New potential diagnostic markers for verrucous hyperplasia and verrucous carcinoma based on RNA-sequencing data.

Verrucous carcinoma (VC) is a rare subtype of squamous cell carcinoma (SCC) characterized by its histological presentation as a low-grade tumor with no potential for metastasis, setting it apart from invasive SCC. However, distinguishing VC from its benign counterpart, verrucous hyperplasia (VH), is challenging due to their clinical and morphological similarities. Despite the importance of accurate diagnosis for determining treatment strategies, diagnosis of VH and VC relied only on lesion recurrence after resection. To address this challenge, we generated RNA profiling data from tissue samples of VH and VC patients to identify novel diagnostic markers. We analyzed differentially expressed (DE) mRNA and long non-coding RNA (lncRNA) in tissue samples from VH and VC patients. Additionally, ChIP-X Enrichment Analysis 3 (ChEA3) was conducted to identify the top five transcription factors potentially regulating the expression of DE mRNAs in VH and VC. Our analysis of mRNA and lncRNA expression profiles in VH and VC provides insights into the underlying molecular characteristics of these diseases and offers potential new diagnostic markers. The identification of specific DE genes and lncRNAs may enable clinicians to more accurately differentiate between VH and VC, leading to better treatment choices.

Verrucous Carcinoma of the Foot: A Single Canadian Center Experience on Diagnosis, Management, and Outcomes.

INTRODUCTION: Verrucous carcinoma (VC) was first described in 1948 by Dr. Ackerman. It is a low-grade cutaneous squamous carcinoma that usually develops in the oral cavity, the anogenital region, and the plantar surface of the foot. Clinically, there is low suspicion for malignancy given the slow growth of VC lesions and their wart-like appearance. Diagnosis can be difficult because of the benign histological appearance with well-differentiated cells and absence of dysplasia. Surgical excision is the only satisfactory form of treatment for plantar VC; however, this becomes difficult given its benign clinical appearance and the pathologic misinterpretation of the lesion as a benign hyperplasia. While there are case reports and retrospective studies of patients with plantar VC in the literature, we present the largest case series of plantar VC within North America, with recurrence despite negative margins. METHODS: We report on all the plantar VC excised between 2014-2023. We report six cases of VC, their treatment, and their outcomes. RESULTS: Six patients obtained a diagnosis of plantar VC by incisional biopsy. All patients underwent excision of their lesions and had negative margins reported on the final pathology. All patients developed nonhealing wounds at the site of their lesion excision; therefore, biopsies were performed to confirm a recurrence. All patients had a recurrence of VC at the initial site. All patients underwent re-excision of the lesions. Despite negative margins again on final pathology, all patients had a subsequent second recurrence. Ultimately, all patients underwent an amputation as definitive management. Each patient had an average of 3 operations. There were 4 different surgeons and different pathologists reporting their findings. CONCLUSIONS: Our experience with plantar VC suggests that an aggressive approach to surgical management is needed. Furthermore, management is optimized with the combined expertise of an experienced dermatopathologist and surgeon. Despite negative margins and repeated excisions, VC lesions recur and invade local tissues to the extent that only amputation of the involved foot has resulted in cure.

Verrucous carcinoma presenting as recalcitrant verruca plantaris.

Verrucous carcinoma (VC) is a rare, low-grade variant of well-differentiated squamous cell carcinoma. Plantar verrucous carcinoma presents as a slow-growing, exophytic, verrucous plaque on weight bearing areas of the foot. Verrucous carcinomas have low metastatic potential, but are high risk for local invasion. We describe a patient with a 20-year history of a slowly growing, ulcerated, verrucous plaque on the sole of the left foot that was erroneously treated for years as verruca plantaris and was eventually diagnosed as invasive verrucous carcinoma. Verrucous carcinomas are a diagnostic challenge due to clinical and histopathologic mimicry of benign lesions. Mohs micrographic surgery should be employed to allow the ability to intraoperatively assess tumor margins while excising the minimal amount of necessary tissue. It is important for clinicians to recognize the characteristics and accurately diagnose verrucous carcinomas. Delays in treatment may require more extensive dissection or amputation.

[Marjolin's ulcer associated with verrucous carcinoma in an immunocompromised patient]. / Úlcera de Marjolin asociada a carcinoma verrugoso en paciente inmunocomprometido.

Background: Marjolin's ulcer is the malignant degeneration of any chronic wound, with a latency period from tissue injury to variable malignant transformation that may occur up to 30 years later. Among the associated neoplasms, squamous cell carcinoma (SCC) is the predominant lineage in up to 71% of cases. The verrucous carcinoma variant has been estimated to have a low presentation, being described in the literature as 2% of all SCC and reported anecdotally in immunosuppressed patients, which justifies the objective of this publication. Clinical case: 65-year-old female patient with a history of being a carrier of human immunodeficiency virus (HIV) infection, who presented a verrucous carcinoma associated to a Marjolin ulcer secondary to herpes zoster and infection of soft tissues in the right leg, with a latency period of 10 years from the initial infectious process to histopathological confirmation. Conclusions: The finding of a verrucous carcinoma on a Marjolin ulcer has been little described in literature, with a lower incidence in the context of a patient with a history of being a carrier of HIV infection, finding 7 case reports, the oldest from 1998. For this reason, it is important to have diagnostic suspicion, to carry out an adequate study protocol and always making clinical-pathological correlation, in order to establish timely and individualized treatment.

Introducción: la úlcera de Marjolin es la degeneración maligna de cualquier herida crónica, con un periodo de latencia desde la lesión tisular a la transformación maligna variable que puede presentarse hasta 30 años después. De las neoplasias asociadas, el carcinoma espinocelular es la estirpe predominante hasta en 71% de los casos. La variante de carcinoma verrugoso se ha estimado con una presentación baja, pues ha sido descrito en la literatura como el 2% de todos los carcinomas espinocelulares y reportado de manera anecdótica en pacientes inmunosuprimidos, lo que justifica el objetivo de esta publicación. Caso clínico: mujer de 65 años con el antecedente de ser portadora de infección por virus de inmunodeficiencia humana (VIH), que presentó un carcinoma verrugoso asociado a una úlcera de Marjolin secundaria a herpes zóster e infección de tejidos blandos en pierna derecha, con un periodo de latencia de 10 años desde el proceso infeccioso inicial hasta la confirmación histopatológica. Conclusiones: el hallazgo de un carcinoma verrugoso asentado sobre una úlcera de Marjolin ha sido poco descrito en la literatura, con una menor incidencia en el contexto de un paciente con antecedente de ser portador de infección por VIH, ante lo cual encontramos 7 reportes de caso, el más antiguo de 1998. Por este motivo es importante contar con la sospecha diagnóstica, para poder hacer un protocolo de estudio adecuado y siempre haciendo correlación clínico-patológica, con la finalidad de instaurar un tratamiento oportuno e individualizado.

Oral verrucous Carcinoma on mandibular right alveolar region.

Verrucous carcinoma, a low-grade variant of squamous cell carcinoma, defined as a diagnostically squamous cell neoplasia involving lip, oropharyngeal, and laryngeal mucosa and named as 'Ackerman's tumour' by Ackerman in 1948. It usually occurs in the lower lip region and this is one such case in which a painful proliferative growth was evident over the right alveolar region for the period of 8 months. Radiological investigations, biopsies were performed followed by surgical excision of the lesion.

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.

Verrucous Carcinoma Arising in an Extended Giant Condyloma Acuminatum.

A 43-year-old heterosexual Tunisian man presented to the dermatology department with complaints of a genital friable mass. He had a past medical history of chronic hepatitis B. He was married and had a history of multiple sexual partners. The lesion had been present for over 10 years and gradually increased in size, disfiguring his genitalia. It had a major impact on his quality of life, preventing sexual intercourse and resulting in poor personal hygiene. On physical examination, the vegetative lesion presented as a giant cauliflower-like tumor (Figure 1) with a foul smell. The tumor involved the left inguinal region, the suprapubic genitalia, and was encircling the entire penile shaft. He also had inguinal lymphadenopathies. Under local anesthesia, a skin biopsy of the vegetative tumor was performed and sent for histopathologic examination. It revealed an exophytic epithelial tumor with papillomatosis, marked acanthosis, and many koilocytes, especially in the superficial layers of the epidermis. These signs along with the preservation of regular cytology were consistent with the diagnosis of condyloma acuminatum (Figure 2a). The histologic examination also showed clusters of atypical keratinocytes with high mitotic activity and keratinization, suggesting nests of squamous cell carcinoma (SCC) (Figure 2b and 2c). DNA-polymerase chain reaction (PCR) marker for Human papilloma virus (HPV) stains 11 was positive. Serology for hepatitis C, HIV, and syphilis non-reactive. Computed tomography scan of the abdomen and pelvis showed inguinal lymphadenopathies. The patient was referred to the oncologist for radiotherapy to reduce the size of the tumor followed by surgery. (SKINmed. 2023;21:53-54).

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.

Cutaneous Verrucous Carcinomas: A Review.

Verrucous carcinoma (VC) is a relatively rare locally aggressive, slow-growing, well-differentiated squamous cell carcinoma with minimal metastatic potential and is most frequent in the mucosa. Although rarely reported on the skin, cutaneous verrucous carcinomas (CVC) can appear anywhere, most commonly on the feet. However, clinical and pathologic diagnosis of CVC has been confusing and challenging. It can easily be mistaken for benign or more malignant conditions such as giant condyloma acuminata, keratoacanthoma, and pseudoepithelioma-like hyperplasia or squamous cell carcinoma, resulting in inappropriate management. In this review, we describe the different aspects associated with CVC, including its pathogenesis and clinicopathologic features. The available evidence for the differential diagnosis and treatment of CVC is discussed, and specific management recommendations are made. After the treatment, careful follow-up examinations of the excised area should be performed at regular intervals.

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.

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.

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.

Oral carcinoma cuniculatum: an unacquainted entity with diagnostic challenges-a case report.

BACKGROUND: Oral carcinoma cuniculatum (OCC) is an unacquainted well-differentiated subtype of oral squamous cell carcinoma, which displays unique clinic-pathological features. Up to date, OCC remains rare with about 75 reported cases, and is frequently missed or even misdiagnosed. CASE PRESENTATION: The aim of the present work was: to report a case of OCC in mandibular gingiva and to highlight its main clinic-pathological diagnostic features: with an exophytic cobble-stone surface and a characteristic endophytic burrowing architecture, as well as to differentiate between it and other closely similar lesions including verrucous carcinoma, papillary squamous cell carcinoma, and well-differentiated conventional oral squamous cell carcinoma. CONCLUSIONS: An accurate diagnosis of OCC entails awareness of the clinicians and pathologists about its entity, proper knowledge of the diagnostic clinical and histopathological evidence, and the ability to differentiate it from closely similar lesions.