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A thickened, white patch - leukoplakia - in the oral cavity is usually benign, but sometimes (in ~9% of individuals) it progresses to malignant tumour. Because the genomic basis of this progression is poorly understood, we undertook this study and collected samples of four tissues - leukoplakia, tumour, adjacent normal, and blood - from each of 28 patients suffering from gingivobuccal oral cancer. We performed multiomics analysis of the 112 collected tissues (four tissues per patient from 28 patients) and integrated information on progressive changes in the mutational and transcriptional profiles of each patient to create this genomic narrative. Additionally, we generated and analysed whole-exome sequence data from leukoplakia tissues collected from 11 individuals not suffering from oral cancer. Nonsynonymous somatic mutations in the CASP8 gene were identified as the likely events to initiate malignant transformation, since these were frequently shared between tumour and co-occurring leukoplakia. CASP8 alterations were also shown to enhance expressions of genes that favour lateral spread of mutant cells. During malignant transformation, additional pathogenic mutations are acquired in key genes (TP53, NOTCH1, HRAS) (41% of patients); chromosomal-instability (arm-level deletions of 19p and q, focal-deletion of DNA-repair pathway genes and NOTCH1, amplification of EGFR) (77%), and increased APOBEC-activity (23%) are also observed. These additional alterations were present singly (18% of patients) or in combination (68%). Some of these alterations likely impact immune-dynamics of the evolving transformed tissue; progression to malignancy is associated with immune suppression through infiltration of regulatory T-cells (56%), depletion of cytotoxic T-cells (68%), and antigen-presenting dendritic cells (72%), with a concomitant increase in inflammation (92%). Patients can be grouped into three clusters by the estimated time to development of cancer from precancer by acquiring additional mutations (range: 4-10 years). Our findings provide deep molecular insights into the evolutionary processes and trajectories of oral cancer initiation and progression. © 2022 The Authors. The Journal of Pathology published by John WileySons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Localized inflammatory or reactive overgrowths are quite more common clinical findings on human gingiva. Most of the lesions are benign and innocuous though some have potency to transfer in to a malignant lesion. These types of lesions are difficult to identify clinically as their appearance are quite similar so only Histopathological evaluation can detect their identity. In this case report we displayed a case of Peripheral Ossifying Fibroma in maxillary anterior tooth region in 32 year old female patient along with clinical, Histopathological evaluation along with present and future treatment details. Peripheral ossifying fibroma (POF) is usually a fibromatic, non neoplastic enlargement of the gingiva which shows areas of calcification or ossification. Synonyms for POF include Peripheral cementifying fibroma, Peripheral fibroma with calcification, Calcifying or ossifying fibrous epulis and Calcifying fibroblastic granuloma. Keywords: Gingival overgrowth, Ossifying fibroma, Peripheral ossifying fibroma, Peripheral cementifying fibroma

The concept of polarity in development, homeostasis and pathological alteration of tissues has emerged as an interesting aspect of the concerned biology. The epithelial cells exhibit apicobasal polarity which is maintained by Crumbs complex located at apical region of tight junction, ‘PAR’ complex at sub-apical region of tight junction and Scribble complex at adherens junction. Any functional perturbation of these proteins cause alteration of normal epithelial physiology en-route to epithelial pathology. In this maiden scientific exercise, we have tried to explore the association of expression of cell polarity proteins in OPMD and OSCC. Here, we have chosen DLG1 as a representative of polarity protein. RNA was isolated from the tissue samples. Then cDNA was prepared by RTPCR technique. qPCR was performed on cDNA samples. Expression data was analysed on the basis of Ct values. Paired t-test was performed with normalized Ct values of disease and normal tissue to determine whether there was any significant difference in expression between them. The statistical tests were done using SPSS software. Results of this study reflected increase in DLG1 expression in high grade dysplasia. There was no significant alteration in expression of DLG1 in WDSCC where there is formation of cluster of neoplastic cells ultimately producing epithelial islands and keratin pearls. But, in case of MDSCC, when the same neoplastic cells keep on invading with minimal keratin pearl formation, they again gain the mesenchymal character in full potential. And this phenomenon supports the upregulation of DLG1 in MDSCC in our study.

White sponge nevus (WSN) is a hereditary mucocutaneous leukokeratosis due to an altered expression of CK 4 and CK 13 genes, thereby causing a defect in keratinization. We report the case of WSN in a 27-year-old who presented with a complaint of white, painless patches in both the cheek mucosa since childhood. The patient was examined and the biopsy was done. Based on the clinical findings, inheritance pattern, and histopathological features, a diagnosis of WSN was made. The patient responded well to our novel treatment approach with amoxicillin suspension (250 mg/5 ml). Regarding the treatment of WSN, no definite pharmacological therapy is available till date. We report this case to emphasize that amoxicillin suspension topical therapy may be used as a novel treatment measure with its unique advantages.

Oral squamous cell carcinoma of the gingivo-buccal region (OSCC-GB) accounts for the highest cancer morbidity and mortality among men in India. It has been observed that about one-third of individuals with oral leukoplakia, a dysplastic precancerous lesion in the oral cavity, progress to oral cancer. We aimed to identify systematic transcriptomic changes as a normal tissue in the oral cavity progresses to frank OSCC-GB. Seventy-two OSCC-GB patients, from multiple hospitals, were recruited, and transcriptome analysis of tumor and adjacent normal tissue (of all patients) and adjacent leukoplakia tissue (of a subset of 25 unselected patients with concomitant leukoplakia) was performed. We have identified many differences in the transcriptomic profiles between OSCC-GB and squamous cell carcinoma of the head and neck regions. Compared to the normal/precancerous tissue, significant enrichment of ECM−receptor interaction, PI3K-Akt signaling, cytokine−cytokine receptor interaction, focal adhesion, and cell cycle pathways were observed in OSCC-GB. Using gene set enrichment analysis, we identified a profound role of interferon receptor signaling in tumor growth by activating immune evasion mechanisms. The role of tumor-infiltrating immune cells further supported the growth and immunosuppressive mechanism of tumor tissues. Some immune evasion genes—CD274, CD80, and IDO1—were found to be activated even in the precancerous tissue. Taken together, our findings provide a clear insight into the sequential genetic dysregulation associated with progression to oral cancer. This insight provides a window to the development of predictive biomarkers and therapeutic targets for gingivo-buccal oral cancer.

Neurofibromatosis type 1 (NF1), also known as von Recklinghausen's disease, is a type of genodermatoses having an autosomal dominant inheritance pattern and is recently considered as a RASopathy. Such patients are very much prone to develop mesenchymal tumors. However, carcinomas are quite rare in NF1 patients. This case study is the first case of oral squamous cell carcinoma (SCC) in tongue of an NF1 patient. A 35-year-old male reported to the Department of Oral Pathology in a tertiary care center with a chief complain of a painful ulcer on tongue for last 1 month. For confirmation of diagnosis of NF1, the “Diagnostic Criteria for Neurofibromatosis Type 1” was followed. Biopsied specimen of the tongue lesion was examined under microscope and histopathological features were suggestive of infiltrating SCC. Immunohistochemistry with Pan CK and beta-catenin was positive. RASopathy, WNT–beta-catenin pathway alteration, heat shock factor 1 production, and miRNA activity are investigated to explain the pathogenesis of malignancies in NF1 patients. In this first case of tongue SCC, we have found out the altered WNT–beta-catenin pathway.

It is hypothesized that same driver gene mutations should be present in both oral leukoplakia and cancer tissues. So, we attempted to find out mutations at one of the driver genes, CASP8, in cancer and adjacent leukoplakia tissues. Patients (n = 27), affected by both of cancer and adjacent leukoplakia, were recruited for the study. Blood and tissue DNA samples were used to identify somatic mutations at CASP8 by next generation sequencing method. In total, 56% (15 out of 27) cancer and 30% (8 out of 27) leukoplakia tissues had CASP8 somatic mutations. In 8 patients, both cancer and adjacent leukoplakia tissues, located within 2-5 cm of tumor sites, had identical somatic mutations. But, in 7 patients, cancer samples had somatic mutations but none of the leukoplakia tissues, located beyond 5cm of tumor sites, had somatic mutations. Mutated allele frequencies at CASP8 were found to be more in cancer compared to adjacent leukoplakia tissues. This study provides mutational evidence that oral cancer might have progressed from previously grown leukoplakia lesion. Leukoplakia tissues, located beyond 5cm of cancer sites, were free from mutation. The study implies that CASP8 mutation could be one of the signatures for some of the leukoplakia to progress to oral cancer.

Hanhart syndrome is a rare congenital and genetic disease, in which the most common signs are short, incompletely developed tongue (hypoglossia), absent or partially missing fingers and/or toes (hypodactylia), malformed arms and/or legs (peromelia), and small jaw (micrognathia). Here, we report a case of Hanhart syndrome in an 18-year-old boy. The boy presented with few extraoral and intraoral abnormalities such as short toes and phalanges along with partial syndactyly in the left hand only were the most relevant. Other features such as micro and retrognathic face, incompetent lips, and wide nasal bridge were also significant. The boy was suffering for difficulties in speech and swallowing due to small tongue size, high arched palate, crowding, and few missing teeth. To provide adequate treatment to a patient with Hanhart syndrome, this study aimed to review and to analyze this literature and treatment protocols.

Objective Growth retardation–alopecia–pseudoanodontia–optic atrophy (GAPO) syndrome (Online Mendelian Inheritance in Man [OMIM] ID 230740) is one of the rarest autosomal recessive syndromes. It is characterized by many phenotypes, including wide anterior fontanel, frontal bossing of the face, depressed nasal bridge, along with the 4 classic phenotypes contained in the name of the syndrome. Recent reports identified nonsense, missense, and splicing mutations at different exons of ANTXR1 responsible for GAPO syndrome in patients from different ethnic populations. Here, we are reporting a mutation at ANTXR1 in an Indian patient with GAPO syndrome. Study design We describe an inherited mutation at ANTXR1 in a 6-year-old Indian boy with GAPO syndrome. Results Genomic DNA from the patient with the GAPO syndrome and his family members were screened for previously reported mutations at ANTXR1 by sequencing. Novel homozygous and heterozygous mutations in exon-3 of ANTXR1 (c.265 G > A, p.Gly89 Arg) were identified in the patient and in other members of the family, respectively. However, no mutated allele was identified in genomic DNA from unrelated healthy individuals. Bioinformatic analysis by different tools predicted the deleterious, damaging, or aberrant splicing effect of mutation on the protein. Conclusions Functional inefficiency of ANTXR1 as a result of mutation might have led to GAPO syndrome.

Oral squamous cell carcinoma (OSCC) is a common oncological problem in India. However, the frequency of developing synchronous carcinomas, i.e., development of second primary tumor (SPT) either simultaneously or within 6 months of the index tumor, in the orofacial region are rare and ranges from 8% to 21%. These lesions are more aggressive, treatment-resistant, and metastasize early. The onset of SPT decreases the 5-year survival by 18–30% as compared to those with a single tumor. Astonishingly, it was found that synchronous OSCCs showed 100% male predominance, with no female predilection. This case of synchronous OSCC in a 58-year-old female had an index tumor involving right side of the mandible and a SPT in the left buccal mucosa. Both the lesions were histopathologically diagnosed well-differentiated squamous cell carcinoma. Hence, the importance of reporting this case lies on the rarity, aggressiveness, and poor prognosis of the lesion and the patient being a female.

Complex regional pain syndrome (CRPS) with localized erythema and hyperthermia of skin can be a perplexing clinical situation and has created varied diagnostic dilemmas for clinicians. Various cases of CRPS in the extremities have been documented, but in the head neck region, it is quite uncommon and only 13 cases have been reported since 1947 and here lies the importance of reporting the case. A 30-year-old female reported to the OPD with complain of severe pain, occasional swelling, change in overlying skin temperature, and color in left lower one-third region of face near mandibular angle since 2½ years. She had a trauma to that region 3 years back. The history and clinical examination revealed that the patient met “Budapest Clinical Criteria” for diagnosis of CRPS Type II and was treated with amitriptyline, pregabalin, methylcobalamine, steroids, and other supportive treatments. The patient showed marked improvement in pain control. Therefore, history and clinical examination and early diagnosis are crucial for the better treatment outcome in CRPS Type II.

Several studies reported that mtDNA mutations may play important roles in carcinogenesis although the mechanism is not clear yet. Most of the studies compared mtDNA sequences in a tumor with those in normal tissues from different individuals ignoring inter-individual variations. In this study, 271 SNPs, 7 novel SNPs (or SNVs), and 15 somatic mutations were detected in mtDNA of 8 oral cancer tissues with respect to reference (rCRS) and adjacent normal tissues, respectively, using Ion PGM next generation sequencing method. Most of the sequence variations (76 SNPs and 1 somatic) are present in D-loop region followed by CyB (36 SNPs), ATP6 (24 SNPs), ND5 (17 SNPs and 5 somatic), ND4 (18 coding and 2 somatic) and other non-coding and coding DNA sequences. A total of 53 and 8 non-synonymous SNPs and somatic mutations, respectively, were detected in tumor tissues and some of these variations may have deleterious effects on the protein function as predicted by bioinformatic analysis. Moreover, significantly low mtDNA contents and expression of several mitochondrial genes in tumor compared to adjacent normal tissues may have also affected mitochondrial functions. Taken together, this study suggests that mtDNA mutations as well as low expression of mtDNA coded genes may play important roles in tumor growth. Although the sample size is low, an important aspect of the study is the use of adjacent control tissues to find out somatic mutations and a change in the expression of mitochondrial genes, to rule out inter-individual and inter-tissue variations which are important issues in the study of mitochondrial genomics.

Deregulation of miRNA expression may contribute to tumorigenesis and other patho-physiology associated with cancer. Using TLDA, expression of 762 miRNAs was checked in 18 pairs of gingivo buccal cancer-adjacent control tissues. Expression of significantly deregulated miRNAs was further validated in cancer and examined in two types of precancer (leukoplakia and lichen planus) tissues by primer-specific TaqMan assays. Biological implications of these miRNAs were assessed bioinformatically. Expression of hsa-miR-1293, hsa-miR-31, hsa-miR-31* and hsa-miR-7 were significantly up-regulated and those of hsa-miR-206, hsa-miR-204 and hsa-miR-133a were significantly down-regulated in all cancer samples. Expression of only hsa-miR-31 was significantly up-regulated in leukoplakia but none in lichen planus samples. Analysis of expression heterogeneity divided 18 cancer samples into clusters of 13 and 5 samples and revealed that expression of 30 miRNAs (including the above-mentioned 7 miRNAs), was significantly deregulated in the cluster of 13 samples. From database mining and pathway analysis it was observed that these miRNAs can significantly target many of the genes present in different cancer related pathways such as "proteoglycans in cancer", PI3K-AKT etc. which play important roles in expression of different molecular features of cancer. Expression of hsa-miR-31 was significantly up-regulated in both cancer and leukoplakia tissues and, thus, may be one of the molecular markers of leukoplakia which may progress to gingivo-buccal cancer.

Genetic variations at microRNA and microRNA processing genes are known to confer risk of cancer in different populations. Here, we studied variations at eight microRNA (miRNA) and four miRNA processing genes in 452 controls and 451 oral cancer patients by TaqMan genotyping assays. Variant allele-containing genotypes at mir-196a2 and variant allele homozygous genotype at Ran increased the risk of cancer significantly [adjusted odds ratio (OR) (95% confidence interval (CI)) = 1.3 (1-1.7) and 2.3 (1.1-4.6), respectively]. Conversely, variant allele-containing genotypes at mir-34b and variant allele homozygous genotype at Gemin3 reduced the risk of cancer significantly [adjusted OR (95% CI) = 0.7 (0.5-0.9) and 0.6 (0.4-1), respectively]. Cumulative risk was also increased by three times with increase in the number of risk alleles at these four loci. In tobacco stratified analysis, variant allele homozygous genotypes at mir-29a and Ran increased [adjusted OR (95% CI) = 1.5 (1-2.3) and 3 (1.1-8.4) respectively], while variant allele-containing genotypes at mir-34b decreased [adjusted OR (95% CI) = 0.6 (0.4-0.9)] the risk of cancer significantly. Thus, genetic variation at miRNA and processing genes altered the risk of oral cancer in this population thereby corroborating studies in other populations. However, it is necessary to validate this result in different Indian sub populations with larger sample sizes and examine the effect of these variations in tumour tissues to explain the mechanism of risk alteration.

Background MicroRNAs have been implicated in cancer but studies on their role in precancer, such as leukoplakia, are limited. Sequence variations at eight miRNA and four miRNA processing genes were studied in 452 healthy controls and 299 leukoplakia patients to estimate risk of disease. Results Genotyping by TaqMan assay followed by statistical analyses showed that variant genotypes at Gemin3 and mir-34b reduced risk of disease [OR = 0.5(0.3–0.9) and OR = 0.7(0.5–0.9) respectively] in overall patients as well as in smokers [OR = 0.58(0.3–1) and OR = 0.68(0.5–0.9) respectively]. Among chewers, only mir29a significantly increased risk of disease [OR = 1.8(1–3)]. Gene-environment interactions using MDR-pt program revealed that mir29a, mir34b, mir423 and Xpo5 modulated risk of disease (p