Oral verrucous carcinoma: a diagnostic and therapeutic challenge.

BACKGROUND: Verrucous carcinoma is a low-grade variant of squamous cell carcinoma with specific morphologic, cytokinetic and clinical features. Despite low mitotic activity and slow growth, it can infiltrate adjacent tissues in advanced stages but does not metastasize. The most frequently affected site is the oral cavity. The following article provides latest updates in the etiology, clinical presentation, diagnostics and treatment options in oral verrucous carcinoma and discusses the existing dilemmas linked to this unique malignancy. CONCLUSIONS: Oral verrucous carcinoma must be differentiated from conventional squamous cell carcinoma due to its less aggressive behaviour with a more favourable prognosis. Close communication between clinician and pathologist is mandatory for making a correct diagnosis. Primary surgery with negative surgical margins seems to be the most successful treatment. However, management recommendations are not uniform since they are mostly based on case reports and small retrospective case series. Prospective and pooled multi-institutional studies are therefore needed.

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.

[Clinicopathological features of verrucous type dysplasia of esophagus].

Objective: To investigate the clinicopathological features of verrucous type (squamous) dysplasia of esophagus. Methods: The clinicopathological data of 18 verrucous type dysplasia of esophagus patients in the 989th Hospital of the Joint Logistics Support Force of the People's Liberation Army (formerly 152 Central Hospital) and Beijing Chaoyang Hospital Affiliated to Capital Medical University from 2009 to 2021 were retrospectively collected. The histomorphologic characteristics and immunophenotype were observed, and human papillomavirus (HPV) genotyping was detected by PCR-fluorescence probe. The relevant literature was reviewed. Results: The median age of the 18 patients was 68 years (range 53-76 years); there were 13 males and 5 females. There were four cases in the upper esophagus, seven in the middle esophagus and seven in the lower esophagus. The median diameter of the lesion was 18 mm (range 6-54 mm). According to the Paris Classification, 11 cases were 0-Ⅱa, one case was 0-Ⅱa+Ⅰ, five cases were 0-Ⅱb, and one case was 0-Ⅱb+Ⅰ. White light endoscopy showed that the surface of the lesion was white plaque, red areas between the plaques, and papillary surface structure could be seen. In narrow-band imaging, some mucosal areas of lesions were opaque or patchy and light brown, and papillary microsurface structures were different in shapes and sizes. Intraepithelial microvessels were elongated, dilated, twisted and varied in diameter. Lugol iodine stain showed nil to faint staining. Histologically, the atypia cells were large with rounded to irregular nuclei, coarse chromatin, mitotic figures, and abundant eosinophilic cytoplasm. The basal cells showed increased atypia, crowding, increased nuclear-cytoplasmic ratio, and active mitosis. The cells were arranged haphazardly. Single cell keratinization, binuclear cells, and hollow-out-like cells, as well as surface epithelial keratinization and parakeratosis were observed in three cases. There were obvious verrucous or papillary structures in the epithelial layer. Five patients had local verrucous carcinoma. Immunohistochemical staining showed that the mutant expression of p53 protein in 6/10 cases; p16 was positive in 5/10 cases; abnormal Ki-67 distribution pattern in 10/10 cases. HPV was negative in all 10 cases tested. The original pathologic diagnosis of preoperative biopsy was high-grade dysplasia in 8 cases, low-grade dysplasia in 6 cases and atypical squamous epithelial cells in 4 cases. Conclusions: Esophageal verrucous dysplasia tumor cells are well differentiated with obvious verrucous or papillary structures. The unique morphological features suggest that it represents a histological subtype of esophageal squamous high-grade dysplasia and it is a precursor of verrucous carcinoma. Its preoperative biopsy diagnosis is challenging.

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.

Radiation vs surgery for early-stage laryngeal verrucous carcinoma: A population-based propensity score matched-study.

BACKGROUND: Verrucous carcinoma (VC) is a rare variant of squamous cell carcinoma. Although VC is considered radioresistant, concrete evidence for this is absent. METHODS: We obtained data on VC treated with surgery or radiation from the Surveillance, Epidemiology, and End Results database. Treatment selection bias was reduced by propensity score matching. Overall survival (OS) and disease-specific survival (DSS) rates were estimated using the Kaplan-Meier method. Hazard ratios (HRs) were estimated using Cox proportional hazards models. RESULTS: Five-year OS rates in the radiation and surgery groups were 72.7% and 72.0%, respectively (P = 0.111); five-year DSS rates in the same were 86.7% and 88.4%, respectively (P = 0.234). HRs of radiation compared with surgery were 1.68 (95% confidence interval (CI), 0.96-2.95) for OS and 1.95 (95% CI, 0.69-5.53) for DSS. CONCLUSIONS: Similar prognoses were observed in patients with VC treated with radiation and surgery. VC can be treated using radiation.

[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.

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.

Lichenoid areas may arise in early stages of proliferative verrucous leukoplakia: A long-term study of 34 patients.

BACKGROUND: Proliferative verrucous leukoplakia is considered an uncommon oral potentially malignant disorder with a high malignant transformation rate. The objective of this paper was to define its cancer incidence and related risk factors. METHODS: A retrospective audit of 34 patients diagnosed with proliferative verrucous leukoplakia from a university-based unit, during the period from 1995 to 2019 was performed. The mean number of visits was 23 ± 18.6. The follow-up was divided into four-time intervals to evaluate the clinical presentation, number of lesions, dysplasia grade, and malignant transformation rate. RESULTS: The majority of patients were females 29 (85.3%), with verrucous component (77.8%), with a gingival presentation (31.8%), and with a preceding lichenoid area (44.1%). Eleven patients (32.4%) were affected by oral cancer during the follow-up, developing a total of 15 carcinomas. The mean age of malignant transformation was 67.2 ± 12.9 years, particularly 8 ± 8.5 from the onset of the lesions. Warty forms presented a higher mean estimate for malignant transformation (15.2 years, 95% confidence interval 4.4-26 years) than nodular forms (1.9 years, 95% confidence interval 1.9-1.9) (p = 0.019). Patients with an initial proliferative verrucous leukoplakia diagnosis suffered a higher risk of malignancy, particularly 15.55 times (95% confidence interval 1.69-143.17; p = 0.015) than those who did present a preceding area with lichenoid morphology. CONCLUSION: Proliferative verrucous leukoplakia presented a high malignant transformation rate and sometimes displayed preceding oral lichenoid areas in early stages. Further studies are needed to understand the impact of these lichenoid areas in proliferative verrucous leukoplakia progression.

Verrucous Squamous Hyperplasia of the Urinary Bladder: A Series of 23 Cases.

CONTEXT.­: There is scant literature describing verrucous squamous hyperplasia of the urinary bladder. OBJECTIVE.­: To investigate the possible association between verrucous squamous hyperplasia and carcinoma. DESIGN.­: The case files of the senior author were searched for cases of verrucous squamous hyperplasia diagnosed between August 2010 and February 2021. Cases with available material were tested for in situ hybridization with human papillomavirus, and cases with available material unassociated with carcinoma underwent immunohistochemistry for p53. RESULTS.­: We gathered a series of 23 cases, the largest to date. Eleven cases were associated with carcinoma at diagnosis. Of the 7 cases unassociated with carcinoma in which follow-up was available, 1 patient (14.3%) was given a clinical diagnosis of carcinoma with recommended cystectomy, 2 (28.6%) had benign diagnoses, and 4 (57.1%) were dead not from disease. Of the 13 cases with available material, 13 (100%) were negative for human papillomavirus by high-risk in situ hybridization. CONCLUSIONS.­: Based on the small number of cases with limited follow-up, it is unclear whether verrucous squamous hyperplasia represents a precursor lesion or simply a high-risk association. Until more evidence is accumulated, patients with verrucous squamous hyperplasia of the urinary bladder should receive close clinical follow-up.

Aggressive oral carcinoma cuniculatum: A rare entity.

Oral carcinoma cuniculatum (OCC) is a rare and distinct clinicopathological variant of oral squamous cell carcinoma (OSCC). The term cuniculatum was derived from a Latin word "cuniculus" meaning burrow, because of the "rabbit burrow" appearance. As it invades the underlying tissue, it forms crypts filled with keratin that are essential in distinguishing this neoplasm from other variants of squamous cell carcinoma (SCC). It is a common lesion of the plantar region of the foot but rare in the oral cavity. The first case of OCC was reported in 1977 by Flieger and Owenski in the jaw, with fewer than 50 cases reported in the English literature till date. Tumor cell cannibalism has been reported in various carcinomas such as lung, gallbladder, hepatobiliary, pancreatic, and SCC. Cell cannibalism when it refers to a cancer cell, either within a tumor mass or cell culture, is "a cell that is contained within another bigger cell with a crescent-shaped nucleus." This report aims to present a rare case of aggressive OCC of the maxillary gingiva with cellular cannibalism and its diverse immunohistochemical expression of E-cadherin, Ki-67, and p53.

Update from the 5th Edition of the World Health Organization Classification of Head and Neck Tumors: Tumours of the Oral Cavity and Mobile Tongue.

The fifth chapter of the upcoming fifth edition of the 2022 World Health Organization Classification of Tumours of the Head and Neck titled Tumours of the oral cavity and mobile tongue, has had some modifications from the 2017 fourth edition. A new section "Non-neoplastic Lesions", introduces two new entries: necrotizing sialometaplasia and melanoacanthoma. The combined Oral potentially malignant disorders and Oral epithelial dysplasia section in the 2015 WHO has now been separated and submucous fibrosis and HPV-associated dysplasia are also discussed in separate sections. Carcinoma cuniculatum and verrucous carcinoma are described in dedicated sections, reflecting that the oral cavity is the most common location in the head and neck for both these entities which have distinct clinical and histologic features from conventional squamous cell carcinoma. This review summarizes the changes in Chapter 5 with special reference to new additions, deletions, and sections that reflect current clinical, histological, and molecular advances.

Postoperative Radiation Therapy in Oral Cavity Verrucous Carcinoma.

OBJECTIVES/HYPOTHESIS: We investigate the clinicopathologic and treatment factors associated with the use of postoperative radiation therapy (PORT) and its effect on overall survival (OS) for patients with oral cavity verrucous carcinoma (VC). STUDY DESIGN: Retrospective cohort study. METHODS: A retrospective cohort study of the National Cancer Database (NCDB) from 2006 to 2015 was performed. Multivariable logistic regression was used to identify independent predictive factors associated with the use of PORT. Cox Regression survival and propensity score analyses were used to evaluate the effect of PORT on mortality. RESULTS: A total of 356 adult patients with primary oral cavity VC who underwent definitive surgical resection were identified. A total of 10.7% of patients underwent definitive surgical resection followed by PORT. Variables associated with PORT included distance to the hospital per 10 miles (adjusted odds ratio [aOR], 0.81 [95% confidence interval (CI), 0.70-0.95]) and stage III-IV disease (aOR, 12.13 and 23.92, respectively). Multivariable Cox regression survival analysis indicated no evidence of survival benefit in patients undergoing PORT compared to surgery alone (adjusted hazard ratio 1.50 [0.74-3.05], P = .23). Propensity score analysis also showed no OS benefit with the use of PORT (P = .41). CONCLUSIONS: Variables associated with the use of PORT on multivariable analysis included closer distance to hospital and stage III-IV disease. No clear survival benefit with PORT was identified on either multivariable survival analysis or propensity score analysis. These results suggest that surgery alone with negative margins may be the optimal treatment for patients with oral cavity VC. LEVEL OF EVIDENCE: 4 Laryngoscope, 132:1953-1961, 2022.

Cuneiform (cuniculatum) variant of oral squamous cell carcinoma revisited: Presentation of two cases and literature review of a rare entity.

BACKGROUND: Oral carcinoma cuniculatum (OCC) is a rare, locally aggressive tumor, which tends to invade underlying bone. We present two cases of OCC, one demonstrating invasion of the mandible and the other limited to the tongue. METHODS: An 87-year-old male presented with a right-sided buccogingival lesion. Biopsy results led to a diagnosis of verrucous hyperplasia, which was later revised to OCC. Additionally, a 94-year-old female presented with a left lateral tongue lesion. A biopsy showed in-situ and invasive keratinizing squamous cell carcinoma that was later defined as a soft tissue OCC. RESULTS: Following surgical resection, the diagnosis of OCC was established in both patients. We provide a comprehensive literature review of OCC in the context of both case presentations. CONCLUSIONS: OCC is a rare entity, which has a tendency to be misdiagnosed. We emphasize the importance of recognizing the common features of OCC in order to aid in accurate diagnosis.