteosarcoma has diverse histological features and is characterized by the presence of malignant spindle cells and pluripotent neoplastic mesenchymal cells that produce immature bone, cartilage, and fibrous tissue. Osteosarcoma most frequently develops in the extremities of long bones, but can occur in the jaw in rare cases. The clinical and biological behavior of osteosarcoma of the jaw slightly differs from that of long-bone osteosarcoma. The incidence of jaw osteosarcoma is greater in the third to fourth decades of life, whereas long-bone osteosarcoma mostly occurs in the second decade of life. Osteosarcoma of the jaw has a lower tendency to metastasize and a better prognosis than long-bone osteosarcoma. Radiographically, osteosarcoma can present as a poorly-defined lytic, sclerotic, or mixed-density lesion with periosteal bone reaction response. Multi-detector computed tomography is useful for identifying the extent of bone destruction, as well as soft tissue involvement of the lesion. The current case report presents a fibroblastic osteosarcoma involving the left hemimandible with very unusual radiographic features.

Nanoparticle-based assay for detection of S100P mRNA using surface-enhanced Raman spectroscopy.

The focus of this work is toward the development of a point-of-care (POC) handheld technology for the noninvasive early detection of salivary biomarkers. The initial of focus was the detection and quantification of S100 calcium-binding protein P (S100P) mRNA found in whole saliva for use as a potential biomarker for oral cancer. Specifically, a surface-enhanced Raman spectroscopy (SERS)-based approach and assay were designed, developed, and tested for sensitive and rapid detection of S100P mRNA. Gold nanoparticles (AuNPs) were conjugated with oligonucleotides and malachite green isothiocyanate was then used as a Raman reporter molecule. The hybridization of S100P target to DNA-conjugated AuNPs in sandwich assay format in both free solution and a vertical flow chip (VFC) was confirmed using a handheld SERS system. The detection limit of the SERS-based assay in free solution was determined to be 1.1 nM, whereas on the VFC the detection limit was observed to be 10 nM. SERS-based VFCs were also used to quantify the S100P mRNA from saliva samples of oral cancer patients and a healthy group. The result indicated that the amount of S100P mRNA detected for the oral cancer patients is three times higher than that of a healthy group.

Spindle-cell variant of ameloblastic carcinoma: a report of 3 cases and demonstration of epithelial-mesenchymal transition in tumor progression.

Ameloblastic carcinoma is a rare odontogenic neoplasm that demonstrates the histologic characteristics of ameloblastoma, accompanied by the cytologic features of malignancy. The spindle-cell variant of ameloblastic carcinoma (SCAC) is exceptionally rare, with a total of 10 cases having been reported in the literature to date. Histologically, a prominent sarcomatoid cell population appears to originate from the epithelial (ameloblastic) component. Like conventional ameloblastic carcinoma, most cases of SCAC occur in individuals older than 40 years of age. Here, 3 additional cases of SCAC are reported, 2 of which occurred in young individuals. Diagnostic criteria to aid in the identification of SCAC are proposed. Finally, histologic and immunohistochemical evidence supporting the occurrence of epithelial-mesenchymal transition in SCAC is presented.

Endogenous Fluorescence Lifetime Imaging (FLIM) Endoscopy For Early Detection Of Oral Cancer And Dysplasia.

We have performed a pilot clinical study, in which multispectral endogenous fluorescence (or autofluorescence) lifetime imaging (FLIM) was performed on clinically suspicious oral lesions of 73 patients undergoing tissue biopsy for oral dysplasia and cancer diagnosis. The results from this pilot study indicated that mild-dysplasia and early stage oral cancer could be detected from benign lesions using a computed aided diagnosis system developed based on biochemical and metabolic biomarkers derived from the endogenous FLIM images. The diagnostic performance of this novel FLIM clinical tool was estimated using a leave-onepatient-out cross-validation approach, which reported levels of sensitivity >90%, specificity >85%, and Area Under the Receiving Operating Curve (ROC-AUC) >0.9.

Longitudinal clinicopathologic data of the progression of oral mucosal melanoma-report of 2 cases and literature review.

Oral mucosal melanoma (OMM) is notorious for having a poor prognosis. Recognition of the early features of OMM by both clinicians and pathologists can play an important role in improving survival. Therefore, the purpose of this report is to increase awareness of the early features of OMM, by presenting 2 cases with longitudinal clinical and histopathologic documentation showing progression of OMM from a deceptively bland premalignant (noninvasive) oral melanocytic lesion (POML). By analyzing the clinical and histopathologic features of POML in our cases, and those in the literature, we found that the concerning features are (1) clinically, a pigmented lesion violating the ABCDE criteria or showing multiple recurrences; and (2) histologically, a melanocytic proliferation, in either a lentiginous or pagetoid pattern with or without cellular atypia. Making a diagnosis of POML prospectively is often challenging. Increasing awareness of the clinical and histopathologic features and complete surgical excision of POML are emphasized.

Handheld tunable focus confocal microscope utilizing a double-clad fiber coupler for in vivo imaging of oral epithelium.

A reflectance confocal endomicroscope with double-clad fiber coupler and electrically tunable focus lens is applied to imaging of the oral mucosa. The instrument is designed to be lightweight and robust for clinical use. The tunable lens allows axial scanning through > 250 ?? ? m in the epithelium when the probe tip is placed in contact with tissue. Images are acquired at 6.6 frames per second with a field of view diameter up to 850 ?? ? m . In vivo imaging of a wide range of normal sites in the oral cavity demonstrates the accessibility of the handheld probe. In vivo imaging of clinical lesions diagnosed as inflammation and dysplasia illustrates the ability of reflectance confocal endomicroscopy to image cellular changes associated with pathology.

Objective Detection of Oral Carcinoma with Multispectral Fluorescence Lifetime Imaging In Vivo.

Successful early detection and demarcation of oral carcinoma can greatly impact the associated morbidity and mortality rates. Current methods for detection of oral cancer include comprehensive visual examination of the oral cavity, typically followed by tissue biopsy. A noninvasive means to guide the clinician in making a more objective and informed decision toward tissue biopsy can potentially improve the diagnostic yield of this process. To this end, we investigate the potential of fluorescence lifetime imaging (FLIM) for objective detection of oral carcinoma in the hamster cheek pouch model of oral carcinogenesis in vivo. We report that systematically selected FLIM features can differentiate between low-risk (normal, benign and low-grade dysplasia) and high-risk (high-grade dysplasia and cancer) oral lesions with sensitivity and specificity of 87.26% and 93.96%, respectively. We also show the ability of FLIM to generate "disease" maps of the tissue which can be used to evaluate relative risk of neoplasia. The results demonstrate the potential of multispectral FLIM with objective image analysis as a noninvasive tool to guide comprehensive oral examination.

Inactivation of Fam20B in Joint Cartilage Leads to Chondrosarcoma and Postnatal Ossification Defects.

During endochondral ossification, chondrocytes embed themselves in a proteoglycan-rich matrix during the proliferation-maturation transition. Accumulating evidence shows that proteoglycans are essential components for chondrocyte proliferation and differentiation. When we conditionally inactivated FAM20B (Family with sequence similarity 20 member-B), which is a newly identified xylose kinase essential for glycosaminoglycan (GAG) formation on the protein core of proteoglycans, from the dental mesenchyme using Osr2-Cre, which is also strongly expressed in joint cartilage, we found chondrosarcoma in the knee joint and remarkable defects of postnatal ossification in the long bones. Mechanistic analysis revealed that the defects were associated with gain of function in multiple signaling pathways in the epiphyseal chondrocytes, such as those derived by WNT, BMP, and PTHrP/IHH molecules, suggesting that the FAM20B-catalyzed proteoglycans are critical mediators for a signaling balance in the regulatory network controlling chondrocyte differentiation and proliferation. In particular, we demonstrated that the WNT inhibitor was able to rescue part of the bone defects in Osr2-Cre;Fam20B(fl/fl) mice, indicating that FAM20B-catalyzed proteoglycans regulate postnatal endochondral ossification partially through the mediation of WNT signaling.

Diagnosis of oral lichen planus: a position paper of the American Academy of Oral and Maxillofacial Pathology.

Despite being one of the most common oral mucosal diseases and recognized as early as 1866, oral lichen planus (OLP) is still a disease without a clear etiology or pathogenesis, and with uncertain premalignant potential. More research is urgently needed; however, the research material must be based on an accurate diagnosis. Accurate identification of OLP is often challenging, mandating inclusion of clinico-pathological correlation in the diagnostic process. This article summarizes current knowledge regarding OLP, discusses the challenges of making an accurate diagnosis, and proposes a new set of diagnostic criteria upon which to base future research studies. A checklist is also recommended for clinicians to provide specific information to pathologists when submitting biopsy material. The diagnostic process of OLP requires continued clinical follow-up after initial biopsy, because OLP mimics can manifest, necessitating an additional biopsy for direct immunofluorescence study and/or histopathological evaluation in order to reach a final diagnosis.