The stromal immunoexpression of CLIC4 may be related to the difference in the biological behavior between oral squamous cell carcinoma and oral verrucous carcinoma

Background: Oral squamous cell carcinoma (OSCC) has high morbidity and mortality rates while oral verrucous carcinoma (OVC), an uncommon variant of OSCC, exhibits a distinct biological behavior. CLIC4 protein plays a role in the cell cycle and apoptosis regulation and participates in the myofibroblasts transdifferentiation process, which are the main cells of the tumor stroma. This study analyzed the immunoexpression of CLIC4 and α-SMA in 20 OSCC cases and 15 OVC cases. Material and methods: A semiquantitative analysis of CLIC4 and α-SMA immunoexpression was performed in the parenchyma and stroma. Nuclear and cytoplasmic reactivity was analyzed separately for the CLIC4 immunostaining. The data were submitted to Pearson's chi-square and Spearman's correlation tests (p ≤ 0.05). Results: In the CLIC4 analysis, there was a significant difference in the immunoexpression of this protein between OSCC and OVC stroma (p < 0.001). It was observed a higher expression of α-SMA in the OSCC stroma. There was a positive and significant correlation between CLIC4 and α-SMA immunoexpression in the OVC stroma (r = 0,612; p = 0,015). Conclusions: The decrease or absence of nuclear CLIC4 immunoexpression in the neoplastic epithelial cells and the increase of its expression in the stroma may influence the difference in biological behavior between OSCC and OVC. (AU)

Elective Neck Dissection for cT1-4 N0M0 Head and Neck Verrucous Carcinoma.

OBJECTIVE: To investigate the survival benefit of elective neck dissection (END) over neck observation in cT1-4 N0M0 head and neck verrucous carcinoma (HNVC). STUDY DESIGN: Retrospective cohort study. SETTING: The 2006 to 2017 National Cancer Database. METHODS: Patients with surgically resected cT1-4 N0M0 HNVC were selected. Linear, binary logistic, Kaplan-Meier, and Cox proportional hazards regression models were utilized. RESULTS: Of 1015 patients satisfying inclusion criteria, 223 (22.0%) underwent END. The majority of patients were male (55.4%) and white (91.0%) with disease of the oral cavity (67.6%) classified as low grade (90.0%) and cT1-2 (81.8%). The minority of ENDs (4.0%) detected occult nodal metastases. The rate of END increased from 2006 to 2017 for both cT1-2 (16.3% vs 22.0%, p = .126, R2 = 0.405) and cT3-4 (41.7% vs 70.0%, p = .424, R2 = 0.232) disease but these trends were not statistically significant. Independent predictors of undergoing END included treatment at an academic facility (adjusted odds ratio [aOR]: 1.75, 95% confidence interval [CI]: 1.19-2.55), cT3-4 disease (aOR: 3.31, 95% CI: 2.16-5.07), and tumor diameter (aOR: 1.09, 95% CI: 1.01-1.19) (p < 0.05). The 5-year overall survival (OS) of patients treated with and without END was 71.3% and 70.6%, respectively (p = .661). END did not significantly reduce the 5-year hazard of death (adjusted hazard ratio: 1.25, 95% CI: 0.91-1.71, p = .172). END did not significantly improve 5-year OS in univariate and multivariate analyses stratified by several patient, facility, tumor, and treatment characteristics. CONCLUSION: END does not confer an appreciable survival benefit in HNVC, even after stratifying univariate and multivariate analyses by several patient, facility, tumor, and treatment characteristics. LEVEL OF EVIDENCE: Level 4.

Atypical Squamous Verrucous Lesions of the Oral Cavity: Challenges in Interpretation of Small Incisional Biopsies.

BACKGROUND: Squamous verrucous proliferative lesions of oral cavity can pose a diagnostic challenge for the general pathologist, especially on small biopsies. The superficial nature of incisional biopsies and inconsistent histologic terminologies used for these lesions contribute to often-discrepant clinical diagnosis, resulting in delayed treatment. This study aims to explore the proliferative squamous lesions of oral cavity, correlate biopsy & resection diagnoses, and evaluate possible reasons for discrepant diagnosis (if any). DESIGN: A retrospective review of oral verrucous squamous lesions was undertaken. Pathology database was searched for oral cavity biopsies from January2018 through August2022 with the keywords: atypical, verrucous, squamous, and proliferative. Cases with follow-up were included in this study. A blinded review of the biopsy slides was performed and documented by a single head and neck pathologist. Demographic data, biopsy and final diagnosis were recorded. RESULTS: Twenty-three cases met criteria for inclusion. The mean patient age was 61.1 years with a male: female ratio of 1.09. Most frequent site was lateral border of tongue (36%) followed by buccal mucosa and retromolar trigone. The most common biopsy diagnosis was "Atypical squamoproliferative lesion, excision recommended" (n = 16/23, 69%) with 13/16 showing conventional squamous cell carcinoma (SCC) on follow-up resection. 2/16 atypical cases underwent repeat biopsy for confirmation of diagnosis. Overall, conventional SCC was the most prevalent final diagnosis (73%, n = 17), followed by verrucous carcinoma (17%, n = 4). On slide review, six initial biopsies were reclassified as SCC, while one final diagnosis was reclassified as a hybrid carcinoma (on resection specimen). Diagnostic concordance (biopsy and resection) was observed in three cases, all three were recurrences. The primary reasons for discrepant diagnosis on initial biopsies were found to be 1. Obscuring inflammation, 2. Superficial biopsies, and 3. Under recognition of morphologic features (e.g., tear shaped rete, loss of polarity, dyskeratotic cells, paradoxical maturation) that help differentiate dysplasia from reactive atypia. CONCLUSION: This study highlights the rampant interobserver variability in diagnosis of oral cavity squamous lesions and emphasizes importance of identifying morphologic clues that can aid in correct diagnosis, thereby helping in adequate clinical management.

The stromal immunoexpression of CLIC4 may be related to the difference in the biological behavior between oral squamous cell carcinoma and oral verrucous carcinoma.

BACKGROUND: Oral squamous cell carcinoma (OSCC) has high morbidity and mortality rates while oral verrucous carcinoma (OVC), an uncommon variant of OSCC, exhibits a distinct biological behavior. CLIC4 protein plays a role in the cell cycle and apoptosis regulation and participates in the myofibroblasts transdifferentiation process, which are the main cells of the tumor stroma. This study analyzed the immunoexpression of CLIC4 and α-SMA in 20 OSCC cases and 15 OVC cases. MATERIAL AND METHODS: A semiquantitative analysis of CLIC4 and α-SMA immunoexpression was performed in the parenchyma and stroma. Nuclear and cytoplasmic reactivity was analyzed separately for the CLIC4 immunostaining. The data were submitted to Pearson's chi-square and Spearman's correlation tests (p ≤ 0.05). RESULTS: In the CLIC4 analysis, there was a significant difference in the immunoexpression of this protein between OSCC and OVC stroma (p < 0.001). It was observed a higher expression of α-SMA in the OSCC stroma. There was a positive and significant correlation between CLIC4 and α-SMA immunoexpression in the OVC stroma (r = 0,612; p = 0,015). CONCLUSIONS: The decrease or absence of nuclear CLIC4 immunoexpression in the neoplastic epithelial cells and the increase of its expression in the stroma may influence the difference in biological behavior between OSCC and OVC.

Whole genome DNA methylation and mutational profiles identify novel changes in proliferative verrucous leukoplakia.

OBJECTIVE: Proliferative verrucous leukoplakia (PVL) is a rare form of oral leukoplakia with a relatively high transformation rate resulting in oral squamous cell carcinoma (OSCC). Molecular analysis of PVL at the genome level is limited and has only identified molecular similarities between PVL and OSCC. However, the clinical profile of PVL suggests that molecular differences may be more important. STUDY DESIGN: Whole exome sequencing of 5 PVL-associated OSCC (PVL-OSCC) and paired blood samples was used to identify somatic mutations common to the tumors. Whole methylome analysis of samples from 4 PVL-associated OSCC and 3 OSCC of non-PVL origin samples was conducted to explore differential methylation. RESULTS: In contrast to conventional OSCC, PVL-associated OSCC showed infrequent TP53 mutation and altered spectra of PIK3CA and NOTCH1 mutations. Unsupervised hierarchical clustering identified 63 probes that discriminated between PVL-associated OSCC and OSCC of non-PVL origin. Differences in methylation were most significant for divalent metal ion transport, particularly calcium movement. CONCLUSIONS: Specific differences in mutation and methylation profiles between PVL-derived OSCC and OSCC of non-PVL origin suggest differences in their transformation pathways. Further studies of early PVL lesions may identify markers of transformation that are also applicable to more common oral premalignant disorders such as oral epithelial dysplasia.

Wolf in sheep's clothing - Oral proliferative verrucous leukoplakia: Progression with longitudinal molecular insights.

BACKGROUND: Oral proliferative verrucous leukoplakia (OPVL) is a chronic form of oral leukoplakia that progresses to a multifocal disease with confluent, exophytic and proliferative features. The clinical differential diagnosis for OPVL includes frictional keratosis, leukoplakia, chronic hyperplastic candidiasis, squamous papilloma, verrucous hyperplasia, verrucous carcinoma and squamous cell carcinoma. In this study, we aimed to delineate the dynamic changes in molecular signature during OPVL progression. We compare to a cohort of oral cavity keratinizing squamous cell carcinoma (OSCC) patients covering the spectrum of verrucous carcinoma to invasive squamous cell carcinoma including cytologically bland cuniculatum variant. METHODS: Samples from a large OPVL lesion that exhibited a histopathologic continuum of OPVL progression. RESULTS: Canonical hotspot TERT promoter mutations were identified in all patients. TERT C228T was dominant and mutually exclusive with TERT C250T. In patients with TERT C250T, there was concurrent PI3 point mutation. TP53 mutations were also consistently found (8/10). At the protein level, p53 was abnormal, with loss of function and gain of function. CONCLUSIONS: OPVL is a pathology that shows proximity to the gene expression profile of OSCC, highlighting signatures in common that can be important targets for drug treatment, as well as in the development of diagnostic and prognostic strategies for this disease.

Squamous Cell Carcinoma of the Foot Occurring in a Wart.

Verrucous carcinoma is a rare form squamous cell carcinoma which appears similar to a wart. When it occurs in the feet, it can be easily misdiagnosed. It rarely metastasizes or recurs posttreatment. We report a case of a septuagenarian with recurrence of verrucous carcinoma diagnosed within 6 months at the site of previous treatment. Unique features in our patient's clinical presentation include his advanced age, being nondiabetic, and the rapid recurrence of carcinoma.Level of Evidence: Level IV: Case report.

Mohs micrographic surgery for verrucous carcinoma: a review of the literature.

Verrucous carcinoma is a rare, low grade variant of squamous cell carcinoma that rarely metastasizes but tends to display aggressive local behavior. Wide local excision is the most common treatment, but has high rates of local recurrence, ranging from 19 to 75% in the literature. The cases of verrucous carcinoma treated with Mohs micrographic surgery in the literature, as well as a previously unpublished case is summarized. PubMed was searched for terms related to verrucous carcinoma and Mohs micrographic surgery, and articles reporting cases of verrucous carcinoma treated with Mohs were reviewed and summarized. A previously unpublished case treated at our institution was also reported. Thirty-eight cases of verrucous carcinoma treated with Mohs surgery were analyzed. The average age of patients was 52.1, and 50% were male. The most common sites were the foot (47%) and the anogenital region (34%). Lesion duration ranged from 0.17 to 40 years with a mean of 4.8 years, and tumor diameter ranged from 1 to 10 cm with a mean of 4.6 cm. The local recurrence rate following Mohs was 16%, with nodal metastasis occurring in 3% and no cases of distant metastasis. As verrucous carcinoma demonstrates locally aggressive behavior and a high risk of local recurrence, Mohs micrographic surgery should be considered as first line treatment. Further research directly comparing wide local excision to Mohs surgery is needed.

Penile squamous cell carcinoma exclusive to the shaft, with a proposal for a novel staging system.

Penile squamous cell carcinomas (SCC) originating in the shaft are rare. pT1/pT2 categories in the American Joint Committee on Cancer (AJCC) staging manual (8th edition) are poorly defined for SCCs arising in the dorsal shaft as anatomic structures differ between the glans and dorsal shaft (corpus spongiosum vs dartos/Buck's fascia, respectively). We reviewed six penile SCC cases exclusive to the shaft, an unusual presentation, identified amongst 120 patients treated with penectomy. We propose a novel pT staging system for dorsal shaft tumors tailored to its anatomic landmarks, where tumors extending to Buck's fascia are considered pT2 instead of pT1. The mean age at penectomy, average duration of follow-up, and mean depth of invasion were 64 years, 45 months, and 9.8 mm, respectively. Four cases were moderately differentiated, HPV-negative SCCs of the usual type and two cases were HPV-positive basaloid and warty-basaloid carcinomas. Three cases had nodal or distant metastasis at the time of penectomy, and histologic assessment in these cases showed invasion into the Buck's fascia or deeper. According to the current AJCC system, only one of these three cases would be staged as ≥ pT2. In contrast, all three metastatic tumors would be staged as ≥ pT2 in the proposed model. At last follow-up, one patient died of disease-related complications. Based on this limited series, the proposed staging model appears to suggest better patient stratification for pT1/pT2 stages. This model incorporates Buck's fascia, which has been postulated as a pathway of tumor infiltration. Additional studies are needed to validate this model.

Oral verrucous xanthoma with oral lichen planus: a case report.

Verrucous xanthoma is a rare benign muco-cutaneous lesion, whereas oral lichen planus is a chronic inflammatory disease relatively common in the clinical setting. Verrucous xanthoma and oral lichen planus can reportedly coexist according to foreign literature. Owing to the low incidence of verrucous xanthoma and the rarity of co-occurrence of these two diseases, the mechanism underlying the co-occurrence of the two diseases remains inconclusive. In this work, a case of oral verrucous xanthoma complicated with oral lichen planus was reported. Related literature was reviewed to discuss the clinical classification, pathological classification, and possible pathogenesis of the two diseases.

Tumor lesions of penis and scrotum according to WHO classification 2022.

Similarly to testicular tumors, key changes on penile and scrotal neoplasia were incorporated into WHO classification 2016. Therein, penile squamous cell carcinomas were divided into two groups based on the pathogenesis, namely HPV-associated and HPV-independent. This remains unchanged in WHO classification 2022. For those carcinomas where HPV status can not be determined, a category of squamous cell carcinoma NOS was added. Variants of squamous cell carcinoma, namely basaloid, papillary-basaloid, warty, warty-basaloid, clear cell and lymphoepithelioma-like carcinomas are not recognized as distinctive variants of HPV-associated group anymore. Similarly, squamous cell carcinoma, usual type, pseudohyperplastic, pseudoglandular, verrucous carcinoma, carcinoma cunniculatum, papillary, adenosquamous, sarcomatoid and mixed carcinoma are no more not recognized as distinctive variants of HPV-independent carcinomas. Instead, these variants are now called subtypes. Some previously distinct subtypes now belong to the morphological spectrum of other subtypes. Basaloid-papillary subtype belongs to basaloid squamous cell carcinoma and carcinoma cunniculatum is currently recognized as morphological variation of verrucous carcinoma. Pseudohyperplastic and mixed subtypes were removed from the classification. Adenosquamous carcinoma is currently termed adenosquamous and mucoepidermoid carcinoma and represents distinct entity. Precursor lesions of squamous cell carcinoma underwent substantial modifications in the WHO classification 2016 as well, and remain unchanged in WHO classification 2022. Terminology for HPV - induced lesions have been unified to low grade squamous intraepithelial lesions (LSIL) and high grade squamous intraepithelial lesions (HSIL). This classification applies to the whole anogenital area, including penis, anus, perianal region, vulva, vagina and uterine cervix. LSIL is further divided to condyloma accuminatum and (penile) intraepithelial neoplasia grade 1 (PeIN1), HSIL is divided to PeIN2 and PeIN3. Penile HPV-independent precursor lesions are named differrentiated penile intraepitelial neoplasia (dPeIN) and are identical to analogous lesions on vulva.

[Expression of TNFAIP6 in oral verrucous carcinoma and oral squamous cell carcinoma and its relationship with clinicopathology].

PURPOSE: This study was designed to establish a 3-dimentional finite element system to simulate the clinical scenario where labial segment was retracted with sliding mechanism in extraction cases treated by individualized lingual orthodontics. METHODS: A typical clinical case was selected. The subject was diagnosed with Class I malocclusion with alveolar protrusion and treated with extraction of 4 first premolars. The subject was under the treatment stage of frontal retraction by eBrace system, an individualized lingual appliance. The subject was also taken cone-beam CT (CBCT) based on which digital 3D reconstruction of dentition structures was formed with Mimics software. With the aid of software platform Pro/E 4.0, the important anatomical structures were defined, and relevant lingual devices, including lingual brackets, arch-wires, mini-screws and other accessories were formed. With the aids of software platform Geomagic Studio 13.0, the 3-dimentional structural mode, featuring maxillary alveolar, upper dentition, periodontal ligament, miniscrew and lingual applicance, were constructed. With the assistance of Ansys Workbench 15.0, 3D model for finite element system was finalised by conducting model meshing and defining the mechanical properties and the interface relations of the selected materials. RESULTS: Based on the digital information drawn from CBCT image, a 3-dimentional finite element system was successfully created, featuring all the elements mimicking the clinical scenario for En masse retraction. This system enabled an insight study on the effects of various retraction modes controlling the incisal torque and maintaining the dental arch integrity. CONCLUSIONS: The creation of a finite element system in this study is based on the digital data from the CBCT image of a real patient diagnosed with prognathic malocclusion and treated by lingual appliance. The clinical scenario of labial segment retraction via sliding mechanism is simulated in this finite element model.

Segmentation of Oral Leukoplakia (OL) and Proliferative Verrucous Leukoplakia (PVL) Using Artificial Intelligence Techniques.

PVL (proliferative verrucous leukoplakia) has distinct clinical characteristics. They have a proclivity for multifocality, a high recurrence rate after treatment, and malignant transformation, and they can progress to verrucous or squamous cell carcinoma. AI can aid in the diagnosis and prognosis of cancers and other diseases. Computational algorithms can spot tissue changes that a pathologist might overlook. This method is only used in a few studies to diagnose LB and PVL. To see if their cellular nuclei differed and if this cellular compartment could classify them, researchers used a computational system and a polynomial classifier to compare OLs and PVLs. 161 OL and 3 PVL specimens in the lab were grown, photographed, and used for training and computation. Exam orders revealed patients' sociodemographics and clinical pathologies. The nucleus was segmented using Mask R-CNN, and LB and PVL were classified using a polynomial classifier based on nucleus area, perimeter, eccentricity, orientation, solidity, entropies, and Moran Index (a measure of disorderliness). The majority of OL patients were male smokers; most PVL patients were female, with a third having malignant transformation. The neural network correctly identified cell nuclei 92.95% of the time. Except for solidity, 11 of the 13 nuclear characteristics compared between the PVL and the LB showed significant differences. The 97.6% under the curve of the polynomial classifier was used to classify the two lesions. These results demonstrate that computational methods can aid in diagnosing these two lesions.

Carcinoma verrucoso, una variante inusual de tumor laríngeo / Verrucous carcinoma, an unusual variant of laryngeal tumor

Introducción: El carcinoma verrucoso es una variante poco común de carcinoma escamoso bien diferenciado, que carece de rasgos citológicos de malignidad, tiene un crecimiento lento, es infiltrativo, pero no metastatiza. Objetivo: Identificar los aspectos clínico-histopatológicos y terapéuticos de una variante inusual de tumor laríngeo. Presentación del caso: Se reporta un nuevo caso de carcinoma verrucoso, paciente masculino de 78 años que se presentó en la consulta de Otorrinolaringología del Hospital Docente general "Enrique Cabrera" con disfonía. Se realizó laringoscopia indirecta y se detectó lesión exofítica sugestiva de neoplasia. Se tomaron tres biopsias, solo la última, fue de utilidad para diagnosticar un carcinoma verrucoso. Se trató con radiaciones y cirugía. El paciente presenta un intervalo libre de enfermedad después de ocho años de seguimiento. Conclusiones: Para el diagnóstico del carcinoma verrucoso es necesario biopsias profundas y la acuciosidad del patólogo para llegar al diagnóstico. Se hace énfasis en la importancia del trabajo en el contexto del grupo multidisciplinario(AU)

Introduction: Verrucous carcinoma is an uncommon variant of a well differentiated squamous carcinoma that lacks cytological features of malignancy and is often slow-growing, infiltrative, but not metastatic. Objective: To identify the clinical, histopathologic and therapeutic aspects of an unusual variant of laryngeal tumor. Case presentation: A 78-year-old male patient who attended the otorhinolaryngology consultation at "Enrique Cabrera" General Teaching Hospital with dysphonia is reported as a new case of Verrucous carcinoma. Indirect laryngoscopy was performed and an exophytic lesion suggestive of neoplasia was detected. Three biopsies were taken, but only the last one was useful to diagnose a Verrucous carcinoma. It was treated with radiation and surgery. The patient has a disease-free survival after eight years of follow-up. Conclusions: Deep biopsies performed by a skillful pathologist are necessary to reach the diagnosis of Verrucous carcinoma. Emphasis is placed on the importance of working in the context of a multidisciplinary team(AU)

Verrucous Carcinoma of the Foot: A Retrospective Study of 19 Cases and Analysis of Prognostic Factors Influencing Recurrence.

This study sought to evaluate a cohort of patients with verrucous carcinoma of the foot with special focus on 5 cases of locally recurrent tumors despite negative margins. Nineteen cases of verrucous carcinoma of the foot were identified through the University of Michigan (Ann Arbor, Michigan) pathology database from 1995 to 2019 and were included in demographic and clinical presentation analyses. Sixteen cases were treated at the University of Michigan and are included in the treatment analyses. A review of medical records was conducted to characterize clinical, surgical, and pathologic features. Recurrent cases were found to have a predilection for nonglabrous skin of the foot and great toe. Otherwise, there was little to differentiate outcomes between recurrent and nonrecurrent groups based on demographic, clinical, surgical, or histopathologic data. Recurrent tumors regrew locally and were not associated with histologic progression to conventional squamous cell carcinoma. Verrucous carcinoma of the nonglabrous surface of the foot should have a higher suspicion for possible local recurrence. Recurrence occurs within months of treatment, deserves early biopsy, and warrants aggressive re-treatment. Future directions should include greater examination of pathologic features and genetic markers to improve management of verrucous carcinoma of the foot.