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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 IRB approved retrospective search of UF and UNMC oral biopsy services was performed for all gingival biopsies. Inclusion criteria included cases (a) exhibiting marginal gingival leukoplakia, and (b) 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 twelve 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 7 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. This article is protected by copyright. All rights reserved.

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.

OBJECTIVES To investigate the clinical characteristics of patients with penile cancer in Japan using the nationwide hospital-based cancer registry database. METHODS Using hospital-based cancer registry data, we described the distribution of age, pathology, tumor-node-metastases classification, and first-course treatment in patients treated between 2012 and 2015. We compared the patterns of first-line treatment between elderly and non-elderly patients. RESULTS A total of 1012 patients were diagnosed with squamous cell carcinoma among 1773 patients with penile tumors who registered under topography code C60. The median age at diagnosis was 74 years, and 85.9% of patients were aged >60 years. The most common pathology was usual-type squamous cell carcinoma (91.9%), followed by verrucous carcinoma (5.0%), sarcomatoid carcinoma (1.1%), papillary carcinoma (0.7%), basaloid carcinoma (0.6%), adenosquamous carcinoma (0.4%), warty carcinoma (0.2%) and mixed carcinoma (0.1%). A total of 61.3% of patients were diagnosed with localized disease. In contrast, the proportions of patients with lymph node and distant metastases were 27.5% and 2.1% at diagnosis, respectively. The proportion of patients who were treated with chemotherapy as the first-course treatment was significantly lower among elderly patients (≥80 years) with clinical stage III (27.6% vs 7.1%, P = 0.0312) and clinical stage IV (53.2% vs 14.3%, P = 0.0086). CONCLUSIONS Most penile cancer patients in Japan are diagnosed with usual-type squamous cell carcinoma, and those with human papilloma virus-related squamous cell carcinomas are

Biological tissues (including oral mucosa) can absorb and re-emit specific light wavelengths, detectable through spectrophotometric devices. Such a phenomenon is known as "autofluorescence" (AF). Several devices evaluating tissue AF have been developed and commercialized in the last two decades. Among these, the VELscope® system has been proposed as a visual diagnostic aid for potentially malignant disorders and malignant lesions of the oral mucosa. In the present pilot study, we investigated which are the main histopathological features possibly related to variations in AF patterns in a set of 20 oral squamous cell verrucous carcinoma. Among all the histological features investigated, only the mean width of keratin was significantly different between hypofluorescent and hyperfluorescent carcinomas. The results of the present study demonstrate that AF features of oral malignant lesions are significantly associated with the width of their keratin layer.

The association of syringocystadenoma papilliferum (SCAP) with verrucous carcinoma (VC) of the skin in the same lesion is a rare, but well-documented event. Although human papillomaviruses (HPV) have been proposed to have an etiologic role in the development of the verrucous proliferations associated with SCAP, most of the immunohistochemical and molecular studies have failed to show the presence of their genomic material in these lesions. We report a series of four cases of SCAP associated with VC in anogenital lesions. In two of the cases, we demonstrated the presence of the BRAF V600E mutation by polymerase chain reaction and immunohistochemistry, both in the glandular and in the squamous component. No HPV-related histopathologic changes were found, nor could the presence of viral DNA be showed.

Non-urothelial carcinomas involving the bladder are uncommon and often diagnostically challenging. These carcinomas may show squamous, adenocarcinomatous or neuroendocrine features, with immunohistochemical stains aiding the diagnosis in only a subset of cases. The clinical history in non-urothelial bladder carcinomas is important, given that the differential diagnosis often includes secondary involvement of the bladder by direct extension or metastasis from carcinomas at other sites. This paper will review non-urothelial carcinomas in each of these three morphological categories, emphasising recent changes in diagnostic grouping and challenges in the histopathological diagnosis. Review of bladder cancers with squamous morphology will include discussion of conventional squamous cell carcinoma and verrucous carcinoma and their distinction from urothelial carcinoma with extensive squamous differentiation. Bladder carcinomas with adenocarcinomatous change will include primary bladder adenocarcinoma, urachal adenocarcinoma and tumours of Müllerian type. Finally, neuroendocrine neoplasms of the bladder, including well-differentiated neuroendocrine tumour and neuroendocrine carcinomas, will be discussed. Associated surface findings, risk factors and prognostic features will be described.

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

Aims Verrucous carcinoma (VC) is a variant of well differentiated squamous cell carcinoma and is in the anal region regarded as synonymous with giant condyloma (Buschke-Lowenstein tumor) (BLT). Etiology, diagnostic criteria and clinical behavior of both lesions are controversial. Recent studies suggest that VC at other sites is not associated with human papillomaviruses (HPV). We hypothesized that anal VC is also not related to HPV, while BLT is a HPV-induced lesion. Methods and results Ten cases of VC and 4 cases of BLT were included. Several techniques were used for HPV detection: in situ hybridization for HPV6, 11, 16 and 18, six different PCR protocols for detection of at least 89 HPV types from Alpha-, Beta-, Gamma- and Mu-PV genera, and in situ hybridization for high risk HPV E6/E7 mRNA. p16 immunohistochemistry and morphometric analysis were also performed. Alpha-, Gamma- and Mu-PVs were not found in any case of VC, while HPV6 was detected in all cases of BLT. p16 overexpression was not present in any of the lesions. Among microscopic features, only the absence of koilocytosis and enlarged spinous cells seem to be useful to distinguish VC from BLT. Conclusions Our results suggest that anal VC, similarly to VC at other sites, is not associated with HPV infection and must be distinguished from BLT which is associated with low risk HPV. Only with well-set diagnostic criteria will it be possible to ascertain clinical behavior and optimal treatment for both lesions. This article is protected by copyright. All rights reserved.

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

ObjectiveLaryngeal verrucous carcinoma (LVC) is a rare, locally invasive neoplasm comprising 1% to 3.4% of laryngeal carcinomas. Management strategies are a topic of ongoing conversation, and no definitive treatment protocol based on T stage and presentation exists. This review examines characteristics, treatment modalities, and patient outcomes of LVC.Data SourcesPubMed, MEDLINE, EMBASE, and Web of Science.MethodsDatabases were searched through October 29, 2015, for literature detailing individual patient cases of LVC. Variables analyzed included patient demographics, tumor characteristics, tumor size, treatment, and outcomes.ResultsThirty-seven articles with 369 cases were included. LVC was found more commonly in males (13.8:1), at an average age of 58.7 years, and located in the glottis (74.0%). Most patients had local disease at presentation (94.9%). The most common presenting symptom was hoarseness (92.3%). The most common primary treatment was surgery alone (72.3%), with local excision as the most c...

We describe a case of progressive, significant, bony destruction of right midface over approximately 27 months from an unknown aetiology. A 58-year-old male patient originally presented with a white lesion in the upper right buccal sulcus, which a biopsy confirmed to be a benign hyperplastic inflammatory lesion. However, 16 months later, the patient returned with signs and symptoms suspicious of a malignant aetiology. A series of computed tomography scans over 27-month period revealed progression of extensive permeative right midfacial bony destruction now with intracranial involvement. Contrary to the clinical and radiological findings, the histology results could not confirm malignancy and have been inconclusive on various occasions. We describe the clinical journey to date of this patient and discuss differential diagnoses: actinomycosis osteomyelitis; avascular necrosis of infective cause, such as mucormycosis; verrucous carcinoma; and Gorham's disease (massive osteolysis). We highlight the importance of a collaborative, multicentre, multidisciplinary approach to explore the results of investigations that conflict with the clinical picture of a complex case like this.

Aims Oesophageal epidermoid metaplasia is defined by a dense granular layer with overlying hyperorthokeratosis, resembling the epidermis of skin. A possible association between epidermoid metaplasia, squamous dysplasia and squamous cell carcinoma has been proposed. The aim of this study was to compare the prevalence of epidermoid metaplasia in patients with oesophageal squamous neoplasms with that in a control cohort. Methods and results Medical records and slides from 1048 consecutive oesophageal biopsies and resections for any indication and 58 patients with oesophageal squamous neoplasms were reviewed. Two cases (0.19%) of epidermoid metaplasia were identified in the 1048-patient control group. The prevalence of epidermoid metaplasia was significantly higher (P < 0.05) in the 58 patients with oesophageal squamous neoplasms, two of whom (3.5%) had concurrent epidermoid metaplasia (odds ratio 18.1, 95% confidence interval 2.5–131). One case was associated with a verrucous carcinoma and the other with a well-differentiated, superficial (pT1), exophytic squamous cell carcinoma. No patients had epidermoid metaplasia in a biopsy prior to the diagnosis of squamous neoplasia. Conclusions The increased prevalence of epidermoid metaplasia observed in patients with squamous neoplasms provides some additional support for the proposed association. The hypothesis that epidermoid metaplasia is a precursor to squamous neoplasms remains unproven.

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.

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

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.

Fabrication and testing of a novel nanostructured surface-enhanced Raman catheter device is reported for rapid detection, classification, and grading of normal, premalignant, and malignant tissues with high sensitivity and accuracy. The sensor part of catheter is formed by a surface-enhanced Raman scattering (SERS) substrate made up of leaf-like TiO2 nanostructures decorated with 30 nm sized Ag nanoparticles. The device is tested using a total of 37 patient samples wherein SERS signatures of oral tissues consisting of malignant oral squamous cell carcinoma (OSCC), verrucous carcinoma, premalignant leukoplakia, and disease-free conditions are detected and classified with an accuracy of 97.24% within a short detection-cum-processing time of nearly 25-30 min per patient. Neoplastic grade changes detected using this device correlate strongly with conventional pathological data, enabling correct classification of tumors into three grades with an accuracy of 97.84% in OSCC. Thus, the potential of a SERS catheter device as a point-of-care pathological tool is shown for the rapid and accurate detection, classification, and grading of solid tumors.

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.

Odar K, Bostjancic E, Gale N, Glavac 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.

Background Verrucous carcinoma (VC) of the anogenital area is an uncommon variant of squamous cell carcinoma (SCC). Its treatment is not standardized, but surgical excision must be performed if possible. The traditional approach does not distinguish between conventional SCC and VC, despite the extremely low metastatic potential of VC. Accordingly, most patients reported in the literature have been treated with radical surgery, including regional lymphadenectomy. Methods We report two cases in order to describe the oncologic, functional, and esthetic results achieved by Mohs micrographic surgery (MMS) in the treatment of this disease. Results Good functional and esthetic results were achieved in both patients. No local or nodal relapses were detected during the respective 12- and 27-month follow-ups. Conclusions Early recognition of VC and the proper evaluation of deep biopsies will avoid misdiagnosis as SCC and may prevent the occurrence of unnecessary disfiguring interventions. The MMS technique may be considered as a surgical approach in genitoanal VC, although further research is required to confirm this.

It is difficult to totally reconstruct the lips and achieve good functional and aesthetic results, such as oral sphincter function, sensation, appearance, color, and movement. There have been few reports of reconstructing complete lip defects. We present a case of completely reconstructing the lip defects of a 55-year-old patient who had verrucous carcinoma of the buccal mucosa and lips. Extensive ablation was performed by wide bilateral excision of the buccal mucosa and marginal resection of the anterior mandible and both lips. The tongue, partial tongue base mucosa, and retromolar trigone were preserved. To reconstruct and resurface the intraoral and lip defects nearly totally, we applied a free anterolateral thigh (ALT) flap in chimeric style with two independent sets of perforators and skin islands. To achieve better oral function and cosmetics, revisions of the ALT flap, full-thickness scrotal skin grafting, autologous fat grafting, and skin tattooing were done in stages. Postoperative oral sphincter function was obtained without drooling; the general appearance of the lips was also acceptable. © 2011 Wiley Periodicals, Inc. Microsurgery, 2012.

J Oral Pathol Med (2012) 41: 131–135 Background: Oral verrucous hyperplasia (VH) and verrucous carcinoma (VC) are two clinicopathologically distinctive oral verrucous lesions. The objective of this study was to investigate the clinicopathological features of the two verrucous lesions and estimate their relationship from China. Methods: Retrospective review of two series of patients with histologically confirmed VH (n = 121) and VC (n = 56) between 1996 and 2009 in our hospital were conducted. Results: The average age of VH was 58.5 years (ratio male:female = 1.37) with the tongue being the predominant site. The average age of VC was 64.3 years (ratio male:female = 1.15) with the lower lip being the predominant site. Multivariate analysis revealed that the elderly patient with verrucous lesion (≥60 years) was associated with 3.06-fold (P = 0.007) increased carcinoma risk compared with the non-elderly patient. The lesion located on lower lip was associated with 13.54-fold (P

OBJECTIVE • To describe the incidence of the development of male genital lichen sclerosus (LS) in non-genital skin grafts used in penile reconstruction after cancer surgery. PATIENTS AND METHODS • Between 1997 and 2009, 177 patients received surgical treatment for penile cancer in the Urology Department at Sunderland Royal Hospital, the regional penile cancer centre for the north-east of England. • Patients who had organ-sparing surgery and non-genital penile graft reconstructions were identified. • Histology reports for specimens obtained from those grafts were reviewed to identify the presence of male genital LS and the incidence of recurrence of squamous cell carcinoma (SCC). RESULTS • The mean (range) age of patients at diagnosis was 61.8 (32-89) years. Of the 177 patients, 139 had SCC, 32 had carcinoma in situ and six had verrucous carcinoma. • In total, 56 penile reconstructive procedures were performed using split-thickness skin grafts obtained from the inner thigh. • From those grafts, 18 specimens were obtained later for cosmetic, diagnostic or curative purposes. • Male genital LS was found in six of the 18 specimens, and one of them was associated with recurrent verrucous carcinoma. CONCLUSIONS • This is the first published series to describe the incidence of male genital LS in penile skin grafts taken from a remote site after penile cancer surgery. • These results represent new information that might help explain the aetiology of male genital LS.

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. (C) 2010 Wiley Periodicals, Inc. Head Neck 33: 581-586, 2011

J Oral Pathol Med (2011) 40: 167–173 Background: Invasion and metastasis are two characteristics of malignant tumors, which perform by proteolytic destruction of the components of basement membrane (BM) and cell migration. The aim of this study was to evaluate the immunohistochemical (IHC) assessment of type IV collagen and laminin-332 γ2 (Ln-332 γ2) chain expression in well-differentiated oral squamous cell carcinoma (OSCC) and oral verrucous carcinoma (OVC), because these two lesions have same histopathologic findings whereas they have different biological behaviors. Methods: Destruction of BM and cell migration were evaluated by IHC in 15 cases of epithelial hyperplasia with no dysplasia (A group), 15 cases of OVC (B group) and 15 cases of well-differentiated OSCC (C group). Results: There was a significant difference in type IV collagen immunohistochemical staining between three groups, but there were no significant differences between B and C groups. Expression of Ln-332 γ2 chain was not detected in A group. Ln-332 γ2 chain labeling index had significantly difference between B and C groups. The number of Ln-332 γ2 chain immunostaining positive cells was less than 5% in B group and over than 5% in C group which there were significantly differences between these two groups. Conclusions: Isolated immunohistochemical study of type IV collagen does not clearly define that a lesion is invasive or non-invasive and evaluation of Ln-332 γ2 chain expression (cut-off 5%) may be useful as a marker for description of biological differences and diagnosis of OVC from well-differentiated OSCC, especially in doubtful cases.

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.

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.

Verrucous hyperplasia and carcinoma are recognized entities in the human pathology, but not documented experimentally. During application of the carcinogen 4-nitroquinoline 1-oxide to the oral cavity of rats three times a week for a maximum of 18 weeks an increasing frequency of verrucous hyperplasias and carcinomas were noted. The majority of the carcinomas were localized to the palate and 3/4 of these were verrucous carcinomas, with or without anaplastic transformation to infiltrating squamous cell carcinomas. The oral verrucous lesions have all the histological characteristics of their human counterparts. The present experimental study supports the idea that tobacco consumption may represent an important etiological factor in the development of human, oral verrucous carcinomas.

SUMMARY A case of verrucous carcinoma of the penis is presented with a brief review of the problems encountered in therapy. The aetiology and pathology of the tumour are discussed as well as the accepted treatment. The indolent course of this lesion, its low incidence of metastasis, and the characteristic gross and microscopic pattern are emphasised.

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.

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.

Papillary squamous cell carcinoma (PSCC) is a rare variant of squamous cell carcinoma. PSCC can occur as either an in situ or invasive tumor. The sites of occurrence in order of the most to least prevalent are the larynx, oropharynx, and nasopharynx. We present an unusual case of PSCC occurring on the gingiva.A 72-year-old white female presented with a chief complaint of tooth mobility in the right posterior mandible. Clinical examination revealed a Miller's Class 2 mobility of tooth #28 along with an erythematous, papillary appearance of the lingual gingiva on teeth #27, #28, and #29. Her dental history revealed treatment of tooth #28 with locally delivered antibiotics. Her medical history revealed a diagnosis of breast cancer 8 years prior to examination that was treated with partial mastectomy and radiation therapy. An initial differential clinical diagnosis of verrucous carcinoma or metastatic carcinoma was made.Surgical therapy included extraction of tooth #28 and an excisional biopsy of the lesion on the lingual gingiva. Microscopic evaluation of the gingival specimen revealed a neoplastic papillary proliferation of the surface epithelium with a thick layer of parakeratin, deep parakeratin-lined crypts, and a thickened spinous cell layer along with islands and strands of malignant epithelium. The microscopic appearance of the lesion was characteristic for PSSC. The patient's tumor was removed via a block resection that included teeth #27 through #31 and a radical neck dissection.This is a case report of PSCC occurring on the gingiva. This report demonstrates that, even though oral cancers involving the periodontium are a relatively rare occurrence, periodontists cannot be complacent about the diagnosis of periodontal bone loss. It also highlights the importance of utilizing a histopathologic examination to confirm the clinical diagnosis for any suspicious lesion.

Objective: Cytokeratins (CKs) are the intermediate filament proteins of the epithelium cells, which have become important markers of normal and abnormal cell differentiation. The goal of the present study was to investigate the expression pattern of CK 10, 13, 14 and 16 in oral verrucous carcinoma (OVC) and oral squamous papilloma (OSP). Material and methods: Formalin-fixed paraffin-embedded sections from eight cases of each lesion were assessed. Immunohistochemistry was carried out using streptoavidin-biotin complex method. Results: In OVC, CK 10 was expressed in suprabasal to superficial layers whereas in OSP mainly in superficial layer. CK 13 was detected in prickle and superficial cells in most cases of OVC and in suprabasal to superficial cells of OSP. All the cell layers of OVC reacted positively for CK 14 while basal and suprabasal layers of OSP were more pronounced for CK 14. Finally, CK 16 was observed in suprabasal to superficial layer in OVC and the majority cases in OSP showed only superficial reactive cells. Conclusions: CK 10, 13, 14 and 16 immunohistochemical profile emphasis the biological behavior of the studied lesions and confirm the use of these proteins as markers of differentiation.

Aim: 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. Methods: 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. Results: 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. Conclusions: 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.

Background and Objectives Our recent studies showed that a new topical 5-aminolevulinic acid-mediated photodynamic therapy (ALA-PDT) protocol using a light-emitting diode (LED) light source is an effective and successful treatment modality for five cases of oral verrucous hyperplasia (OVH) and one case of verrucous carcinoma. In this study, we treated eight OVH lesions with the same topical ALA-PDT protocol to further confirm the efficacy of this protocol on OVH lesions. In addition, our recent study demonstrated an unsatisfactory clinical outcome for 24 oral leukoplakia (OL) lesions treated once a week by the same topical ALA-PDT protocol. Therefore, in this study 24 OL lesions were treated twice a week by the same protocol to compare whether the twice-a-week treatment modality could result in a better clinical outcome than the once-a-week treatment modality. Study Design/Materials and Methods In this study, 8 OVH and 24 OL lesions were treated by the same topical ALA-PDT once a week and twice a week, respectively. Results All the former eight OVH lesions treated once a week showed complete response (CR) after 2–5 (mean, 3.8) treatments of ALA-PDT. The latter 24 OL lesions treated twice a week demonstrated CR in 8, partial response (PR) in 16, and no response in none. The present 24 OL lesions treated twice a week had a significantly better clinical outcome than the previous 24 OL lesions treated once a week (P = 0.000, chi-square test). Conclusions We conclude that complete regression of OVH lesions can be achieved by less than six treatments of topical ALA-PDT once a week. Although the response of OL lesions to the topical ALA-PDT is not as good as the response of OVH lesions to the same therapy, all OL lesions can have at least PR after eight treatments with the topical ALA-PDT twice a week. In addition, OL lesions treated twice a week have a significantly better clinical outcome than OL lesions treated once a week. Lasers Surg. Med. © 2005 Wiley-Liss, Inc.

Background: Verrucous carcinoma, a variant of squamous cell carcinoma, is distinct from squamous cell carcinoma in morphology and behavior. It preferentially occurs on the oropharyngeal mucosa, the urogenital mucosa, and the soles. In contrast to its malignant clinical picture, the tumor grows locally invasive but is histologically benign and metastasizes rarely. Methods: We report the uncommon occurrence of a large verrucous carcinoma on apparently uninvolved skin in the right axilla in a 47-year-old male. Results: Histologic examination reveals a cauliflower-like tumor consisting of deep invaginated epidermal proliferation with rabbit burrow-like, keratin-filled sinus formations; the basement membrane, however, remains intact. Immunohistology showed positivity for pancytokeratin (KL-1) and cytokeratin (CK) 18 and negativity for CK7, and assessment of the proliferative activity of the tumor cells revealed low percentage of Ki-67 expression. Furthermore, there were only scattered cells expressing p53 or bcl-2. Polymerase chain reaction excluded the presence of human papillomavirus. After complete excision, no signs of recurrence occurred over a follow-up period of three years. Conclusion: Verrucous carcinoma should be distinguished from typical squamous cell carcinoma. The clinicopathological features, differential diagnosis, and therapy are discussed here together with the molecular biologic aspects of the tumor.

Squamous cell carcinoma (SCC) of the oral cavity is a highly invasive tumour of stratified squamous epithelium that spreads through degradation of the basement membrane (BM) and extracellular matrix (ECM). There are currently no reliable tissue or serum markers to predict whether the tumour has metastasized at the time of diagnosis. Verrucous carcinoma (VC) of the oral cavity is a rare low-grade variant of oral SCC that penetrates into the subepithelial connective tissue. Many matrix metalloproteinases (MMPs), such as MMP-1, -2, -7, -9, -13, and -14, as well as integrin receptors have been implicated in cancer invasion. Integrin alphavbeta6 is induced in SCC and appears to be involved in up-regulation of MMP-9 expression by oral keratinocytes and promotion of their migration. The aim of this study was to investigate whether the pattern of MMP expression or that of alphavbeta6 integrin contributes to the differences in the biological behaviour of oral SCC and VC. The results show that the less aggressive nature of oral VC may be connected to its MMP expression profile. Typically, VCs were devoid of epithelial MMP-3, -7, -9, -12 and -13 expression, compared with SCCs. MMP-19 was expressed by epithelial keratinocytes in hyperproliferative areas of verrucous hyperplasia, VC, and SCC, but was absent in the invasive cancer cell nests of SCC. MMP-26 was expressed by hyperproliferative keratinocytes in VC as well as by invasive cancer cells in SCCs. MMP-10 was expressed widely in the epithelium of all SCC specimens. alphavbeta6 integrin expression was also detected in some cases of epithelial hyperplasia but was significantly more abundant in cancers at the invasive front. The absence of MMP-7, -9 and -12 from epithelial cells may serve as a good prognostic marker of non-invasive oral carcinoma. Blocking the activity of invasion-specific MMPs or alphavbeta6 integrin might offer novel therapeutic modalities in early-stage oral carcinoma.

Background: Moesin, a member of ERM (ezrin/radixin/moesin) family, links actin filaments of cell surface structure to the cell membrane. The purpose of the study is to assess the shifts in cellular distribution of moesin in normal oral epithelium, oral epithelial dysplasia (OED), verrucous carcinoma (VC), and oral squamous cell carcinoma (OSCC). Methods: The expression of moesin was evaluated immuohistochemically in paraffin-embedded tissues of 59 specimens of OSCC, 35 specimens of OED, 17 specimens of VC, and five specimens of normal oral epithelium. Results: In the normal oral epithelia, all specimens showed a pattern of membranous expression against the anti-moesin antibody in the basal layer cells. In the OED specimens, moesin was dominantly expressed in the cell membrane except for the cornified layer. In VC and OSCC specimens, almost the whole of the carcinoma cells were stained with anti-moesin antibody. However, in OSCC samples, moesin was markedly expressed increasingly in the cytoplasm and decreasingly in the cell membrane, as compared with OED and VC. In addition, there was a significant correlation between the pattern of moesin expression and tumor differentiation in OSCC. Conclusions: Our results suggest that it is useful to detect the moesin expression as adjunct to screening mucosal lesions in the oral cavity.

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.