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Background: ANXA5, a notable tumor marker, displays irregular expression in diverse solid cancers, and links to local recurrence and metastasis rates. We aimed study the expression of ANXA5 in oral squamous cell carcinoma (OSCC) and its diagnostic and prognostic values., Methods: 520 head and neck squamous cell carcinoma (HNSCC) patients in TCGA database and 124 OSCC patients in Nanjing stomatology hospital were enrolled in our study. Immunohistochemical analyses were performed using ANXA5 antibodies. Chi-square test was used to analyze the clinicopathological features. Survival rates were determined using the Kaplan-Meier method and log-rank test., Results: Our results showed significantly elevated ANXA5 at the gene and protein levels in HNSCC and OSCC compared to non-tumor tissues. Histopathologically, ANXA5 was broadly present in OSCC tumor cells and fibroblast-like cells but absent in tumor-infiltrating lymphocytes, particularly at the invasive tumor front. Patients exhibiting high ANXA5 expression in these cells demonstrated poor differentiation, aggressive invasion patterns, and heightened lymph node metastasis risk, contributing to poorer postoperative outcomes. Remarkably, ANXA5 in fibroblast-like cells emerged as an independent risk factor impacting survival in OSCC patients. Gene set enrichment analysis (GSEA) highlighted ANXA5's involvement in key pathways like epithelial-mesenchymal transformation (EMT), TGF-beta signaling, and hypoxia, which correlated with adverse clinical outcomes in OSCC., Conclusion: ANXA5 emerges as a significant prognostic biomarker for OSCC, potentially influencing its metastasis via the EMT pathway., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Aims: Different regions of oral squamous cell carcinoma (OSCC) have particular histopathological characteristics, and the individual histological characteristics of the tumors are poorly understood. Therefore, calculating the proportion of tumor cells in different regions that allow assessment of the prognostic outcomes for OSCC patients would be of great clinical significance., Methods and Results: We established an open-source software-based analytic pipeline that defines the inner tumor and invasive tumor front (ITF) in pancytokeratin-stained whole slide images (WSIs) and quantifies the tumor-stroma ratio (TSR) within the two regions. We applied this method to 114 patients with OSCC and predicted patient prognosis by the TSR. The proportion of tumor area in the inner tumor was generally higher than that in the ITF (p < 0.0001). TSR was an independent prognostic factor for overall survival (OS) (p = 0.016), disease-free survival (DFS) (p = 0.026), and relapse-free survival (RFS) (p = 0.037) in inner tumor, and TSR was an independent prognostic factor for OS (p = 0.00052), DFS (p = 0.035), and metastasis-free survival (MFS) (p = 0.038) in the ITF. Tumor-low status was associated with poorer prognosis. There was a significant correlation between the TSR and perineural invasion (PNI) in the inner tumor (p = 0.009)., Conclusions: The histopathological characteristics of different regions of OSCC may be used to develop the potential prognostic markers. The TSR of the inner tumor is more targeted in predicting prognosis and accurately assesses the risk of PNI+., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: The invasive tumor front (ITF) of oral squamous cell carcinoma (OSCC) and the reactive changes in regional lymph nodes (RLNs) are believed to carry integral prognostic information about the tumor's invasive capacity and insight into host immune response, respectively., Aim: This study aims to evaluate the reactivity patterns of RLNs in relation to the tumor stage, grade and various histopathological parameters at the ITF of primary tumor, in an attempt to elucidate the nature of host-immune response to tumor., Materials and Methods: Pattern of invasion (POI) using Bryne's criteria, peritumoral inflammation, and status of connective tissue (CT) stroma of 50 OSCC cases, that underwent selective neck dissection were assessed at the ITF. Immunoreactivity patterns in corresponding 450 RLNs were assessed as proposed by Tsakraklides and Ioachim. Further, 97 metastatic lymph nodes (LNs) were evaluated for degree and pattern of tumor invasion. The datasets were subjected to the Chi-square analysis., Results: There was statistically significant association (P = 0.001) of Type III and Type IV POI as well as mild peritumoral inflammation (P = 0.024) with the advanced stages of OSCC as compared to early stages. Significant association was observed between LN reactivity pattern and tumor stage (P = 0.05), with metastatic nodes exhibiting germinal center predominance (97.9%) and lymphocyte predominance (69.1%) largely observed in nonmetastatic nodes. Majority of metastatic nodes showed Grade 3 invasion (54.7%) in the form of large islands (57.7%), whereas two (2.1%) nodes were totally effaced by tumor metastasis. Statistical significance was observed between CT stroma at ITF and degree of tumor invasion in metastatic LN (P = 0.001). POI also showed significant correlation with peritumoral inflammation (P = 0.002), CT stroma (P = 0.02), and LN reactivity pattern (P = 0.03)., Conclusion: This study supports the presence of a strong immunological host-tumor relationship., Competing Interests: None

Background: The invasive front is presumed to contain the most aggressive subpopulation of tumor cells that ultimately invade, spread locally and metastasize. Studying the histopathological grading of the tumor/ tissue interface at the invasive front may help in developing the treatment plan., Objectives: The aim of this study was to check the reliability of the tumor/tissue interface in predicting lymph node metastasis in oral squamous cell carcinoma (OSCC) of the tongue by evaluating the following: the histopathological grading of hematoxylin and eosin (H&E)-stained excision biopsy specimens according to the modified version of Broder's classification system; and the invasive tumor front (ITF) with the modified version of Bryne's grading system. The study also aimed at studying the lymph nodes for metastases and comparing these histopathological grading systems and lymph node metastases., Material and Methods: All retrospective and prospective cases from the archives of the Department of Oral Pathology and Microbiology of the A.B. Shetty Memorial Institute of Dental Sciences (ABSMIDS), NITTE University in Mangalore, India, collected during the period from 2012 to 2014 were considered for histopathological grading., Results: This study found a significant association between the modified version of Bryne's ITF grading system and lymph node metastases whereas the widely used modified version of Broder's classification failed to show any statistical significance. Only the multifactorial malignancy grading of the deep invasive margins of OSCC proved to be of high prognostic value., Conclusions: The study found that the degree of keratinization, nuclear polymorphism, the pattern of invasion, and the host response showed significant variation at the invasive front of the tumor as compared to superficial parts, which makes Bryne's grading system more reliable than Broder's grading system.

Background: Transforming growth factor-β (TGF-β) exerts its versatile function (oncogenic or tumor suppressive role) during the carcinogenesis in tumor microenvironment-dependent manner. Considering the tumor heterogeneity, spatial and temporal distribution of TGF-β in oral squamous cell carcinoma (OSCC) remained to be elucidated., Methods: Formalin-fixed, paraffin-embedded sections derived from 73 patients with OSCC were immunostained, revealing expression patterns of TGF-β, both at the regions of tumor center (TC) and invasive tumor front (ITF)., Results: The TGF-β levels on tumor cells, fibroblast-like cells (FLCs), and tumor-infiltrating lymphocytes (TILs) were comparable and showed to be cell-type-independent manner. Although TC regions harbored less positive staining of TGF-β than ITF in tumor cells (TGF-β Tumor cell ) (89.0% vs 98.3%; P = 0.037), FLCs (TGF-β FLC ) (86.3% vs 96.6%; P = 0.043), and TILs (TGF-β TIL ) (83.6% vs 94.8%; P = 0.044), respectively, TGF-β at TC regions, not at ITF, correlated to poor clinical outcomes. At TC regions, patients with high TGF-β Tumor cell had high recurrence rate, and patients with high TGF-β TIL showed inferior worst pattern of invasion. Of note, high TGF-β Tumor cell at TC predicted shorter overall survival time, recurrence-free survival, and disease-free survival in patients with OSCC, whereas high TGF-β TIL had no association with survival time. Cox regression analyses indicated that tumor cell-derived TGF-β at TC was an independent risk factor for survival outcome in patients with OSCC., Conclusions: Tumor cell-derived TGF-β at TC regions, but not at ITF, could be a promising predictor for disease recurrence and poor prognosis of patients with OSCC., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Aim: The aim of the present study was to: (a) analyze the nature of collagen with respect to cohesive and discohesive invasive tumor front (ITF) of oral squamous cell carcinoma (OSCC); (b) analyze the clinicopathological correlation with the nature of collagen at the ITF of OSCC; and (c) correlate the nature of collagen with Broder's and Bryne's histological grading system of OSCC., Methods: Tissue sections of 29 OSCC with ITF were stained with hematoxylin-eosin and picrosirius red staining for evaluation under a polarized microscope., Results: Tumors with a cohesive front had a thick collagen fiber, are predominantly organized, red-yellow in color, well packed, and show strong birefringence (P<.005). A gradual change in the nature of the collagen fiber was observed in the discohesive tumor front, where the collagen fibers were thin, disorganized, yellow-orange to green-yellow in color, loosely packed, and with weak birefringence (P<.005)., Conclusion: A cohesive tumor front with organized collagen fibers prevents tumor invasion and metastasis. As it is inhibits an increase in tumor size, it is associated with the initial stage of tumor (I & II), whereas in a discohesive tumor front, the fibers might enhance the movement of tumor cells, resulting in invasion and metastasis., (© 2017 John Wiley & Sons Australia, Ltd.)

Introduction: Oral squamous cell carcinoma (OSCC) accounts 94% of all malignant lesions in the oral cavity. In the assessment of OSCC, nowadays the WHO grading system has been followed widely but due to its subjectivity, investigators applied the sophisticated technique of computer-assisted image analysis in the grading of carcinoma in larynx, lungs, esophagus, and cervix to make it more objective., Aims and Objectives: Access, analyze, and compare the cellular area (CA); cytoplasmic area (Cyt A); nuclear area (NA); nuclear perimeter (NP); nuclear form factor (NF); and nuclear-cytoplasmic ratio (N/C) of the cells in different grades of OSCC., Materials and Methods: Fifty OSCC cases were obtained and stained with hematoxylin and eosin which were graded according to the WHO classification. The sections were subjected to morphometric analysis to analyze all the morphometric parameters in different grades of OSCC and subjected to one-way ANOVA statistical analysis., Results: CA and Cyt A decreased from normal mucosa with dedifferentiation of OSCC. The NA and NP increased in carcinoma group when compared to normal mucosa but decreased with dedifferentiation of OSCC (P < 0.05). NF had no significance with normal mucosa and different grades of OSCC (P > 0.05), while N/C ratio increased from normal mucosa through increasing grades of OSCC, reaching the highest value in poorly differentiated squamous cell carcinoma (P < 0.05)., Conclusion: Both cellular and nuclear variables provide a more accurate indication of tumor aggressiveness than any single parameter. Morphometric analysis can be a reliable tool to determine objectively the degree of malignancy at the invasive tumor front., Competing Interests: There are no conflicts of interest.