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ABSTRACT Objective Materials and Methods Results Conclusion Proliferative verrucous leukoplakia (PVL) is an oral potentially malignant disorder. Forms that affect only one tissue are poorly studied, especially the exclusively gingival PVL (gPVL), which may have a more increased malignant transformation potential. The aim of the present study was to characterise the gPVL and its risk of malignant transformation to better raise awareness of this specific disorder.The systematic review was performed on PubMed, Scopus, Web of Science and Google Scholar. Only articles reporting primary studies, case reports and case series were included. The meta‐analysis was performed for the cancer prevalence, proportion of smokers, age and sex ratio, recurrences of gPVL and mortality.A total of 1298 studies were assessed for eligibility by reading titles and abstracts. Fourteen original articles were included with a total of 58 patients. The malignant transformation rate of gPVL was 47.75%. The mortality was 5.84%. The mean follow‐up duration before malignant transformation was 3 years.gPVL seems to have a faster malignant transformation rate than the other forms of PVL. Finding anatomo‐pathological or genetic markers could be a line of research to predict gPVL malignant transformation and improve its diagnosis and treatment. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Key Clinical Message: Well‐differentiated variant of squamous cell carcinoma. Slow growing, exophytic, cauliflower‐like growth easily confused with a viral wart. Cutaneous, anogenital, and oral variant exist. Risk factors for oral variant include alcohol and smoking. Histopathologically exhibits lobules with a pushing margin and blunt borders. Verrucous carcinoma (VC) is a low‐grade variant of squamous cell carcinoma with specific clinicopathologic features and good prognosis when affecting skin. We report the case VC of lip in a‐70‐year‐old lady. She underwent surgical excision with excellent outcomes. A brief review of the literature is provided. [ABSTRACT FROM AUTHOR]

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 [ABSTRACT FROM AUTHOR]

This is a difficult task, due to the thick keratin layer on the tumour surface and hard tumour consistency, and requires a special effort from the clinician, which usually is not necessary in case of biopsy of papilloma or typical SCC. Diagnosis is difficult because the tumour appears macroscopically "malignant" and microscopically "benign".5 The presence of the thick layer of keratin on the tumour surface creates major obstacles for obtaining an adequate biopsy material, which frequently results in inadequate traditional biopsy and inconclusive histologic response. In order to obtain an adequate biopsy specimen for histologic confirmation of the nature of tumour, flexible endoscopic snare diathermy excision under local anaesthesia with lidocaine 2% was used. [Extracted from the article]

Aims: Oesophageal verrucous carcinoma (VSCC) is a rare and morphologically distinct type of oesophageal squamous cell carcinoma (SCC). Diagnosing VSCC on biopsy material is challenging, given the lack of significant atypia and the presence of keratinising epithelium and exophytic growth. The molecular pathogenesis of VSCC remains unclear. The aim of this study was to characterise the genomic landscape of VSCC in comparison to conventional oesophageal SCC. Methods and results: Three cases of VSCC from the Brigham and Women's Hospital pathology archive were identified. Formalin‐fixed, paraffin‐embedded (FFPE) tumour tissue was used for p16 immunohistochemistry (IHC), high‐risk human papillomavirus (HPV) in‐situ mRNA hybridisation (ISH) and DNA isolation. Tumour DNA was sequenced using a targeted massively parallel sequencing assay enriched for cancer‐associated genes. Three additional cases of VSCC were identified by image review of The Cancer Genome Atlas (TCGA) oesophageal SCC cohort. VSCC cases were negative for p16 IHC and high‐risk HPV ISH. TP53 mutations (P < 0.001) and copy number variants (CNVs) for CDKN2A (P < 0.001), CDKN2B (P < 0.01) and CCND1 (P < 0.01) were absent in VSCC and significantly less frequent in comparison to conventional SCC. Five VSCC cases featured SMARCA4 missense mutations or in‐frame deletions compared to only four of 88 conventional SCC cases (P < 0.001). VSCC featured driver mutations in PIK3CA, HRAS and GNAS. Recurrent CNVs were rare in VSCC. Conclusions: VSCC is not only morphologically but also genetically distinct from conventional oesophageal SCC, featuring frequent SMARCA4 mutations and infrequent TP53 mutations or CDKN2A/B CNVs. Molecular findings may aid in establishing the challenging diagnosis of VSCC. [ABSTRACT FROM AUTHOR]

Background: Potentially malignant lesions of the gingiva may frequently present as well-demarcated white lesions confined to the marginal gingiva. These lesions often become thick and verrucoid and spread along the marginal gingiva to encircle the tooth. Some cases of marginal gingival leukoplakia, over time, progress to extensively involve the gingiva fulfilling the criteria for proliferative verrucous leukoplakia (PVL). The objective of this study is to raise awareness of this pattern of leukoplakia by reporting a series of cases of marginal gingival leukoplakia.Methods: An Institutional Review Board approved retrospective search of University of Florida and University of Nebraska Medical Center oral biopsy services was performed for all gingival biopsies. Inclusion criteria included cases exhibiting marginal gingival leukoplakia, and with accompanying clinical images.Results: A total of 30 cases of marginal gingival leukoplakia were included. All cases presented as well-demarcated leukoplakias, either on the buccal or lingual gingival margin, or circumferentially forming a "ring around the collar" of single or multiple teeth. Eight patients had recurrent lesions and 12 had multifocal involvement. Six of the 12 patients with multifocal involvement presented with a "ring around the collar." The histopathologic diagnoses were representative of benign lesions in seven cases, premalignant in 13, and malignant or suggestive of malignancy in 10 cases. Seven patients had carcinoma at the time of first biopsy, whereas 6 cases showed progression at time of follow-up.Conclusion: This study aims to raise awareness that marginal gingival leukoplakia may represent potentially malignant lesions, and if circumferential and/or thick, may be the first manifestation of PVL. [ABSTRACT FROM AUTHOR]

The tumour was categorized as suspicious for verrucous carcinoma. gl Transurethral resection of the bladder tumour was attempted again to re-resect the entire lesion and to obtain more specimens for histopathological assessment. Keywords: bladder cancer; cystectomy; papillomatosis; squamous cell carcinoma; squamous metaplasia; verrucous carcinoma EN bladder cancer cystectomy papillomatosis squamous cell carcinoma squamous metaplasia verrucous carcinoma 457 459 3 03/31/22 20220401 NES 220401 Abbreviations: FDG fluorodeoxyglucose SCC squamous cell carcinoma TURBT transurethral resection of bladder tumour VC verrucous carcinoma Case Conundrum A 71-year-old male was diagnosed with high-grade, non-invasive, stage Ta urothelial carcinoma with squamous metaplasia. Bladder cancer, cystectomy, papillomatosis, squamous cell carcinoma, squamous metaplasia, verrucous carcinoma. [Extracted from the article]

Verrucous carcinomas are a rare variant of squamous cell carcinoma. Vulval verrucous carcinoma comprises only 1% of vulval malignancies. This case report discusses the successful management of aggressive recurrent vulval verrucous carcinoma with acitretin, an oral synthetic retinoid used to manage severe psoriasis, after multiple surgical interventions and radiotherapy had failed. This is the first reported case in which verrucous carcinoma had recurred in a musculocutaneous graft. To manage the recurrence, the patient underwent radiotherapy, which did not resolve the condition. The patient was then administered acitretin 25 mg once daily, which successfully resolved the condition, and the patient has been symptom free for 6 months. This report aims to propose the use of acitretin as a management option for recurrent verrucous carcinomas. [ABSTRACT FROM AUTHOR]

Background: Increased tissue stiffness (also termed modulus) has been shown to be a characteristic of potential tumor metastasis. Measured values of the stiffness of tumors and cancer cells are reported in the literature to increase compared to neighboring normal tissues. Yet the relationship between the mechanical properties of cells and the extracellular matrix has yet to be correlated with the histopathology of cancerous lesions. Materials and Methods: We have developed a technique to do virtual biopsies of skin lesions by combining images made using optical coherence tomography with stiffness measurements made simultaneously using vibrational analysis. The technique is termed vibrational optical coherence tomography (VOCT). Results: In this paper, we report that precancerous and cancerous lesions are characterized by changes in both the morphology and stiffness of the cellular components of the skin. The ratio of the peak heights that correspond to the epidermal (40‐60Hz) and dermal (140‐160 Hz) resonant frequencies appear to be different for benign and cancerous or precancerous lesions compared with normal skin and scar. Conclusions: Cell‐to‐cell and epidermal‐to‐dermal interactions may be very important in evaluating the potential of skin lesions to become malignant. These interactions can be evaluated using VOCT, a new technique for performing "virtual biopsies" of skin lesions. [ABSTRACT FROM AUTHOR]

Introduction: Verrucous carcinoma (VC) is a rare, variant of squamous cell carcinoma with benign cytohistopathologic features and a generally favorable prognosis. Epidemiologic and clinical outcomes data are lacking as a result of limited cases of sinonasal VC. Objective: To describe the incidence and determinants of survival of patients with verrucous carcinoma of the sinonasal tract between the years of 1973 to 2014 using the Surveillance, Epidemiology, and End Results (SEER) database. Methods: The SEER registry was utilized to calculate survival trends for patients with verrucous carcinoma of the sinonasal tract between 1973 and 2014. Patient data then was analyzed with respect to age, sex, race, and treatment modalities (surgery and radiation therapy). Overall survival (OS) and disease‐specific survival (DSS) were calculated. Results: A total of 86 cases of VC of the sinonasal tract were identified. The cohort was comprised of 69.8% males. The mean age at diagnosis was 67.4 years. The nasal cavity was the most common primary site (51.2%), followed by the maxillary sinus (40.7%) and nasopharynx (5.8%). The median OS was 97.6 months. 89.5% of cases underwent surgery and 20.9% received both surgery and radiation therapy. Overall survival at 2, 5, and 10 years was 73%, 59%, and 36%, respectively. On multivariate analysis, advanced age (P < 0.05) and primary site (P < 0.05) were associated with worse OS and DSS, respectively. Primary nasopharyngeal tumor site was associated with reduced DSS (P < 0.05). Surgery improved OS (P < 0.001) and DSS (P < 0.001). Conclusion: Verrucous carcinoma of the sinonasal tract is associated with a generally favorable prognosis. Age, primary site, and surgical therapy are independent predictors of OS and DSS, respectively. We present the first population‐based analysis of sinonasal VC, thus clarifying the prognosis and reinforcing the management of this malignancy. Level of Evidence: 4. Laryngoscope, 128:651–656, 2017 [ABSTRACT FROM AUTHOR]

Objectives: To describe the incidence and determinants of survival of patients with verrucous carcinoma (VC) of the oral cavity between the years of 1973 and 2012 using the Surveillance, Epidemiology, and End Results (SEER) database.Study Design: Retrospective cohort study using a national database.Methods: The SEER registry was utilized to calculate survival trends for patients with VC of the oral cavity between 1973 and 2012. Patient data was then analyzed with respect to histopathology, age, sex, race, stage, grade, and treatment modalities (surgery and radiation therapy). Overall survival (OS) and disease-specific survival (DSS) were calculated.Results: A total of 1,481 cases of VC of the oral cavity were identified. The cohort was composed of 50.5% males. The mean age at diagnosis was 69.5 years. The oral tongue was the most common primary site (28.9%), followed by the alveolar ridge (21.4%) and buccal mucosa (19.0%). The vast majority of cases (79.1%) presented with stage I and stage II disease. Nodal disease was present in only 1.6% of cases. The median OS was 94.6 months. Eighty-seven percent of cases underwent surgery, and 11.5% received both surgery and radiation therapy. Overall survival at 2, 5, and 10 years was 83%, 64%, and 42%, respectively. On multivariate analysis, advanced age (P < 0.001) and stage (P < 0.001) were associated with worse OS, whereas surgery improved OS (P = 0.047).Conclusion: We provide the first population-based analysis of prognostic factors affecting survival outcomes in patients with oral cavity VC. Verrucous carcinoma of the oral cavity is associated with a generally favorable prognosis. Age, stage, nodal status, and surgical therapy are independent predictors of OS.Level Of Evidence: 4. Laryngoscope, 128:393-397, 2018. [ABSTRACT FROM AUTHOR]

Keratoacanthoma ( KA) is characterized by exoendophytic growth with a central keratin-filled crater, representing the crateriform architecture. We herein report five rare cases of KA without a central keratin-filled crater. These KA cases histopathologically showed that one or a few infundibular structures/isthmic lobules had their own open keratotic pores on the surface without a common merged keratotic plug/horn, clinically representing verrucous (keratotic) plaque/nodule, namely, ' KA en plaque/nodule'. KA rarely but on occasion does show verrucous plaque (or nodular) lesions without a central keratin-filled crater, as the notion that KA invariably shows crateriform architecture is nonsensical. [ABSTRACT FROM AUTHOR]

Objective To analyze the impact of adjuvant radiation therapy (RT) on overall survival (OS) and disease-specific survival (DSS) in patients with verrucous carcinoma (VC) as compared to squamous cell carcinoma (SCC) of the oral cavity. Study Design Cross-sectional population analysis. Methods Cases of nonmetastatic VC/SCC of the oral cavity were extracted from the Surveillance, Epidemiology, and End Results (SEER) database (1988-2013). Kaplan-Meier survivals, stratified according to T stage, were compared between VC and SCC for treatment with or without adjuvant RT. Results A total of 18,819 VC/SCC cases were identified. There were 581 (3.1%) VC (mean age 69.6 years, 48.9% female) versus 18,238 (97.0%) SCC (mean age, 65.3, 37.1% female) patients. Verrucous carcinoma patients receiving surgery alone (N = 539) demonstrated a trend toward improved OS versus VC patients receiving surgery and RT (N = 40) (117.0 vs. 71.4 months, respectively, P = 0.119). There was a statistically significant improvement in DSS in VC patients receiving surgery alone (217.2 vs. 110.9 months, P = 0.05). Verrucous carcinoma patients treated with adjuvant RT demonstrated a trend toward a worse OS (71.4 vs. 93.0 months, P = 0.992) and DSS (110.9 vs. 162.3 months, P = 0.275) compared to SCC treated with adjuvant RT, suggesting a different biology and radiosensitivity between VC and SCC. Conclusion Verrucous carcinoma treated with adjuvant RT had a worse OS and DSS compared to both VC treated with surgery alone and SCC treated with surgery and adjuvant RT. Consideration should be given to surgical re-section rather than adjuvant RT in patients with positive margins or local recurrence. Level of Evidence 2C. Laryngoscope, 127:1334-1338, 2017 [ABSTRACT FROM AUTHOR]

Key Clinical Message: Giant condyloma acuminatum is a rare variant of genital warts also known as Buschke‐Löwenstein tumor. It is characterized by a slow progression of exophytic, ulcerative, and cauliflower‐shaped tumor with benign histological features. Verrucous carcinoma however is a rare variant of well‐differentiated squamous cell carcinoma with limited metastatic potential. Giant condyloma acuminatum is a rare variant of genital warts also known as Buschke‐Löwenstein tumor. It is characterized by a slow progression of exophytic, ulcerative, and cauliflower‐shaped tumor with benign histological features. Verrucous carcinoma however is a rare variant of well‐differentiated squamous cell carcinoma with limited metastatic potential. [ABSTRACT FROM AUTHOR]

Background: Verrucous carcinoma is a non-metastasizing variant of welldifferentiated squamous cell carcinoma, which has been associated with reactive oxygen species generated by betel quid chewing. Salivary antioxidant systems have been suggested to play a protective role in reducing the oxidative damage. Herein, we investigated the difference of the enzymatic antioxidant system expressions in oral verrucous carcinoma and oral squamous cell carcinoma.Methods: The enzymatic antioxidant system expressions, including manganese superoxide dismutase, glutathione peroxidase, and catalase were evaluated by immunohistochemistry in a series of 202 surgically resected oral squamous cell carcinoma and 20 oral verrucous carcinoma specimens, using tissue microarray slides.Results: The immuno-staining intensities of superoxide dismutase and glutathione peroxidase were strongest in the oral squamous cell carcinoma group than in verrucous carcinoma. The catalase expression showed no difference between different pathological groups.Conclusions: The different degrees of superoxide dismutase and glutathione expressions in verrucous carcinoma and squamous cell carcinoma may be helpful for pathologists to differentiate these two entities, especially between oral verrucous carcinoma and well differentiated oral squamous cell carcinoma. [ABSTRACT FROM AUTHOR]

Objective Exophytic oral verrucous hyperplasia ( OVH) is a new entity described by an expert working group from South Asia. First reported in Taiwan, there are no reports so far from an Indian population. The aim was to use the microscopic features described by the expert group to differentiate OVH from other oral verruco-papillary lesions in an Indian archive. Materials and methods In a retrospective multicentre study, using pathology archives, 188 verruco-papillary lesions were retrieved from pathology archives. A proforma listing histopathological criteria for OVH based on published guidelines (Annals of Dentistry, University of Malaya, 2013) was used. Patients' demographic and clinical data were transcribed from patient charts. The Pearson chi-square test was used to determine associations between clinical and histopathological features. Results Of 188 oral verruco-papillary lesions that were evaluated, based on microscopic features the cases were reclassified as OVH (57), verrucous carcinoma (VC) (84), oral squamous cell carcinoma (16), and other verruco-papillary lesions (31). Both OVH (70%) and VC (60%) showed male predominance and commonly affected buccal mucosa ( OVH 74% and VC 57%). Absence of downward growth of the hyperplastic epithelium into lamina propria when compared with the level of the basement membrane of the adjacent normal epithelium was a distinct feature in OVH. Keratin plugging, epithelial dysplasia and subepithelial lymphocytic infiltration were found to be significantly different ( P < 0.05) in OVH versus VC. The sample size of other verruco-papillary lesions was insufficient for statistical comparison. Conclusion Apart from the absence of an endophytic growth pattern in OVH, we noted the presence of dysplasia in OVH. This significant observation does institute a debate as to whether this enigmatic lesion could possibly be a precedent of oral squamous or verrucous carcinoma. We propose OVH is a distinct entity in our Indian population and should be considered in the classification of oral potentially malignant disorders. [ABSTRACT FROM AUTHOR]

Background: The Akt/mTOR pathway is activated in many malignancies, including oral squamous cell carcinoma (OSCC). However, the role of the Akt/mTOR pathway in oral verrucous carcinoma (OVC), a low-grade variant of OSCC, remains unknown. Thus, the objective of this study was to investigate the activation level of important markers of the Akt/mTOR pathway in OVC and to compare the results with OSCC samples.Methods: The expression of p-Akt (Thr308), p-Akt (Ser473), and p-RPS6 was evaluated by immunohistochemistry in 30 OSCC cases, 18 OVC cases, and 30 control cases (normal epithelium overlying fibromas). Statistical analysis was performed to determine the differences in protein expression between samples.Results: All OVC cases were positive for p-Akt (Thr308), p-Akt (Ser473), and p-RPS6. There were significant differences in expression level of all studied proteins between OVC and control, as well as between OVC and OSCC. However, OVC showed significant lower staining scores than OSCC.Conclusions: Our findings demonstrate that the Akt/mTOR pathway is upregulated in OVC, indicating a role for this pathway in the development and progression of this malignancy. [ABSTRACT FROM AUTHOR]

Objective: Verrucous carcinoma of the larynx (VCL) is a rare entity with reportedly favorable prognosis. Current analyses are limited primarily to case reports and case series, thus making a population-based analysis useful in characterizing frequency, incidence, and survival trends to guide clinical diagnosis and decision making.Study Design: Analysis of the National Cancer Institute's SEER (Surveillance, Epidemiology, and End Results) database.Methods: Cases of VCL diagnosed between 1973 and 2011 were searched in the SEER database. Analysis was carried out with respect to patient demographics, tumor characteristics, incidence, treatment modality, and survival.Results: In sum, 516 patients with VCL were identified. Males composed 88.4% of cases. Whites accounted for 88.4% of cases, with 8.1% of cases occurring in black patients. Most cases (79.7%) arose in the glottis, a statistically significant predilection when compared with other laryngeal malignancies (P < .0001). Incidence of VCL decreased from 2000 to 2011, with an annual percent change of -5.4%. Overall 1-, 5-, and 10-year disease-specific survival for VCL was 97.5%, 88.0%, and 77.4%, while 1-, 5-, and 10-year relative survival was 98.1%, 85.5%, and 74.2%, respectively. Surgery seemed to confer better prognosis when compared with other treatment modalities.Conclusions: This large population-based analysis of VCL demonstrates that this entity has a good prognosis, arises in the glottis, and is decreasing in incidence. Five-year survival seems highest when surgery is utilized. However, this finding may be subject to selection bias in high-stage lesions. [ABSTRACT FROM AUTHOR]

The aim of the study was to identify specific human papillomavirus (HPV) type responsible for malignancy in penile tissue samples using laser micro-dissection and TaqMan quantitative real-time PCR (qPCR). The study was based on two pre-malignant and seven malignant penile tissue samples and laser micro-dissection was performed on all. Genotyping was performed on whole tissue sections and laser micro-dissection samples using qPCR. Two whole tissue section samples were HPV negative while seven were HPV positive. In four samples that were single HPV infections with whole tissue section PCR, identical HPV types were confirmed with laser micro-dissection PCR. Clearly confirming that the single HPV type detected is responsible for malignancy. In two samples that had multiple HPV infections with whole tissue section PCR, only one HPV type with the highest viral load was detected with laser micro-dissection PCR, suggesting that the HPV type with the highest viral load is most likely the cause of that particular lesion. HPV 11 and/or HPV 16 were the only types detected with laser micro-dissection PCR in these cases, compared to multiple HPV types (HPV 11, HPV 16, HPV 18, HPV 31, HPV 33, HPV 35, and HPV 39) initially detected with whole tissue section PCR. HPV 11 was associated with verrucous lesions while HPV 16 was associated with squamous cell carcinoma and PIN 3 lesions. This study confirms that laser micro-dissection and qPCR are essential tools in identifying the HPV types responsible for malignancy in penile lesions, particularly in samples with multiple infections. J. Med. Virol. 87:1761-1768, 2015. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Background Variants of squamous cell carcinoma (SCC) make up 15% of all cases of SCC of the upper aerodigestive tract. There are 5 main histologic variants of SCC in the head and neck region: verrucous (VSCC), papillary (PSCC), spindle cell (sarcomatoid) (SCSC), basaloid (BSCC), and adenosquamous (ASC). Conventional sinonasal SCC has been studied extensively, but far less is known about its major variants. Methods The Surveillance, Epidemiology, and End Results (SEER) database was used to extract frequency and survival data from 1973 to 2009. A total of 4382 cases of conventional sinonasal SCC and 328 cases of its major variants were found. Statistical comparisons of data for sinonasal SCC and its variants were carried out with respect to varying demographic and disease specific parameters, such as gender, race, age at diagnosis, and specific anatomic site affected. Results Sinonasal BSCC was diagnosed at a significantly lower mean age than sinonasal SCC. Sinonasal SCSC significantly affected the maxillary sinus more commonly than SCC. In the setting of advanced stage disease, sinonasal VSCC, PSCC, and BSCC appear to be associated with a better prognosis than conventional sinonasal SCC, whereas the impact of histologic subtype on prognosis in early stage disease appears to be more limited. Survival for SCSC and ASC, both regarded as more lethal variants, was statistically similar to conventional SCC. Conclusion Our study supports the practice of distinguishing between conventional sinonasal SCC and its major histologic variants, because histologic subtype appears to carry important prognostic implications. [ABSTRACT FROM AUTHOR]

Association between verrucous carcinoma ( VC) of the head and neck and human papillomaviruses ( HPV) is highly controversial. Previous prevalence studies focused mostly on α- PV, while little is known about other PV genera. Our aim was to investigate the prevalence of a broad spectrum of HPV in VC of the head and neck using sensitive and specific molecular assays. Formalin-fixed, paraffin-embedded samples of 30 VC and 30 location-matched normal tissue samples were analysed, by using six different polymerase chain reaction-based methods targeting DNA of at least 87 HPV types from α- PV, β- PV, γ- PV and μ- PV genera, and immunohistochemistry against p16 protein. α- PV, γ- PV and μ- PV were not detected. β- PV DNA was detected in 5/30 VC (16.7%) and in 18/30 normal tissue samples (60.0%): HPV-19, -24 and -36 were identified in VC, and HPV-5, -9, -12, -23, -24, -38, -47, -49 and -96 in normal tissue, whereas HPV type was not determined in 2/5 cases of VC and in 6/18 normal tissue samples. p16 expression was detected in a subset of samples and was higher in VC than in normal tissue. However, the reaction was predominantly cytoplasmic and only occasionally nuclear, and the extent of staining did not exceed 75%. Our results indicate that α- PV, γ- PV and μ- PV are not associated with aetiopathogenesis of VC of the head and neck. β- PV DNA in a subset of VC and normal tissue might reflect incidental colonization, but its potential biological significance needs further investigation. [ABSTRACT FROM AUTHOR]

Background Carcinoma cuniculatum and verrucous carcinoma are both very well differentiated forms of squamous carcinoma and thus difficult to separate histologically from pseudocarcinomatous hyperplasia. The diagnosis of each often requires clinical-pathologic correlation. Methods We reviewed the literature on cases reported as carcinoma cuniculatum and compared these to the cases originally reported by Aird et al. In addition, we report an additional case of this entity that we encountered in our practice. Results In reviewing the literature it is evident that most authors consider carcinoma cuniculatum and verrucous carcinoma to be synonymous even though Aird's original two cases had no verrucous features. The lack of a clear conceptual distinction between these two entities may cause diagnostic confusion. Conclusion The purpose of this report is to record a case of carcinoma cuniculatum which the authors believe to be similar to those reported by Aird et al., to emphasize the differences between carcinoma cuniculatum and verrucous carcinoma, and to explain how the lack of a clear conceptual distinction between these two tumors can lead to further delay in an already difficult diagnosis. [ABSTRACT FROM AUTHOR]

Odar K, Boštjančič E, Gale N, Glavač D & Zidar N (2012) Histopathology 61, 257-265 Differential expression of microRNAs miR-21, miR-31, miR-203, miR-125a-5p and miR-125b and proteins PTEN and p63 in verrucous carcinoma of the head and neck Aims: To investigate the expression of microRNAs miR-21, miR-31, miR-203, miR-125a-5p and miR-125b and proteins phosphatase and tensin homologue (PTEN) and p63 in verrucous carcinoma (VC) of the head and neck. Methods and results: Thirty cases of VC, 50 cases of conventional squamous cell carcinoma (SCC) and 30 samples of normal epithelium of the head and neck were included. Real-time polymerase chain reaction and immunohistochemistry were used to analyse the expression of microRNAs and proteins, respectively. In comparison to normal epithelium, miR-21 was overexpressed in both VC and SCC and miR-31 was overexpressed in VC and in well- and moderately differentiated SCC. Levels of miR-203 were elevated in VC but unaltered or reduced in SCC, and levels of miR-125a-5p and miR-125b were reduced in VC but unaltered in SCC. PTEN was down-regulated in both VC and SCC, whereas p63 was down-regulated in VC but up-regulated in SCC. Differential expression of p63 in VC correlated inversely with the expression of miR-21 and miR-203. Conclusions: Differences between VC, SCC and normal epithelium in expression profiles of investigated molecules indicate their association with the pathogenesis and clinicopathological characteristics of VC. Our results suggest that some microRNAs and proteins, particularly miR-125b, miR-203 and p63, might be useful in the diagnosis of VC. [ABSTRACT FROM AUTHOR]

Background. Metastases formation depends on the ability of tumor cells to invade basement membranes in a process involving enzymes capable of degrading extracellular matrix components. Methods. We examined the expression of heparanase in oral carcinomas and correlated its staining extent, intensity, and cellular localization with patients’ outcome. Results. Quantitative real-time polymerase chain reaction (PCR) revealed over 4-fold increase in heparanase levels in oral carcinomas compared to adjacent normal tissue. Normal oral epithelium was found negative for heparanase, while all oral carcinomas stained positively for heparanase. Heparanase staining was associated with Ki67 staining, a measure of cell proliferation. Notably, whereas cytoplasmic localization of heparanase was associated with high-grade carcinomas, nuclear localization of the enzyme was found primarily in low-grade, well-differentiated tumors, and in all oral verrucous carcinomas. Conclusion. Expression level and cellular localization of heparanase could serve as an important diagnostic marker in patients with oral cancer. [ABSTRACT FROM AUTHOR]

Although the association and clinical significance of human papillomavirus (HPV) infections with a subset of head and neck cancers, particularly for oropharyngeal carcinoma, has recently been well documented, the involvement of HPV in laryngeal cancer has been inadequately evaluated. Herein we review the currently known associations of HPV infections in diseases of the larynx and their potential for oncogenicity. Using several methods of detection, HPV DNA has been detected in benign (papillomatosis), indolent (verrucous carcinoma), and malignant (squamous cell carcinoma) lesions of the larynx. Consistent with the known oncogenic risk of HPV infections, common HPV types associated with laryngeal papillomatosis include low-risk HPV types 6 and 11, with high-risk HPV types 16 and 18 more commonly present in neoplastic lesions (verrucous carcinoma and squamous cell carcinoma). Although a broad range of prevalence has been noted in individual studies, approximately 25% of laryngeal squamous cell carcinomas harbor HPV infections on meta-analysis, with common involvement of high-risk HPV types 16 (highest frequency) and 18. Preliminary results suggest that these high-risk HPV infections seem to be biologically relevant in laryngeal carcinogenesis, manifested as having viral DNA integration in the cancer cell genome and increased expression of the p16 protein. Despite this knowledge, the clinical significance of these infections and the implications on disease prevention and treatment are unclear and require further investigation. © 2010 Wiley Periodicals, Inc. Head Neck, 2011 [ABSTRACT FROM AUTHOR]

Background. Oral verrucous hyperplasia is a precancerous lesion of oral verrucous carcinoma. Methods. This study used immunohistochemistry to examine the expression of p53, murine double minute 2 (MDM2), p21, heat shock protein 70 (HSP 70), and human papillomavirus (HPV) 16/18 E6 proteins in 48 oral verrucous carcinoma and 30 oral verrucous hyperplasia samples. Results. The mean labeling indices of p53, MDM2, p21, HSP 70, and HPV 16/18 E6 proteins in oral verrucous carcinoma samples were 21%, 31%, 7%, 17%, and 0.5%, respectively, and those in oral verrucous hyperplasia samples were 19%, 35%, 11%, 14%, and 0.3%, respectively. Conclusions. Immunohistochemistry with the above-cited 5 biomarkers could not help differentiate oral verrucous hyperplasia from oral verrucous carcinoma. The low expression of p21 may partially explain abnormal epithelial overgrowth in both verrucous lesions. The pathogenesis of both verrucous lesions may be at least partially attributed to the overexpression of MDM2 protein and moderate expression of HSP 70 protein in both lesions. [ABSTRACT FROM AUTHOR]

J Oral Pathol Med (2010) 39: 559–564 Background: Tumor-associated macrophages (TAMs) are a major cellular component of human cancers, yet there is still no consensus as to their role in cancer growth and angiogenesis. Methods: The association between TAMs and angiogenesis was investigated in formalin-fixed, paraffin-embedded archival material of oral squamous cell carcinoma (OSCC) and oral verrucous carcinoma (OVC). TAMs shown by immunohistochemistry for CD68 and microvessels demonstrated by immunohistochemistry for CD31 were quantified using an image analyzer computer system. Results: TAMs were observed in all studied specimens. The area percentage of CD68 immunoreactivity and microvessel density (MVD) were significantly lower in OVC compared with the different grades of OSCC ( P = 0.0009), ( P = 0.0045). Both parameters increased in high-grade malignancy of OSCC. Linear regression analysis revealed a positive correlation between the area percentage of CD68 immunoreactivity and the MVD in the studied tumors. Conclusions: Increased TAMs is associated with angiogenesis and higher histopathological grades in oral cancer. [ABSTRACT FROM AUTHOR]

Background The association of lichen sclerosus (LS) with genital squamous cell carcinoma is well recognized. However, the relationship between LS and verrucous carcinoma remains unclear. Objective To evaluate the associations of genital and perianal verrucous carcinomas with LS. Methods We conducted a retrospective study on patients with a genital or perianal verrucous carcinoma and reviewed their histopathology specimens and clinical notes. We also conducted a literature review. Results We identified a total of 13 patients (including 6 women and 7 men) with a genital or perianal verrucous carcinoma. All 5 women with vulval verrucous carcinoma had coexisting LS (5/5), and 1 man with penile verrucous carcinoma had coexisting LS (1/3). In contrast, no coexisting LS was found in all 5 cases of perianal verrucous carcinoma (0/5). Half of the cases of verrucous carcinoma with coexisting LS had recurrences (3/6), while no recurrences were found in those without coexisting LS (0/7). Conclusions Our study and review of the literature demonstrate that vulval verrucous carcinoma is strongly associated with LS. In contrast, perianal verrucous carcinoma is not associated with LS. When genital verrucous carcinoma is diagnosed, it is important to consider LS as a potential concomitant diagnosis and offer appropriate treatments and close follow-up to detect recurrence of verrucous carcinoma. [ABSTRACT FROM AUTHOR]

Background. We evaluated the effectiveness of intraarterial methotrexate infusion as a primary therapy for oral verrucous carcinoma (VC). Methods. Fifteen male patients (mean age, 55 years) were included. By using an implantable port-catheter system and a portable pump, methotrexate was continuously infused to the external carotid artery for a mean period of 7.5 days (50 mg/day), followed by weekly bolus of methotrexate (25 mg) via intraarterial route for a mean period of 10 weeks. Results. The tumor regressed dramatically and disappeared completely after treatment within a mean period of 2.5 months. All patients obtained complete remission and recovered without disfigurement. All patients were alive without disease recurrence at a median follow-up of 43 months. The side effects were tolerable. Conclusions. The results of our treatment modality for oral VC appear to compete favorably with the results of surgical series and even more with those of radiotherapy series. © 2007 Wiley Periodicals, Inc. Head Neck, 2008 [ABSTRACT FROM AUTHOR]

Background. This study aims to compare the alterations in the methylation profiles of E-cadherin in oral cancer, especially in tumors with lowest metatastic potential. Methods. Nine oral verrucous carcinomas (VCs), 20 oral well-differentiated squamous cell carcinomas without lymph node involvement (SCC-pN0), and 17 with lymph node involvement (SCC-pN+) were analyzed using methylation-specific polymerase chain reaction and immunohistochemical expression of E-cadherin gene. Results. The immunohistochemical expression of E-cadherin in VC was significantly higher (p = .016) when compared with SCC-pN0 and SCC-pN+ groups. The E-cadherin gene methylation was not correlated with its abnormal immunohistochemical expression in VC and SCC-pN0. All tumors of the SCC-pN+ group with unmethylated E-cadherin gene showed significant loss of E-cadherin immunoexpression (p = .044). Conclusions. The E-cadherin gene methylation presence in tumors with lowest invasive and metastatic potential, such as VC, suggests the early involvement of this epigenetic event in the multistep progression of the oral carcinogenesis. © 2007 Wiley Periodicals, Inc. Head Neck, 2008 [ABSTRACT FROM AUTHOR]

Background: Proliferative verrucous leukoplakia (PVL) is a distinct clinical form of oral leukoplakia defined by its progressive clinical course, changing clinical and histopathological features, and potential to develop into cancer. PVL behaves in a more aggressive and relentless manner than the more innocuous white oral lesions that it can resemble clinically. Methods: A PubMed search was conducted which identified studies that examined patients with PVL and reported data meeting inclusion criteria. Results: PVL is seen much more frequently in females and most often diagnosed after the sixth decade of life. Tobacco use is not strongly linked to the presence of PVL (63% of patients did not use tobacco products). Most (74%) of the patients with PVL progressed to oral carcinoma. Conclusion: PVL is a persistent and progressive oral lesion that requires very close follow-up along with early and aggressive treatment to increase the chances of a favorable outcome. [ABSTRACT FROM AUTHOR]

Proliferative verrucous leukoplakia (PVL) is a distinct clinical form of oral leukoplakia defined by its progressive clinical course, changing clinical and histopathologic features, and potential to develop into cancer. PVL behaves in a more aggressive and relentless manner than the more innocuous white oral lesions that it can resemble clinically. We present three cases of PVL that progressed to carcinoma and discuss the histopathologic findings that may either hinder or assist in the diagnosis. [ABSTRACT FROM AUTHOR]

Our recent study found that a new topical 5-aminolevulinic acid-mediated photodynamic therapy (ALA-PDT) protocol composed of multiple 3-min fractionated irradiations with a light emitting diode (LED) red light at 635 ± 5 nm for a total of 1000 s (fluence rate: 100 mW/cm2; light exposure dose: 100 J/cm2) after topical application of 20% ALA for 1.5 or 2 h can be used successfully for the treatment of oral verrucous hyperplasia. In this case report, we tested the efficacy of this new treatment protocol of ALA-PDT for an extraoral verrucous carcinoma (VC) lesion at the right mouth angle and an intraoral VC lesion at the right buccal mucosa of a 56-year-old male areca quid chewer and smoker. The extraoral tumor was cleared after six treatments of topical ALA-PDT and the intraoral tumor showed complete regression after 22 treatments of topical ALA-PDT. No recurrence of the VC lesion was found after a follow-up period of 6 months. We suggest that PDT using a topical application of 20% ALA followed by multiple 3-min fractionated irradiations with an LED red light is also an effective and successful treatment modality for VC.J Oral Pathol Med(2005)34: 253–6 [ABSTRACT FROM AUTHOR]

To evaluate the coexistence of verrucous and squamous carcinoma of the vulva and to assess the clinical course, survival and rate of recurrent disease of these patients.The records of 17 patients who were diagnosed with verrucous carcinoma of the vulva over a 12-year period were studied retrospectively. Presence of genuine verrucous carcinoma or coexistence of verrucous and squamous carcinoma of the vulva on vulvar biopsies, results of histopathological assessment of final vulva and inguino-femoral node specimens and histological evaluation of recurrent disease specimens were the main outcome measures.Five of the 17 patients (29.5%) initially underwent radical vulvectomy and inguino-femoral lymphadenectomy. Histology of the specimens verified the coexistence of verrucous and squamous carcinomas in four of the five cases. Twelve women (70.5%) underwent simple vulvectomy for genuine verrucous carcinoma; in the final histology, 10 of these women (58.8%) were confirmed as having genuine verrucous carcinomas while two (11.7%) were found to have both verrucous and squamous carcinomas and were further managed by lymphadenectomy. None of our patients died of the disease. Three women (17.5%) presented with local relapse of the tumour, and were managed by wide local excision of the tumour.In the present study, 35% of patients with verrucous carcinomas of the vulva had coexistent squamous carcinoma. Separation of the cases of genuine verrucous carcinoma from coexistent verrucous and squamous tumours is based on the establishment of correct diagnosis by a large and deep vulvar biopsy as well as the meticulous assessment of the specimen by the pathologist. This will result in the decrease of the rate of over- and under-treatment of these patients. [ABSTRACT FROM AUTHOR]

Objectives: To establish the incidence, appearance, behavior, and appropriate treatment of intranasal verrucous carcinoma and determine its relationship to inverting papilloma and human papillomavirus (HPV). Study Design: Retrospective review of all cases of intranasal verrucous carcinoma seen at the Mayo Clinic from 1960 through May 1996. Methods: Retrospective chart review and data collection for age, sex, smoking history, location, association with inverting papilloma, treatment, recurrence, and follow-up. Polymerase chain reaction (PCR) testing for the presence of HPV DNA was performed on all specimens. Results: Of the 13 patients identified, most presented with nasal obstruction (10) or a noticeable intranasal lesion (8). The maxillary sinus was the extranasal site most often involved. Five patients had verrucous cancer develop in an inverting papilloma, and one had squamous cell carcinoma with the verrucous component (a hybrid tumor). All but one patient underwent surgery as initial treatment; only one patient had preoperative radiation therapy. Surgical procedures ranged from local excision to a craniofacial resection. Follow-up ranged from 2 months to 32 years (mean, 6.5 y). Four patients had a single recurrence and two tumors recurred a second time. No metastases developed and no one died from the tumor. In seven patients (10 specimens), DNA was successfully amplified for PCR testing, and no HPV DNA was detected. Conclusions: When verrucous tumors are discovered early, they can be treated effectively with wide local excision. In some cases, a more extensive procedure may be required. A possible role for HPV in the etiology of these tumors was not found. [ABSTRACT FROM AUTHOR]

ABSTRACT A 77-year-old man presented with a 6-month history of intractable toe web intertrigo located in the third and fourth web spaces of his left foot. Biopsy and histological examination confirmed the presence of a verrucous carcinoma. Verrucous carcinoma of the foot has been called epithelioma cuniculatum, a case arising in the intertriginous area of the foot is presented. [ABSTRACT FROM AUTHOR]

We describe a patient with an exophytic oral lesion diagnosed as verrucous carcinoma. The lesion existed without metastases, at least 5 years. Local excisions led to recurrences and continuous expansion. Scalpel biopsies for histopathological and polymerase chain reaction examination were obtained from characteristic regions of the lesion. Brush biopsies for exfoliative cytology (EC) were taken, in order to screen the mucosal area covered by the lesion. After Feulgen restaining of the smears, nuclear DNA contents were measured using a TV image analysis system. An exophytic lesion of the buccal mucosa was diagnosed as low-grade malignant through histopathology and EC combined with DNA-image cytometry (peritetraploid DNA-aneuploidy). Due to almost normal microscopic appearance of the epithelium of verrucous carcinoma, thorough cytological/DNA-cytometric and histological examinations are needed. Brush biopsies of such neoplastic oral lesions showing DNA-aneuploidy with peritetraploid stemlines should be used for diagnosis and follow-up examination of these patients. [ABSTRACT FROM AUTHOR]