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Background Verrucous carcinoma is a rare mucocutaneous malignancy characterized by slow, relentless growth and a low metastasis rate. Objective Herein we summarize surgical success rates and review newer approaches to the treatment of verrucous carcinomas.Methods & Materials: PubMed electronic searches were performed by B.F. and C.V. using combinations of the following terms: ''verrucous carcinoma,'' ''Ackerman tumor,'' ''Buschke Lowenstein,'' ''epithelioma cuniculatum,'' ''carcinoma cuniculatum,'' ''papillomatosis cutis,'' ''treatment,'' ''therapeutics,'' ''management,'' ''mohs surgery,'' and ''excision.'' A systematic review was conducted on 49 articles in accordance with PRISMA guidelines. Results Surgical management remains first-line therapy. Wide local excision is most commonly utilized, with highly variable margins (0.5-3.0 cm) and recurrence rates (4.6-75.0%). Mohs Micrographic Surgery has also been used, especially for recurrent tumors, with an overall recurrence rate of 12.9%. Conclusion Surgery is the treatment of choice, either by Mohs Micrographic Surgery or wide local excision. However, surgical recurrence rates are high, and tissue-sparing therapies are desirable given the sensitive locations involved. Ultimately, randomized control trials are needed to develop evidence-based guidelines for the management of VCs.

Buschke-Lowenstein (B-L) tumors or giant condylomata are large fungating lesions that are caused by human papillomavirus (HPV) and develop in the anogenital region. Although uncommon, physicians and surgeons who treat sexually transmitted diseases or other diseases involving the anogenital area will encounter these patients. The purpose of this study is to review the current literature regarding these lesions. We evaluated every published study in PubMed and Embase from 1925 to 2020, concentrating on the clinical data included in each report, such as presentation and treatment. We also evaluated each work for any definition used and found that there is no accepted definition for these lesions. As such, we provide an inclusive, workable definition. In addition, there are many misconceptions about B-L that continue to be propogated as more case reports are published every year. After evaluating every published case, we refute the fact that these lesions have a high mortality or a high malignancy rate. Furthermore, we refute that these lesions are synonymous with verrucous carcinoma. In addition to a definition, we also propose a simple grading system that we hope can be used to assist in the study and management of these patients moving forward. Although the literature is very heterogenous regarding B-L, they are caused by HPV and are distinct from verrucous carcinoma. Because of the majority of information is based on case reports, the literature concentrates on treatment, but more work is clearly needed to delineate the association with specific HPV types and optimal management of this disease.

Summary Hemorrhoidectomy specimens serve as an excellent resource for study of incidental anal pathology. Detection of most incidental findings is quite rare, although diagnosing clinically significant lesions can have profound impact on the clinical follow-ups. While there are many case reports of incidental findings in hemorrhoidectomy specimens, there are few large studies focused on this topic. The aim of this study was to describe the spectrum and likelihood of detecting incidental findings in hemorrhoidectomy specimens. We reviewed all hemorrhoidectomy specimens that showed incidental clinically significant diagnoses over a 16-year period (2003–2019) for this study. Patient's age, sex, and significant clinical history (Human Immunodeficiency Virus (HIV) status, precursor lesions, other malignancy) were recorded from clinical notes. We identified incidental clinically significant findings in 72 of 1612 (4.5%) specimens. We identified 7 incidental malignancies (squamous cell carcinoma, verrucous carcinoma, adenocarcinoma, mixed adenocarcinoma and neuroendocrine carcinoma, poorly differentiated neuroendocrine carcinoma, melanoma), 54 anal intraepithelial neoplasias (AINs), and 11 benign findings (melanocytic lesions, colorectal polyps, angiokeratoma, infectious/inflammatory). Within the AIN group, the detection of low-grade squamous intraepithelial lesions (LSILs) remained steady; there was a recent, sustained rise in detection of high-grade squamous intraepithelial lesions (HSILs), with more cases showing HSILs (2.6%) than only LSILs (0.7%). In 72.2% of patients, the incidental secondary finding represented a first diagnosis for that entity in the anal canal. Thirty seven percent of patients with anal dysplasia in the hemorrhoidectomy specimen had a prior diagnosis of squamous dysplasia in the anogenital tract. Overall, significant incidental findings were detected in 4.5% (72/1612) of hemorrhoidectomies, supporting routine histological examination of these specimens.

Proliferative verrucous leukoplakia (PVL) is a rare and refractory form of oral mucosal leukoplakia of unknown origin, characterized by high rates of malignant transformation. Different diagnostic criteria, terminologies, and therapeutic approaches have been proposed since the first report in 1985. There remains no general agreement regarding the clinical and histological diagnosis, prevention, and correct management of this disease. This retrospective study investigated 48 patients affected by PVL showing at least one malignant transformation and followed up at 2-month intervals. Twenty-five were female (52.1%) and 23 (47.9%) were male; their median age was 67 years (range 40-93 years). Follow-up ranged from 18 to 240 months. Clinical examination included the use of Lugol's solution to prevent clinical underestimation of the margins and toluidine blue for suspicious areas. Surgical excision by scalpel was the preferred treatment for suspicious lesions, with only five carcinomas surgically removed by diode laser and two by CO2 laser. All specimens were accurately mapped after formalin fixation. Fifteen patients (31.3%; 10 female, five male) developed one oral carcinoma, while 33 (68.7%) developed two or more primary tumours (range 3-12). Only four patients (8.3%), who developed between 2 and 8 oral squamous cell carcinomas (OSCCs), died of tumour-related causes. The pre-surgical clinical workup, subsequent surgical treatment, and follow-up are key to success for patients affected by PVL with malignant transformation into stage 1 OSCC and/or verrucous carcinoma, leading to a high overall survival rate.

Background Verrucous carcinoma, a rare low-grade well-differentiated squamous cell carcinoma, is known for its favorable biological behavior and lack of metastatic potential. However, aggressive resection is problematic in terms of compromised function and aesthetics. Hence, more conservative treatments are needed. Methods: To identify the up-to-date general biological behavior, diagnosis, and treatment trends, we searched PubMed using the keyword “penile verrucous carcinoma” without restrictions on publication date. Results: Current treatments for penile verrucous carcinoma include wide surgical excision, seldom preventive lymphadenectomy, and conservative chemotherapy without surgery or local excision with safe margins. Despite the advent of partial penectomy to minimally impact function and aesthetics, affected patients experience psychosexual problems. Local excision can be used to save the penile shaft and glans penis without preventive lymphadenectomy or adjuvant therapy and can achieve good clinical prognosis with rare recurrence. Conclusions: To preserve the functional and cosmetic aspects, we recommend local excision, especially for tumors measuring

We report two cases of histologically documented pseudoepitheliomatous keratotic and micaceous balanitis in middle-aged male patients, which showed positivity for low-risk serotype human papillomavirus DNA. To our knowledge, only one other case has been documented. Further immunohistochemical proliferative markers were performed and compared to literature findings in penile epithelial proliferations. Evolution to invasive verrucous carcinoma has been associated with absence of HPV DNA. Thus, if confirmed by further studies, HPV testing should be included in pseudoepitheliomatous keratotic and micaceous balanitis assessment to address prognosis, and management.

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.

Enhancer of zeste homolog 2 (EZH2), a component of the polycomb repressive complex 2 that catalyzes trimethylation of H3K27 (H3K27me3), has been shown to promote tumor development and progression. Expression of EZH2 is associated with cell cycle regulation and cell proliferation in various neoplasms. Oral verrucous hyperplasia (OVH) and Oral verrucous carcinoma (OVC) are rare entities and share several clinical and histopathologic features. Problems distinguishing these lesions are added by a lack of adjacent normal tissue of the biopsy samples and poorly oriented tissue sections. The aim of this study was to investigate the expression of EZH2 and H3K27me3 in OVH and OVC and comparing the expression with normal oral mucosa and oral squamous cell carcinoma (OSCC). Seventy-eight samples, including 25 cases of OVC, 8 cases of OVH, 35 cases of OSCC and 10 cases of normal oral mucosa, were retrieved and submitted for immunohistochemical staining. The results demonstrated that the mean labeling indices (LIs) of EZH2 and H3K27me3 expression were highest in OSCC, followed by the OVC, OVH, and normal mucosa. Statistical differences in EZH2 LI were observed among these lesions whereas H3K27me3 LI was significantly different among OSCC, OVH and normal mucosa. EZH2 LI was found to have a sensitivity of 72.00% and specificity of 87.50% in distinguishing OVH from OVC, and a sensitivity of 57.14% and specificity of 84.00% in distinguishing OVC from OSCC. A positive correlation between EZH2 and H3K27me3 expression was significantly found in OVC but not in OVH and OSCC. These findings highlight the involvement of epigenetic regulation by EZH2-mediated H3K27me3 in the pathogenesis of OVH and OVC, and EZH2 expression indicates disease progression of these verrucous lesions. Diagnostic test analysis further suggests that EZH2 may be used as an additional test for differentiating OVH from OVC in questionable cases. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s12105-020-01209-0) contains supplementary material, which is available to authorized users.

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

Cystic squamous cell carcinomas (SCCs) of the jaws, including carcinoma cuniculatum, are rare, slow growing, and relentlessly invasive. The aim of this article is to present 12 cases, 4 of which were designated as carcinoma cuniculatum on the basis of deeply endophytic, anastomosing channels of cystic stratified squamous epithelium and keratin microabscesses. The other 8 were also cystic, but more heterogeneous morphologically and were diagnosed as well differentiated SCCs. Six patients were female, 6 were male (mean age = 74.0 years, range = 50-94 years). Six tumors affected the mandible, 6 the maxillary alveolus with or without extension into the hard palate. All patients underwent primary resection with neck dissection and were staged as T4a N0 M0. In 4 patients, diagnosis was delayed as a result of superficial biopsies and/or confusing histopathology. Cystic SCCs of the jaws can be difficult to diagnose and clinicoradiological correlation is essential. Long-term follow-up is mandatory.

Background: Squamous cell carcinoma antigen (SCCA) is used as a prognostic marker for recurrence of squamous cell carcinoma in various sites, including head and neck. Studies suggest that its high serum levels are correlated to some clinical features, such as nodal metastasis. However, it is still unknown if high SCCA in patients with SCCA tissue expression in tumor cells are related to peripheral T-lymphocytes. Therefore, we did this study to evaluate SCCA expression in squamous cell carcinoma and verrucous carcinoma and to compare it with normal oral mucosa, also investigating the correlation between serum-based and tissue-based antigen levels. Methodology: In this study, the immunohistochemistry (IHC) technique was used to determine the SCCA1 expression pattern in 81 specimens divided into 3 groups, including oral squamous cell carcinoma, verrucous carcinoma, and normal oral mucosa. Serum-based and tissue-based antigen levels of 20 oral squamous cell carcinoma cases were compared by the western blot assay. SCCA expression was also evaluated and compared in both tumor cells and peripheral T-lymphocytes by the immunofluorescence assay. Results: Our results showed that the SCCA levels in SCC specimens were significantly lower than in verrucous carcinoma and normal and hyperplastic oral mucosa specimens. We found no correlation between the IHC expression of SCCA and serum levels. SCCA was well expressed in both tumor cells and peripheral T-lymphocytes. Conclusion: Decreasing SCCA in SCC specimens suggested that SCC tumor cells may affect more than the serum levels of SCCA in some patients. In addition, expression of SCCA in peripheral T-lymphocytes showed that both tumor cells and T-lymphocytes may cause serum SCCA.

Oral cancer is a significant cause of morbidity and mortality worldwide. In this article we present two cases of potentially innocuous looking lesions, initially thought to be traumatic in origin, but later diagnosed as cancer. The first patient presented with a persistent laceration thought to be caused by an accidental shaving injury, which was subsequently diagnosed as squamous cell carcinoma. The second patient presented with a hyperplastic mucosal lesion, suspected as forming due to denture-clasp irritation, which was subsequently diagnosed as proliferative verrucous carcinoma. The importance of early detection and palpation of suspicious lesions is emphasised in this article.

Verrucous carcinoma is a warty variant of squamous cell carcinoma. It most often affects the oral cavity, with the buccal mucosa being the most common site. It is more prevalent among tobacco users with male predominance. Here, that scenario changed. A 42-year-old female patient presented with a chief complaint of discomfort in the left side of her mouth that had been present for 7 days. History revealed patient had a habit of chewing quid for 7-8 times each day. On general examination, the patient exhibited a normal walk and posture, as well as being well oriented, aware, and moderately built. On intraoral examination, a proliferative verrucous growth was seen across the left buccal mucosa, extending anteroposteriorly from the retrocommissural region to the posterior buccal mucosa and superoinferiorly from the upper buccal vestibule to about 1 cm above the lower vestibule. The lesion was 7x4cm in size, clearly defined, and had irregular borders. The surface was uneven at the periphery, with finger-like projections in the centre. The colour ranged from reddish in the peripheral region to white in the centre. On palpatory findings, size, location, surface, and form were validated. With uneven and firm borders, the lesion was painful and raised from surrounding mucosa. Incisional biopsy of the lesion was done. H and E section showed stratified squamous epithelium with hyperplastic in nature and down growth into the cellular connective tissue. Parakeratin plugging was found in a number of cleft-like areas. The basal cell layer showed hyperplasia and some cells with mitotic activity were noticed. Infiltration of many darkly stained inflammatory cells was seen in the underlying connective tissue. Final diagnosis of verrucous carcinoma was given. For treatment, surgical excision was done and advised for regular follow-up.

Purpose This study aims to provide an overview of the literature on carcinoma arising from giant perianal condyloma acuminatum. Methods We present a new case of squamous cell carcinoma arising from giant perianal condyloma acuminatum. We also conducted a systematic search of the medical literature using PubMed, Medline, Google, and Google Scholar related to carcinoma arising from giant perianal condyloma acuminatum. The following search terms were used in various combinations: condyloma acuminatum, giant condyloma acuminatum, Buschke-Lowenstein tumor, squamous cell carcinoma, and verrucous carcinoma. The search included articles published before in the English language November 2020. Results A total of 55 article concerning 97 patients with carcinoma (squamous cell carcinoma, verrucous carcinoma, basaloid cell carcinoma, carcinoma insitu) arising from giant perianal condyloma acuminatum meeting the aforementioned criteria were included. The patients were aged from 24 to 82 years (median: 49.6, IQR: 21); 20 were female (median age: 52.5, IQR: 20.5), and 75 were male (median age: 53, IQR: 17.5). The gender data of the remaining two patients could not be obtained. The histopathological features of tumors arising from giant condyloma acuminatum are as follows: squamous cell carcinoma (n = 56), squamous cell carcinoma in situ (n = 16), verrucous carcinoma (n = 19) and basaloid cell carcinoma (n = 1), squamous cell carcinoma + verrucous carcinoma (n = 1), squamous cell carcinoma + squamous cell carcinoma in situ (n = 1), squamous cell carcinoma + basaloid cell carcinoma (n = 1) and malignant behavior (n = 2). Conclusion Giant condyloma acuminatum is a rare variant of anogenital warts. It is known that this tumor, which is mostly thought to be benign, has a high potential for local recurrence and transformation into invasive cancer. Therefore, it is vital that the tumor is resected with clean surgical margins, even if it looks benign, and that aggressive treatment options are not avoided when necessary.

A transgender female in her 40s with history of HIV and testicular cancer status post-genital X-irradiation presented with a perianal mass and pruritic rash across her chest. Physical examination revealed a bulky, verrucous tumor protruding outward from the anus involving the medial buttocks. Examination of the chest and arms showed numerous guttate, pink, flat-topped papules coalescing into plaques. Clinically and histologically the lesions were consistent with Buschke-Lowenstein condyloma (BLC) and acquired epidermodysplasia verruciformis (AEDV). Buschke-Lowenstein condyloma incisional biopsy tested negative for common low- and high-risk human papillomavirus (HPV) subtypes, including 6, 11, 16, and 18, possibly implicating beta HPV subtype or a less common pathogenic subtype. The patient underwent abdominoperineal resection of the BLC, which tested positive for low-risk HPV subtypes, suggesting the possibility of multiple implicated HPV subtypes in the same tumor. This case demonstrates a possible role of beta HPV or rarer HPV subtypes in the pathogenesis of verrucous carcinoma, particularly in the setting of immunosuppression.

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.

The pathogenesis of vulvar squamous neoplasia has 2 pathways: human papillomavirus (HPV)-dependent and HPV-independent. The HPV-dependent pathway in the vulva follows the same progression as HPV-dependent lesions elsewhere in the gynecologic tract-HPV infection results in high-grade squamous intraepithelial lesion with subsequent progression to basaloid squamous cell carcinoma. The HPV-independent pathway is more complex, with a variety of precursor lesions and molecular alterations. Although the most recognized form of HPV-independent vulvar lesion is differentiated vulvar intraepithelial neoplasia, recent explorations have elucidated new precursors. This review provides an update on HPV-independent risk factors and precursor lesions for squamous cell carcinoma of the vulva.

BACKGROUND Verrucous carcinoma (VC) of the vulva is a variation of squamous carcinoma (SCC). Etiology and treatment of VC are still unclear. CASE REPORT A 50-year-old female visited our clinic with a giant vulvar tumor (8 cm of diameter maximum). Biopsy revealed a suspicious well differentiation squamous cancer. PET/CT (positron emission tomography/computed tomography) scan found suspicious lymph node in bilateral iliac vessel region and bilateral inguinal region. She underwent radical vulvectomy and bilateral inguinal lymph node dissection, and bilateral pelvic lymph node dissection. Pathology turns out to be VC and no lymph nodes involvement. Due to the large defection, vulvar reconstruction was performed 5 weeks later using skin grafts and pudendal thigh flap. This patient was disease free after 12 months follow-up. CONCLUSIONS In patients with VC, a satisfactory biopsy is important and systemic inguinal lymphadenectomy might be omitted. For patients with large defection, flap-based reconstruction is recommended.

The use of diverse terminology may lead to inconsistent diagnosis and subsequent mistreatment of lesions within the proliferative verrucous leukoplakia (PVL) spectrum. The objectives of this study were: (a) to measure inter-observer variability between a variety of pathologists diagnosing PVL lesions; and (b) to evaluate the impact of diverse terminologies on understanding, interpretation, and subsequent treatment planning by oral and maxillofacial surgeons (OMFS). Six oral pathologists (OP) and six head and neck pathologists (HNP) reviewed 40 digitally scanned slides of PVL-type lesions. Inter-observer agreement on diagnoses was evaluated by Fleiss’ kappa analysis. The most commonly used diagnostic terminologies were sent to ten OMFS to evaluate their resulting interpretations and potential follow-up treatment approaches. The overall means of the surgeons’ responses were compared by Student t test. There was poor inter-observer agreement between pathologists on the diagnosis of PVL lesions (κ = 0.270), although there was good agreement (κ = 0.650) when diagnosing frankly malignant lesions. The lowest agreement was in diagnosing verrucous hyperplasia (VH) with/without dysplasia, atypical epithelial proliferation (AEP), and verrucous carcinoma (VC). The OMFS showed the lowest agreement on identical categories of non-malignant diagnoses, specifically VH and AEP. This study demonstrates a lack of standardized terminology and diagnostic criteria for the spectrum of PVL lesions. We recommend adopting standardized criteria and terminology, proposed and established by an expert panel white paper, to assist pathologists and clinicians in uniformly diagnosing and managing PVL spectrum lesions. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s12105-019-01035-z) contains supplementary material, which is available to authorized users.

Primary gastric squamous cell carcinoma (SCC) is a rare histological subtype of gastric cancer. Here, we report the first case of primary gastric verrucous carcinoma (VC), a well-differentiated variant of SCC. Gastroscopy revealed a papillary polypoid lesion at the posterior wall of the upper gastric body and isolated squamous epithelium at the greater curvature of the fornix in a 78-year-old woman. Endoscopic submucosal dissection was performed. Microscopically, the lesion comprised very well-differentiated squamous epithelium with minimal atypia and exhibited coarse papillary structure and bulbous epithelial downgrowth with submucosal invasion. Conventional SCC or adenocarcinoma components were not included, and the lesion was surrounded by the metaplastic intestinal mucosa. Human papillomavirus infection was not detected. Although the pathogenesis of primary gastric SCC remains controversial, here, the disease is suggested as having originated from squamous epithelium. Knowledge of primary gastric VC and difficulty in diagnosing it using surface biopsy is necessary.

Giant condyloma acuminatum, also known as Buschke-Löwen-stein tumor, is a rare variant of verrucous carcinoma presenting in the ano-genital region. While its metastatic potential is limited, aggressive local growth is common, with invasion and destruction of the surrounding tissues often causing important therapeutic challenges. Also, data to inform the optimal management approach are scarce and mostly limited to anectodical reports. We present the case of a human immunodeficiency virus-associated locally advanced Buschke Löwenstein tumor that was successfully treated with extensive surgery., SCOPUS: re.j, info:eu-repo/semantics/published

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

Carcinoma cuniculatum (CC) is a rare clinicopathologic variant of squamous cell carcinoma. Histologically, it is characterized by invasive growth of bland, acanthotic, and keratinizing squamous epithelium that forms multiple rabbit burrow-like, keratin-filled crypts and sinuses. We present a 51-year-old male smoker with CC of the left vocal cord. The tumor was staged T1a and the patient was disease-free 12 months after surgery. To our knowledge, this is the fourth case of CC of the larynx reported in the English literature and the first, due to its early diagnosis, where radical surgery was not performed. We highlight the necessity for awareness of this entity and coordination between otolaryngologists, radiologists, and pathologists for early diagnosis and organ-sparing surgical treatment.

Verrucous carcinoma of the esophagus is a rare disease leading to dysphagia, chest pain, and weight loss. The diagnosis is difficult because even repeated biopsies are often without tumor evidence. We present a patient with verrucous carcinoma of the esophagus and a literature review. A 64-year-old patient with dysphagia and sore throat received esophagogastroduodenoscopy illustrating segmental circumferential verrucous inflammation and Candida esophagitis in the middle part of the esophagus. Repeated mucosal biopsies revealed reactive hyperkeratosis of the squamous epithelium with minimal atypia but without ulcera, eosinophilic esophagitis, or suspicion of cancer. Mucosal infection with adenovirus, herpes simplex virus 1, human papilloma virus types, and cytomegaly virus was ruled out. Veruccous carcinoma was detected finally by endoscopic mucosal resection. The patient was successfully treated by esophageal resection. Tumor stage was G1, pT1b, pN0, L0, V0, Pn0, R0. The results suggest that macroscopic suspicion of verrucous esophageal carcinoma should lead to resections of larger tissue specimens by EMR to confirm the diagnosis. Das verruköse Ösophaguskarzinom ist eine seltene Erkrankung, die zu Dysphagie, Brustschmerzen und Gewichtsverlust führen kann. Die Diagnose ist schwierig, da selbst wiederholte Biopsien negativ sein können. Wir stellen einen Patienten mit verrukösem Ösophaguskarzinom und eine Literaturübersicht vor. Ein 64-jähriger Mann erhielt wegen Dysphagie und Sodbrennen eine Ösophagogastroduodenoskopie, die eine segmentale verruköse Entzündung und Soorinfektion im mittleren Ösophagus zeigte. Mehrmalige Biopsien ergaben eine reaktive Hyperkeratose des Plattenepithels mit minimalen Epithelatypien ohne Hinweise auf Ulzera, eosinophile Ösophagitis oder Karzinom. Mukosainfektionen mit Adenoviren, Herpes simplex Viren, Humanem Papilloma Virus und Cytomegalie Viren wurden ausgeschlossen. Das verruköse Karzinom wurde schließlich durch eine endoskopische Mukosaresektion (EMR) festgestellt. Der Patient wurde erfolgreich ösophagektomiert. Das Tumorstadium war G1, pT1b, pN0, L0, V0, Pn0, R0. Die Ergebnisse zeigen, dass bei endoskopischem V. a. ein verruköses Ösophaguskarzinom größere Gewebeentnahmen zur Sicherung der Diagnose erforderlich sind.

Penile verrucous carcinoma exhibits a high potential for recurrence. Traditional treatment for penile verrucous carcinoma is radical surgery. Extensive resection generally leads to the loss of the patient’s sexual function and limits the tolerance for additional additional surgical resection. Herein, we present a case of penile verrucous carcinoma, who achieved complete remission after 3 sessions of PDT and 6 months Acitretin. There was no recurrence at 12 months of follow-up. This case suggests that photodynamic therapy combined with acitretin is a treatment option for penile verrucous carcinoma.

Introduction: Oral verrucous carcinoma is a special form of well-differentiated squamous cell carcinoma which possesses specific clinical, morphologic and cytokinetic features that differ from other types of oral cancers and hence diagnosis requires immense experience in histopathology. Hence it is certainly important to distinguish such a lesion from other oral tumors as treatment strategies vary widely between them. Objective: In search of a critical diagnostic marker in distinguishing oral verrucous carcinoma from oral squamous cell carcinoma, Notch4 receptor, one of the key regulatory molecules of the Notch signaling family has been aberrantly activated in the progression of several types of tumors. However its function in oral verrucous carcinoma remains unexplored. Thus the present study aims in determining the differential expression pattern of Notch4 in oral verrucous carcinoma and oral squamous cell carcinoma. Methods: Ten patients reported positive for oral cancer (5 patients with oral verrucous carcinoma and 5 patients with oral squamous cell carcinoma). Five normal tissue samples were also obtained and evaluated for clinicopathological parameters and immunohistochemistry, western blotting and real time polymerase chain reaction for Notch4 expression. Results: Our results reveal that the expression of Notch4 was considerably high in oral squamous cell carcinoma lesions compared to normal tissue, whereas in oral verrucous carcinoma, irrespective of the clinicopathological features, complete regulação descendente of Notch4 was observed. Conclusions: These preliminary findings strongly support the fact that Notch4 is downregulated in oral verrucous carcinoma and could be considered as a suitable prognostic marker in distinguishing oral verrucous carcinoma from oral squamous cell carcinoma. This distinguishing marker can help in improving therapeutic options in patients diagnosed with oral verrucous carcinoma. Resumo: Introdução: O carcinoma verrucoso de cavidade oral é uma forma especial de carcinoma de células escamosas bem diferenciada que tem características clínicas, morfológicas e citocinéticas específicas que diferem de outros tipos de cânceres orais. Por essa razão, o diagnóstico requer grande experiência em histopatologia. Portanto, é certamente importante distingui-lo de outros tumores orais, pois as respectivas estratégias de tratamento variam muito. Objetivo: Em busca de um marcador de diagnóstico crítico na distinção entre o carcinoma verrucoso e o carcinoma de células escamosas de cavidade oral, o receptor Notch4, uma das principais moléculas reguladoras da família de sinalizadores Notch, foi ativado de maneira anormal na progressão de vários tipos de tumores. No entanto, sua função no carcinoma verrucoso permanece inexplorada. Assim, o presente estudo tem como objetivo determinar o padrão de expressão diferencial de Notch4 no carcinoma verrucoso e de células escamosas de cavidade oral. Método: Dez pacientes tiveram resultado positivo para câncer oral (cinco pacientes com carcinoma verrucoso e cinco pacientes com carcinoma de células escamosas) e cinco amostras normais foram também obtidas. Além da avaliação dos parâmetros clínico-patológicos, foram feitos análise imuno-histoquímica, Western Blot e reação de polimerase em cadeia em tempo real para a expressão de Notch4. Resultados: Nossos resultados revelam que a expressão de Notch4 foi consideravelmente alta em carcinomas de células escamosas em comparação com os tecidos normais, enquanto que no carcinoma verrucoso, independentemente das características clínico-patológicas, observou-se regulação descendente completa de Notch4. Conclusão: Esses achados preliminares apoiam fortemente o fato de que Notch4 estava regulado para baixo no carcinoma verrucoso oral e poderia ser considerado um marcador prognóstico adequado para distinguir entre carcinoma verrucoso e carcinoma de células escamosas de cavidade oral. Esse marcador distintivo pode ajudar a melhorar as opções terapêuticas em pacientes com diagnóstico de carcinoma verrucoso oral. Keywords: Oral verrucous carcinoma, Oral squamous cell carcinoma, Notch4, Prognostic marker, Palavras-chave: Carcinoma verrucoso oral, Carcinoma de células escamosas oral, Notch4, Marcador prognóstico

The epithelium adjacent to an oral squamous cell carcinoma is at risk of undergoing precancerous changes. Even after such changes occur, however, the adjacent epithelium remains histologically similar to normal mucosa. We investigated five argyrophilic nucleolar organizer region (AgNOR)-related features in samples of oral verrucous carcinoma (VeCa) and their corresponding adjacent lining epithelium (adj. VeCa). Morphometric characteristics of AgNORs in oral adj. VeCa and oral VeCa were compared to normal mucosa epithelium, squamous cell carcinoma and oral mucosa epithelium adjacent to squamous cell carcinoma findings that we published earlier. Although adj. VeCa and normal oral mucosa were histologically similar, total AgNOR volume differentiated adj. VeCa from normal oral mucosa, but revealed no significant difference between VeCa and adj. VeCa. Total AgNOR volume/nuclear volume discriminated VeCa from adj. VeCa and normal oral mucosa. Certain AgNOR parameters provide a complementary tool for discriminating VeCa from adj. VeCa and normal oral mucosa, and also for detecting incipient malignant changes in epithelium adjacent to VeCa. Use of the AgNOR technique is cost-effective, because it can be performed on paraffin sections.

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.

Background: Verrucous carcinoma (VC) should be considered a distinct clinicopathologic entity different from the more common oral squamous cell carcinoma (OSCC) because of its unique biological behavior. Best way to understand the behavior of these carcinomas is to study them by means of molecular methods, especially in tumor progression tests and Bcl-X is an important antiapoptotic member of the Bcl-2 family and is one of the newest and most useful markers to determine the aggressiveness of many carcinomas. The relationship between this Bcl-X protein and carcinomatous behavior toward it is not studied extensively, which we attempted to evaluate using immunohistochemical analysis in selected carcinomas of the head and neck region. Method: We studied Bcl-X protein expression in sections of thirty OSCC and ten VC samples and correlated this with tumor differentiation. Results: There was a significant difference in cytoplasmic staining of Bcl-X expression with statistical analysis (P < 0.005) for VC and OSCC when compared as a group. No significance was seen among the different histological grades of OSCC and when compared with VC individually. Conclusion: The significant result between OSCC and VC suggests that their biologic course is comparable and can be helpful in differentiating them with each other for establishment of a better treatment protocol.

Acral melanoma (AM) is a rare subtype of cutaneous malignant melanoma found on acral skin, primarily on the soles of the feet. Although rare, it is the most common subtype of melanoma found in patients of African or Asian ethnicity and has a poor prognosis, often because of the more advanced stage of presentation at diagnosis. In the second of this two-part series, we review the clinical presentation, histopathology, diagnosis and management of AM. Clinically, AM presents as a variegated lesion with blue-black pigment and irregular borders on acral skin. A parallel-ridge pattern is a very specific dermoscopic finding for AM. The differential diagnoses of AM include acral naevus, pyoderma gangrenosum, pyogenic granuloma, verrucous carcinoma and peripheral neuropathy-induced foot ulcers. If there is a clinical suspicion of AM, an excisional biopsy should be taken. Once diagnosis is confirmed by histology, surgical excision is the standard treatment. Overall, dermoscopy and histopathology are key tools in the diagnosis of AM. A greater emphasis on melanoma screening and awareness is essential in minority populations to improve survival outcomes in AM.

Verrucous carcinoma (VC) is a very rare variant of squamous cell carcinoma of the cervix, difficult to point out in histology because of its benign appearance. We present the case of a 29-year-old woman with a locally advanced cervical VC who underwent radiotherapy followed by radical hysterectomy. After local relapse and despite pelvic exenteration, her condition deteriorated. Treatment of choice in VC is surgery, because of the risk of anaplastic transformation under irradiation, raising the chances of distant spread and converting this rather benign-like type of cancer to an aggressive cancer.

Verrucous hyperplasia (VH) is a rare exophytic oral mucosal lesion which can transform into verrucous carcinoma (VC), its malignant but clinically similar counterpart. These entities can be distinguished by the lack of invasive growth in VH cases; as such, it is essential to include a margin with adequate depth when performing a biopsy of the epithelium of the lesion. We report an 80-year-old male patient who presented to the Bapuji Dental College & Hospital, Davangere, Karanataka, India, in 2011 with a warty whitish-pink growth on the inside of his cheek. The patient was treated with wide surgical excision of the lesion and a diagnosis of VH was made based on histopathological features. There was no evidence of recurrence at a five-year follow-up. This report highlights the histological variations, pathogenesis and differential diagnosis of VH.

Adult T-cell Leukemia/Lymphoma (ATLL) is classified as a peripheral CD4+ T-cell neoplasm caused by the human T-cell lymphotropic virus type 1 (HTLV-1). Typical symptoms are associated with leukemic infiltration; however, atypical and exaggerated manifestations of verrucous carcinoma have also been described.We present here the case of a patient with multiple skin lesions, ischemic necrosis in the hallux and lymphadenopathies. Biopsies were taken, which showed verrucous epidermal carcinoma and cutaneous lymphoma. Splenomegaly and adenopathy in mesentery, retro peritoneum and lymph node chains in the limbs were observed. Bone marrow examination showed findings compatible with T-cell leukemia/lymphoma; and it was ELISA positive for HTLV-1/2.The patient had a good initial response to a CHOP scheme (cyclophosphamide, doxorubicin, vincristine and prednisone) with filgrastim. However, the patient had a relapse and died before the second cycle.Comorbidity could lead to the associated risk factors model. According to this model, secondary immunodeficiency caused by HTLV-1 may induce the development of verrucous carcinomas; alternatively, the disease could be due to a correlation between HTLV-1 and the human papillomavirus (HPV).La leucemia/linfoma de células T del adulto se clasifica como una neoplasia de células T CD4+ periféricas desencadenada por el virus linfotrópico de células T humanas tipo 1 (HTLV-1). Los síntomas típicos se asocian a la infiltración leucémica; sin embargo, también se ha descrito la manifestación atípica y exagerada de carcinomas verrucosos.Se presenta el caso de una paciente con lesiones múltiples en piel, necrosis isquemica del hallux y linfadenopatías. se realizaron biopsias que reportaron carcinoma epidermoide verrugoso y linfoma cutáneo. Se detectó esplenomegalia y adenopatías en mesenterio, región retroperitoneal, y cadenas ganglionares de las extremidades. la medula ósea presentó hallazgos compatibles con leucemia/linfoma de células T y ELISA positivo para HTLV-1/2.La paciente presentó buena respuesta inicial al esquema CHOP (ciclofosfamida, doxorrubicina, vincristina, prednisona) con filgrastim. Sin embargo, presentó recaída de la enfermedad antes del segundo ciclo y falleció.La comorbilidad podría conducir al modelo de factores de riesgo asociados. De acuerdo con este modelo, la inmunodeficiencia secundaria causada por HTLV-1 puede inducir el desarrollo de carcinomas verrucosos; Alternativamente, la enfermedad podría deberse a una correlación entre el HTLV-1 y el virus del papiloma humano (VPH).

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.

A 49-year-old woman with a past history of several infundibular cysts in the head and neck region presented with a 6-month history of a nonhealing perianal abscess on a background of 13 years of chronic sacral-buttock abscesses and discharging sinuses as part of hidradenitis suppurativa. After 2 surgical procedures and inadequate healing, a wide local excision was performed. The surgical specimen revealed an extensive, infiltrating, cystic and deeply penetrating, dermal and subcutaneous neoplasm with multiple fistulous tracts extending to the skin surface. The histopathology was consistent with carcinoma cuniculatum, a rare, slow growing, verucciform variant of squamous cell carcinoma. An entirely subcutaneous verrucous carcinoma of the sacrogluteal region is exceptionally rare, and this represents the first documentation of such a case in a female.

Verrucous carcinoma is a rare variant of squamous cell carcinoma. The oral cavity, genitals, larynx, esophagus, and skin are usually affected, and the head and neck regions are the most affected areas. Few studies reported about head and neck verrucous carcinoma (VC) in the literature. Therefore, we conducted an extensive population-based study about the VCs to use population-based data to further investigate the incidence, treatment, and survival of head and neck verrucous carcinoma. Patients from Surveillance, Epidemiology, and End Results database (SEER) between 1973 and 2015 were brought into our study. The data of VCs and other head and neck malignancies (OHNMs) patients were extracted for analysis. We compared characteristics of patients with VC with those of patients with OHNMs. Results were obtained for 2039 cases of VC and 394,739 cases of OHNM. Compared to patients with OHNM, patients with VC were more often female (36.6% vs 31.1%; P

Background and aim: Verrucous hyperplasia (VH) and verrucous carcinoma (VC) of the head and neck are two (pre)malignant entities that are slowly progressive with low tendency to metastasize. However, they can reduce the patient’s Quality of Life (QoL) and may even transform into squamous cell carcinoma (SCC). As they are typically approached by surgical resection, some patients do not qualify for surgery. Methotrexate may be a systemic alternative but the response is mostly not durable. This case report tries to illustrate the potential role of methotrexate in VH/VC of the head and neck. Method: We describe four cases of patients with VH or VC of the head and neck who received methotrexate (40–60 mg/m2) in a weekly or two-weekly interval. Results: Two patients received methotrexate in a neoadjuvant setting. The first patient achieved a macroscopical complete response after 16 cycles and remained in remission after surgery. The second patient suffered from residual disease after 26 cycles and refused radical surgery. Two other patients refused surgery at the time of diagnosis and were proposed methotrexate as a salvage treatment. The first patient had an ongoing response on methotrexate after >60 cycles. The second patient achieved macroscopical complete remission after 28 cycles of methotrexate but suffered relapse by developing an oropharyngeal SCC in the same region. Conclusion: When surgery is not desirable in VH and/or VC, patients can be treated with methotrexate which has a reasonable effect and seems to be well tolerated. Nevertheless, surgery should be the preferred strategy to achieve complete remission.

Verrucous skin lesions on the feet of diabetic patients in conjunction with a neuropathic foot ulcer is an uncommon incident. Currently, there are approximately 20 reported cases in the literature. Herein we report two cases of verrucous lesions superimposing a chronic diabetic ulcer. Patients failed several conservative treatments, and several biopsies were performed with inconclusive results, suggesting possible underlying verrucous carcinoma. Given the possibility of underlying malignancy, both patients were treated with wide excision, and both were negative for malignancy, thus confirming verrucous skin lesions on the feet in diabetic neuropathy. We also summarize the current literature on verrucous skin lesions on the feet in diabetic neuropathy.

Background and Aims Carcinoma cuniculatum (CC) is a rare variant of an extremely well-differentiated squamous cell carcinoma. The most commonly involved site is the skin, with a preference for the sole. Only 15 cases of esophageal CC have been reported so far. Based on published data, the clinical behavior of CC has not been clearly defined. We describe the clinical-pathologic features of two cases of esophageal CC, and provide a review of the available literature, to shed more light on this unusual tumor. Methods A detailed gross and histologic analysis was performed on two cases of surgically treated esophageal CC. The patients were followed-up after surgery. A systematic search was also done concerning studies focused on esophageal CC. A search of the electronic databases MEDLINE-PubMed was conducted using the following research terms: (esophagus) AND (cuniculatum carcinoma). Results Both patients were alive at last follow-up at six and nine months from surgery without any recurrence. Concerning the fifteen cases reported from the systematic review, median follow-up after surgery was very long as compared to common esophageal cancers (4.0 years), with only one recurrence observed. Conclusion CC shows an indolent clinical behavior, with a low recurrence rate after radical surgery. The diagnosis of this rare tumor is typically made after surgery. An aggressive approach is required with curative intents.

A 65-year-old male patient with chronic dysphagia was found to have a 2 cm mass at gastro-oesophageal junction on endoscopy. Biopsy showed squamous hyperplasia without malignancy. Controlled radial expansion balloon dilatation and partial resection were performed but the symptoms recurred. He finally underwent endoscopic mucosa resection and histology showed well-differentiated verruciform squamous proliferation limited to the mucosa. Small amounts of tumour remnants were treated during subsequent follow-up endoscopies and the patient has been tumour free since then. Diagnosis of oesophageal verrucous carcinoma can be challenging and could be managed with endoscopic resection. In this report, we review the literature and present our experience with a patient with oesophageal verrucous carcinoma.

Abnormal expression of microRNAs (miRNAs) is involved in the development of and anti‑apoptotic effects in various types of human cancer. However, miRNA‑mediated regulation of oral verrucous carcinoma (OVC) remains to be elucidated. The present study aimed to investigate the expression of miR‑181b in OVC and oral squamous cell carcinoma (OSCC). The expression levels of miR‑181b were determined using reverse transcription‑quantitative polymerase chain reaction. The expression levels of B‑cell lymphoma 2 (Bcl‑2) and leucine rich repeats and immunoglobulin like domains 1 (LRIG1), were evaluated using immunohistochemical staining. The correlation between Bcl‑2 and LRIG1 expression was determined using a Pearson correlation analysis. The expression levels of miR‑181b and Bcl‑2 in OVC were significantly higher compared with normal mucosal tissue (NM); however, lower compared with the OSCC. The key target of miR‑181b was LRIG1 and it was significantly lower in OVC tissues compared with NM tissue; however this was higher when compared with OSCC tissue. The expression levels of Bcl‑2 were correlated with expression levels of LRIG1 in OVC tissues. Therefore, LRIG1 may be associated with anti‑apoptotic function in OVC tissues.