Global gene expression profile of proliferative verrucous leukoplakia and its underlying biological disease mechanisms.

BACKGROUND: Proliferative verrucous leukoplakia (PVL) is a rare and enigmatic oral potentially malignant disorder which almost invariably results in oral squamous cell carcinoma (OSCC). The aims of this project were to use transcriptome profiling to characterise PVL gene expression patterns for biomarker identification and gain insight into the molecular aetiopathogenesis of PVL. METHODS: Forty-three oral cavity mucosal biopsies from 32 patients with oral lesions clinically compatible with either PVL or non-PVL conventional oral leukoplakia (OLK) underwent transcriptome profiling by RNA sequencing. Data was analysed by hierarchical clustering, differential gene expression, functional enrichment and network analysis, sparse partial least squares discriminant analysis sPLS-DA, and immune cell phenotypic estimation. RESULTS: We found 464 genes significantly differentially expressed at least 2-fold between PVL and non-PVL OLK (193 up and 271 down). HOX genes, including HOXA1 and HOXB7, keratin-associated proteins (KRTAPs) and olfactory receptor G proteins (OR) were significantly upregulated in PVL. Other upregulated genes in PVL included FOS, WNT16 and IFNA1. Pathway analysis showed that there was a significant downregulation of connective tissue signalling in PVL. Classifying multivariate models based upon 22 genes discriminated PVL from non-PVL OLK. Bioinformatic profiling showed that immune cell profiles in PVL and OLK were similar except that fibroblast markers were reduced in PVL. CONCLUSION: These results demonstrate that PVL and conventional OLK are molecularly distinct with upregulation of many cancer-associated genes. They provide insight into the pathogenesis of PVL and show that biomarker based molecular diagnostics is feasible to discriminate and inform diagnosis and management.

Well-differentiated Squamous Cell Carcinoma With Sarcomatous Differentiation in Patient With a History of Recurrent Verrucous Carcinoma.

Human papillomavirus-independent vulvar squamous cell carcinoma has a peak incidence in about the eighth decade of life. A variable portion of the vulvar squamous cell carcinoma are human papillomavirus-independent comprising 20% to 80% of all cases. Verrucous carcinoma (VC) is part of the spectrum of human papillomavirus-independent carcinomas and its combination with well-differentiated squamous cell carcinoma with sarcomatous differentiation is an extremely unusual neoplasm. The available literature on VC is currently limited to case reports and small single-institution studies. Here, we present a case concerning an 81-year-old woman with a history of chronic itching, swelling, and lichen sclerosis with variable-sized multiple white-pink plaques of the vulva. The pathologic diagnosis of VC was made. The patient later on developed multiple lesions of biopsy proved VC and most recent biopsy shows well-differentiated squamous cell carcinoma with abrupt sarcomatous differentiation. A review of the literature shows the rarity of this lesion of the female genital tract. Clinicians and patients should be aware of the aggressive behavior of cancers and adjust their surgical management together with the follow-up strategy. To the best of our knowledge, this is the first description of a VC and well-differentiated squamous cell carcinoma with abrupt sarcomatous differentiation occurring in the vulva.

Molecular landscape of proliferative verrucous leukoplakia: a systematic review.

Proliferative verrucous leukoplakia (PVL) is a rare oral potentially malignant disorder characterised by multifocal origin and unpredictable long-term evolution to oral squamous cell carcinoma (OSCC) or oral verrucous carcinoma (OVC). Currently no predictive biomarkers are in clinical use. We aimed to explore the genomic profile of PVL. A total of 685 cases in 26 studies were included in this review. Genomic data were presented in 15% of studies and biomarker analysis was reported in 85% of studies. At first clinical presentation, PVL is characterised by a high loss of heterozygosity (LOH), similar to OSCC, and low copy number alterations (CNA). As these progress, more CNAs and mutations in CDKN2A and alterations to ELAVL1 expression are noted, but no TP53 mutations are identified. There is significantly lower LOH at 17p in early PVL compared with OSCC (p = 0.037). Deletions in chromosomal loci 17q12, 5q31.1 and amplifications in 7q11.2, 7q22 are shared between early lesions and OVC. PVL shows CNAs at 11q31. WNT signalling pathway genes (SUZ12, CTTN and FOLR3) are enriched in CN-altered regions. PVL stroma shows significantly lower α-SMA and higher CD34 expression than OVC and OSCC. The exact genomic landscape is currently unclear, and further studies are necessary to unravel this mystery.

Proliferative verrucous leukoplakia/multifocal leukoplakia in patients with and without oral submucous fibrosis.

BACKGROUND: Oral submucous fibrosis (OSF) and proliferative verrucous leukoplakia (PVL) are established as oral potentially malignant disorders. Dual pathology of the two conditions is not commonly encountered in clinical practice. This study aims to present a case series of multifocal leukoplakia in patients with and without OSF to outline the clinical behavior and challenges in the management of this high-risk group in clinical practice. MATERIAL AND METHODS: We retrospectively analyzed cases of six Indian patients (four with OSF) managed over a period of 5.5 to 13 years at the Government Dental College, Nagpur. Patient data consisting of age, gender, medical history, habits, clinical findings, and biopsy reports were recorded at the initial visit. During follow-up visits, the clinicopathological data were reassessed. When surgical intervention failed to arrest the disease or when surgery was contraindicated metronomic therapy with Folitrax 15 mg once a week and Celecoxib 100mg twice daily was initiated. RESULTS: All patients developed PVL after the initial pathology diagnosis of OSF or oral leukoplakia. Initial lesions were either homogenous or non-homogenous leukoplakia. All patients developed multiple recurrences, regional or systemic metastasis. Despite thorough interventions, the patients died of, or with the disease. CONCLUSIONS: The occurrence of two or more oral potentially malignant disorders poses challenges in patient management and possibly presents a higher risk of malignant transformation. More clinical trials are necessary to assess the benefits of metronomic therapy for patients diagnosed with aggressive PVL concurrently found with OSF.

Epidemiological, clinical and oncological outcomes of laryngeal verrucous carcinomas: a systematic review.

OBJECTIVE: To investigate epidemiological, clinical and oncological outcomes of patients with laryngeal verrucous carcinomas (LVC). METHODS: Two independent authors investigated PubMed, Scopus and Cochrane Library for studies dedicated to epidemiological, clinical and oncological outcomes of patients with LVC. The following outcomes were investigated with PRISMA criteria: age; gender; tobacco/alcohol consumption; HPV infection; anatomical, pathological, therapeutic and survival outcomes. Studies were analyzed for bias through a validated clinical tool. RESULTS: Of the 212 identified articles, 15 retrospective studies and one prospective uncontrolled study met our inclusion criteria. Three studies reported findings from national databases. The males/females ratio is 9/1. Mean age was 60.3 years, which was younger compared to other laryngeal malignancies. The alcohol, cigarette overuse and the HPV status of patients were lacking in most studies. Glottis and supraglottis were the most common anatomical locations, corresponding to 78.7% and 12.4% of cases, respectively. The main therapeutic approaches consisted of surgery, radiotherapy, surgery followed by radiotherapy. Treatments reported 5-year overall survival and disease-specific survival of 86.3 and 90.8, respectively. The 5- and 10-year local control rate were 83.6 and 72.6, respectively. The 10-year disease-specific survival was 80.2. Heterogeneity between studies was found for inclusion criteria, comorbidity data, and treatments. CONCLUSION: LVC is a rare laryngeal cancer associated with better survival and recurrence outcomes than laryngeal squamous cell carcinoma. The role of radiotherapy in the treatment regimen needs to be investigated in future prospective controlled studies.

Proliferative verrucous leukoplakia: a case report of multiple metachronous oral verrucous carcinoma.

Proliferative verrucous leukoplakia (PVL) is a distinct progressive and multi-focal form of oral leukoplakia, not associated with the traditional risk factors (ie, tobacco and alcohol consumption). The incidence of oral squamous cell carcinoma in PVL patients is high. Here, we describe the case of a patient affected by PVL, who developed two metachronous oral verrucous carcinomas at different sites of the oral mucosa. Owing to the high risk of multiple oral squamous cell carcinoma, periodical clinical and histopathological follow-up is mandatory and should continue lifelong.

[Research progress in the diagnosis and management of proliferative verrucous leukoplakia].

Proliferative verrucous leukoplakia (PVL) is one of the oral potentially malignant disorders (OPMD) with the highest malignant potential. PVL tends to be easily misdiagnosed owing to the resemblance in clinical manifestations between PVL and other diseases such as oral leukoplakia or oral lichen planus. PVL is considered as a special type of oral leukoplakia by some scholars, which is characterized by its tendency of recurrence and metastasis, along with its high risk of malignant transformation. So far, the accurate clinic diagnosis and management of PVL are still intractable due to the lack of definite histopathological definition, unified diagnostic criteria and effective treatment modalities. This review aims to provide the clinical practitioners with a series of advices on the clinical diagnosis and management of PVL by systematically reviewing the diagnostic logistics, therapeutic strategies, malignant transformation detection based on tremendous relevant data and evidence-based medicine.

[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.

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)

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.

Detection of variable genotypes in common human papillomavirus-associated invasive penile squamous cell carcinomas: a study of 177 human papillomavirus-positive cases.

Human papillomavirus (HPV) is detected in 30-50% of invasive penile carcinomas, and it is frequently associated with basaloid and warty morphological features. Based on this heterogeneity and different clinical behaviors, we hypothesized a variation in their HPV genotypic composition. To test this, we evaluated 177 HPV-positive cases: basaloid (114), warty-basaloid (28), and warty (condylomatous) (35) invasive carcinomas. HPV DNA detection and genotyping was performed using the SPF-10/DEIA/LiPA25 system. Nineteen HPV genotypes were detected. High-risk HPVs predominated (96%), and low-risk HPVs were rarely present. Most common genotype was HPV16 followed by HPVs 33 and 35. According to the genotypes identified, 93% of the cases would be covered with current vaccination programs. There was a significant variation in the distribution of HPV16 and non-HPV16 genotypes according to histological subtype. HPV16 was significantly frequent in basaloid (87%) and was less frequent in warty carcinomas (61%). This molecular difference, along with their distinctive macro-microscopic and prognostic features, makes basaloid and warty carcinomas unique. The gradual decreasing frequency of HPV16 demonstrated in basaloid, warty-basaloid, and warty carcinomas suggest that the basaloid cell, present in those types in decreasing proportions, may be responsible for the differences.

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.