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Objective The Netherlands converted to high-risk (hr)HPV-based screening in 2017. An increase in referral of hrHPV-positive women with low risk for cervical intraepithelial neoplasia grade 3 or more (CIN3+) is anticipated and reduction of unjustified referrals will have priority. The relevance of koilocytosis in relation to the underlying risk of high-grade CIN in a primary HPV screening setting is unclear. The aim was to investigate whether the risk for CIN3+ differs between hrHPV-positive atypical squamous cells of undetermined significance (ASC-US)/low-grade squamous intraepithelial lesion (LSIL) with or without koilocytosis. Methods Retrospective cohort study, using data from the Dutch national pathology database (PALGA). The population was 1201 hrHPV-positive women with cytological diagnosis of ASC-US/LSIL. Reporting of koilocytosis was assessed as well as detection rates of CIN1 or less, CIN2 and CIN3+ for ASC-US/LSIL cytology stratified by presence or absence of koilocytosis. Crude and adjusted odds ratios were determined. Results Koilocytosis was present in 40.1% of ASC-US and 45.9% of LSIL cases. CIN3+ is significantly less often found when koilocytosis is present (7.8% for hrHPV-positive ASC-US with- vs 15.8% without koilocytosis). For hrHPV-positive LSIL this was 11.7% vs 20.2%. The crude and adjusted odds ratios for CIN3+ was 0.45 for hrHPV-positive ASC-US and 0.52 for hrHPV-positive LSIL. Conclusions The presence of koilocytosis is a negative predictor of CIN3+. The risk of hrHPV-positive ASC-US with koilocytosis is in the same range as hrHPV-positive/cytology negative cases and in a setting of primary hrHPV screening these cases could be followed conservatively by repeat cytology. The results should be confirmed by the first data from the Dutch HPV-based screening programme.

Condylomatous, or warty squamous cell carcinoma (SCC) of the uterine cervix, is a rare variant of invasive SCC. Here, we describe a case of aggressive condylomatous SCC of the uterine cervix. A 43-year-old woman was monitored for 3 years for suspected low-grade squamous intraepithelial lesion. A whitish papillary mass occupied the cervix, and the colposcopic diagnosis was condyloma acuminatum. A cervical biopsy revealed papillary proliferating thick squamous epithelium, which consisted of koilocytes and atypical cells with enlarged nuclei. Hysterectomy specimens showed a thick layer of atypical squamous epithelium with koilocytosis invading the stroma. Immunohistochemistry revealed negative p16 expression. Hysterectomy specimens tested positive for low-risk human papillomavirus type 6, but negative for other high-risk human papillomavirus types. The bilateral pelvic and para-aortic lymph nodes were positive for metastases. In spite of adjuvant chemotherapy, the case relapsed with multiple lymph nodes and lung metastases shortly after the operation.

In Iran, human papillomavirus (HPV) vaccination is not currently included in the national vaccination program and there are no comprehensive approaches to cervical screening program. Regional data on distribution of HPV types in women is important to predict the impact of current HPV vaccines. Although several studies on distribution of HPV types in cervical precancer and cancer have been conducted in Iran, in most of them HPV positive samples were subjected to specific-primer genotyping (mainly 16 and 18), and leaving the other HPV genotypes almost undetermined. Therefore, the present study aimed to investigate the distribution of HPV types in cervical neoplasia from West and Northwest of Iran. A total of 112 women with atypia, cervical intraepithelial neoplasia, and invasive cervical cancer were included. A PCR assay was performed in all samples to detect the presence of the HPV genome using the GP5+/6+ L1 consensus primer set. All HPV positive samples were subjected for sequencing. In overall, HPV prevalence was 20% in atypica, 44.5% in cervical intraepithelial neoplasia I, 92.3% in cervical intraepithelial neoplasia II-III, and 98.2% in invasive cervical cancer. The most frequent HPV type was HPV 16 (79.2%), which was followed by HPV types 18, 6, and 33 at the frequencies of 6.5%, 5.1%, and 2.7%, respectively. The least HPV types were found to be 31, 45, 53, 58, and 66. In conclusion, this study shows that the current HPV vaccines could have great impact to reduce the burden of cervical cancer in Iran.

Aim The programmed death 1/programmed death 1 ligand (PD-1/PD-L1) pathway can decrease the immune clearance effects of antigen-presenting cells and T lymphocytes to promote immune evasion of cervical cancer cells. However, the effects of this pathway on cervical intraepithelial neoplasia (CIN) progression and squamous cell carcinoma (SCC) metastasis are not clear. We herein investigated whether human papillomavirus infection could affect PD-1 and PD-L1 expression in CIN, and whether their expression is associated with CIN progression and SCC metastasis. Methods We collected paraffin-embedded samples from two cohorts of patients: (i) CIN samples from cohort I (40 women who tested positive or negative for high-risk human papillomavirus [HR-HPV] with grades 0, I, and II–III CIN); and (ii) paired primary and metastatic tumor samples from cohort II (20 SCC patients with or without metastasis). Immunohistochemistry was used to detect expressions of PD-L1 in tumor cells and PD-1 in tumor-associated macrophages and tumor-infiltrating lymphocytes. We also measured P16INK4a expression and interferon-γ levels in the cervical tissues. Results The most common HPV type seen in both cohorts of patients was HPV16, followed by HPV18. Increase in PD-L1 and PD-1 expression was positively correlated with HPV-positivity, increase in CIN grade, and tumor metastasis. Furthermore, upregulation of the PD-1/PD-L1 pathway was associated with decreased expression of the pro-inflammatory cytokine, interferon-γ and increased expression of P16INK4a. Conclusion Expression of PD-L1 and PD-1 could be used as clinical prognostic biomarkers for evaluating CIN and cervical cancer because of its positive correlation with CIN progression and tumor metastasis.

Aim To examine the effect that human papillomavirus (HPV) vaccination has had in Akita Prefecture, by comparing cervical cytology results from women aged 20–24 years with or without HPV vaccination. Methods We examined cervical cytology results from 2425 subjects who underwent cervical cancer screening under the jurisdiction of the Akita Foundation for Healthcare between January 2014 and October 2016. We compared the prevalence of cytologic abnormalities among women aged 20–24 years with or without HPV vaccination. Results The rate of atypical squamous cells of undetermined significance (ASC-US) or worse was 0.242% (1/413) with HPV vaccination, and 2.04% (41/2012) without HPV vaccination. Overall, the prevalence of abnormal cytology results was significantly lower in women aged 20–24 years who had received an HPV vaccination than in those who had not (P = 0.011). The reduction in the rate of abnormal cervical cytology results by HPV vaccination was 88.1%. Conclusion Within a 4-year–5-year period following vaccination, women aged 20–24 years who received an HPV vaccination had significantly lower rates of abnormal cervical cytology results than those who did not receive the vaccine.

Human papillomavirus (HPV) causes greater than 5% of cancers worldwide, including all cervical cancers and an alarmingly increasing proportion of oropharyngeal cancers (OPCs). Despite markedly reduced cervical cancer incidence in industrialized nations with organized screening programs, cervical cancer remains the second most common cause of death from cancer in women worldwide, as developing countries lack resources for universal, high-quality screening. In the United States, HPV-related OPC is only 1 of 5 cancers with a rising incidence since 1975 and now has taken over the cervix as the most common site of HPV-related cancer. Similar trends follow throughout North America and Europe. The need for early detection and prevention is paramount. Despite the common etiologic role of HPV in the development of cervical cancer and HPV-associated OPC, great disparity exists between incidence, screening modalities (or lack thereof), treatment, and prevention in these 2 very distinct cohorts. These differences in cervical cancer and HPV-associated OPC and their impact are discussed here. Cancer 2017;123:2219-2229. © 2017 American Cancer Society.

Objective Much of what is known about the significance of human papillomavirus (HPV) in oropharyngeal squamous cell carcinoma is derived from single-institution retrospective studies, post hoc analyses of tissue specimens from clinical trials, and tissue bank studies with a small sample size. The objective of this study is to investigate the impact of HPV on the frequency and clinical presentation of oropharyngeal carcinoma in a large, national sample with information from patients who underwent HPV testing. Study Design Retrospective, cross-sectional study. Methods We identified a comprehensive national sample of 8,359 patients with oropharyngeal carcinoma and known HPV status diagnosed between 2010 and 2011 within the National Cancer Database. Multivariable logistic regression was used to assess correlates of patient and tumor characteristics on HPV status. Results Among patients with oropharyngeal carcinoma, the frequency of HPV-related squamous cell carcinoma in the United States was 65.4%. HPV-related oropharyngeal carcinoma was associated with younger age, male sex, and white race (P < 0.001). Advanced primary tumor stage was associated with HPV-negative disease (P < 0.001), whereas increasing nodal burden was associated with HPV-positive disease (P < 0.001). Despite less-advanced nodal disease, HPV-negative tumors were associated with a higher likelihood of metastasis at presentation (P < 0.001). Conclusion HPV now accounts for the majority of newly diagnosed oropharyngeal carcinoma in the United States and is associated with a distinct clinical profile, supporting efforts to re-evaluate the staging and treatment paradigm for HPV-associated oropharyngeal cancer. Level of Evidence 4. Laryngoscope, 127:2270–2278, 2017

Human Papillomavirus 16 (HPV16) causes 70% of invasive cervical cancers (ICC) worldwide. Interaction between HPV16 genetic diversity, host genetics and target tissue largely determine the chances to trigger carcinogenesis. We have analyzed the differential prevalence of viral variants in 233 HPV16-monoinfected squamous (SCC), glandular (ADC) and mixed (ADSC) ICCs from four continents, assessing the contribution of geographical origin and cancer histology. We have further quantified the contribution of viral variants and cancer histology to differences in age at tumor diagnosis. The model fitted to the data explained 97% of the total variance: the largest explanatory factors were differential abundance among HPV16 variants (78%) and their interaction with cancer histology (9.2%) and geography (10.1%). HPV16_A1-3 variants were more prevalent in SCC while HPV16_D variants were increased in glandular ICCs. We confirm further a non-random geographical structure of the viral variants distribution. ADCs were diagnosed at younger ages than SCCs, independently of the viral variant triggering carcinogenesis. HPV16 variants are differentially associated with histological ICCs types, and ADCs are systematically diagnosed in younger women. Our results have implications for the implementation of cervical cancer screening algorithms, to ensure proper early detection of elusive ADCs.

A systematic review of the literature was conducted to determine the estimates of and definitions for human papillomavirus (HPV) persistence in women following treatment of cervical intra-epithelial neoplasia (CIN). A total of 45 studies presented data on post-treatment HPV persistence among 6,106 women. Most studies assessed HPV persistence after loop excision (42%), followed by conization (7%), cryotherapy (11%), laser treatment (4%), interferon-alpha, therapeutic vaccination, and photodynamic therapy (2% each) and mixed treatment (38%). Baseline HPV testing was conducted before or at treatment for most studies (96%). Follow-up HPV testing ranged from 1.5 to 80 months after baseline. Median HPV persistence tended to decrease with increasing follow-up time, declining from 27% at 3 months after treatment to 21% at 6 months, 15% at 12 months, and 10% at 24 months. Post-treatment HPV persistence estimates varied widely and were influenced by patient age, HPV-type, detection method, treatment method, and minimum HPV post-treatment testing interval. Loop excision and conization appeared to outperform cryotherapy procedures in terms of their ability to clear HPV infection. This systematic review provides evidence for the substantial heterogeneity in post-treatment HPV DNA testing practices and persistence estimates.

Background Human papillomavirus (HPV)-positive oropharyngeal cancer is generally associated with excellent response to therapy, but some HPV-positive tumors progress despite aggressive therapy. The purpose of this study was to evaluate viral oncogene expression and viral integration sites in HPV16- and HPV18-positive squamous cell carcinoma lines. Methods E6/E7 alternate transcripts were assessed by reverse transcriptase-polymerase chain reaction (RT-PCR). Detection of integrated papillomavirus sequences (DIPS-PCR) and sequencing identified viral insertion sites and affected host genes. Cellular gene expression was assessed across viral integration sites. Results All HPV-positive cell lines expressed alternate HPVE6/E7 splicing indicative of active viral oncogenesis. HPV integration occurred within cancer-related genes TP63, DCC, JAK1, TERT, ATR, ETV6, PGR, PTPRN2, and TMEM237 in 8 head and neck squamous cell carcinoma (HNSCC) lines but UM-SCC-105 and UM-GCC-1 had only intergenic integration. Conclusion HPV integration into cancer-related genes occurred in 7 of 9 HPV-positive cell lines and of these 6 were from tumors that progressed. HPV integration into cancer-related genes may be a secondary carcinogenic driver in HPV-driven tumors. © 2017 Wiley Periodicals, Inc. Head Neck 39: 840-852, 2017.

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.

This article describes a case of multiple, recurrent, cutaneous inverted papillomas (CIPs) in a German shepherd dog, combined with a retrospective follow-up assessment of eight cases.A 3-year-old, black, female German shepherd dog presented with four rapidly growing, alopecic, domed, hyperpigmented, shiny nodules, compatible with CIP. The dog was managed for pruritus, associated with atopic dermatitis, with long-term prednisolone therapy and this therapy was continued after the surgical excision. Twelve months after the initial presentation the dog was represented for two new CIP lesions, coinciding with an increased dosage of prednisolone during an allergic flare-up period.Histopathological evaluation was conducted on both the original and subsequent lesions from the case with recurrence. Eight cases of CIP, based on histopathological findings, were identified retrospectively from the authors' diagnostic pathology service over the previous two years. All nine cases had lesions that exhibited varying degrees of inverted epithelial hyperplasia, multiple, endophytic, papillary epidermal projections, a cup-shaped base with central hyperkeratosis and active viral pathological findings (koilocytes). The submitting veterinarians were contacted and follow-up regarding recurrence and concurrent medications was obtained.CIP is uncommonly reported, typically as a single lesion with no previous reports of recurrence, although one group of dogs with severe combined immunodeficiency developed invasive malignancies. In seven of eight retrospective cases no recurrence of CIP was recorded. The authors speculate that the recurrence in the German shepherd dog may have been associated with chronic (although low-dose) glucocorticoid administration.Cet article décrit un cas de papillomes inversés cutanés, récidivants, multiples (CIPs) chez un berger allemand, associé à une série rétrospective de huit cas. MÉTHODES: Une femelle berger allemand de 3 ans, noire présentée pour quatre nodules brillants alopéciques, hyperpigmentés, bombés à croissance rapide compatibles avec CIP. Le chien était géré pour prurit, associé à une dermatite atopique, avec un traitement à la prednisolone au long cours et ce traitement a été poursuivi après exérèse chirurgicale. Douze mois après la présentation initiale le chien a été de nouveau présenté pour deux nouvelles lésions de type CIP, coïncidant avec l’augmentation de dose de prednisolone administrée au cours d’une poussée allergique. RÉSULTATS: Une évaluation histopathologique a été réalisée sur la lésion initiale et la lésion récidivante. Huit cas de CIP, basés sur les données histopathologiques, ont été identifiés rétrospectivement dans le service de pathologie des auteurs sur une période de deux ans. Tous les neufs cas avaient des lésions qui présentaient des degrés variables d’hyperplasie épithéliale inversée, multiple, endophytique, projections épidermiques papillaires, une base en forme de coupe avec hyperkératose centrale et des signes d’atteinte virale active (koïlocytes). Les vétérinaires ont été contactés et un suivi concernant les récidives et les traitements en cours a été obtenu.Le CIP est rapporté rarement, typiquement comme une lésion unique sans antécédent de récidive, bien qu’un groupe de chiens avec immunodéficience sévère associée ai développé des lésions malignes invasives. Dans sept des huit cas rétrospectifs aucune récidive de CIP n’a été notée. Les auteurs supposent que la récidive chez le berger allemand pourrait être associée à l’administration chronique (bien qu’à faible dose) de corticoïdes.INTRODUCCIÓN: este artículo describe un caso de papilomas invertidos cutáneos (CIPs) múltiples y recurrentes en un perro pastor alemán, combinado con una evaluación de seguimiento retrospectiva de ocho casos. MÉTODOS: Una perra pastor alemán negra de 3 años presentó cuatro nódulos alopécicos, abovedados, hiperpigmentados y brillantes de rápido crecimiento, compatibles con CIPs. El perro estaba siendo tratado por prurito, asociado con dermatitis atópica, con prednisolona de larga duración y esta terapia se continuó después de la escisión quirúrgica. Doce meses después de la presentación inicial, el perro estuvo se presentó por dos nuevas lesiones de CIP, coincidiendo con un aumento de la dosis de prednisolona durante un período de exacerbación alérgica. RESULTADOS: se realizó una evaluación histopatológica tanto de las lesiones originales como de las posteriores recidivas. Se identificaron retrospectivamente ocho casos de CIPs, basados ​​en hallazgos histopatológicos, del servicio de patología diagnóstica de los autores durante los dos años anteriores. Los nueve casos tenían lesiones que presentaban diversos grados de hiperplasia epitelial invertida, múltiples proyecciones epidérmicas papilares endofíticas, una base en forma de copa con hiperqueratosis central y hallazgos patológicos virales activos (coilocitos). Se contactó con los veterinarios remitentes y se realizó un seguimiento con respecto a la recurrencia y la medicación administrada. CONCLUSIONES E IMPORTANCIA CLÍNICA: los CIPs se observan con poca frecuencia, por lo general como una sola lesión sin recidivas, aunque un grupo de perros con inmunodeficiencia combinada grave desarrolló neoplasias malignas invasivas. En siete de ocho casos retrospectivos no se observó recidiva de CIPs. Los autores especulan que la recidiva en el perro pastor alemán puede haber estado asociada con la administración crónica (aunque en dosis bajas) de glucocorticoides.In diesem Artikel wird der Fall eines multiplen, wiederkehrenden, kutan invertierten Papilloms (CIPs) bei einem Deutschen Schäferhund zusammen mit einer retrospektiven Follow-Up Analyse von acht Fällen beschrieben.Eine drei Jahre alte schwarze Deutsche Schäferhündin wurde mit vier rasch wachsenden, haarlosen, kuppelartigen, hyperpigmentierten, glänzenden Knoten, die mit CIP vergleichbar waren, vorgestellt. Der Hund wurde wegen Juckreiz im Zusammenhang mit atopischer Dermatitis mit einer Langzeit Prednisolon Therapie gemanagt und nach der chirurgischen Exzision wurde diese Therapie fortgesetzt. Zwölf Monate nach der Erstvorstellung wurde der Hund mit zwei neuen CIP Veränderungen vorgestellt, was mit einer Erhöhung der Prednisolon Dosis während einem allergischen Schub zusammenfiel.Eine histopathologische Evaluierung wurde sowohl von der Erstveränderung wie auch von der nachfolgenden Veränderung während des Wiederauftretens durchgeführt. Acht Fälle von CIP wurden - basierend auf den Ergebnissen der histopathologischen Untersuchung - retrospektiv aus dem diagnostischen Pathologie Service des Autors über den Zeitraum der vorherigen zwei Jahre identifiziert. Alle neun Fälle wiesen Veränderungen auf, die ein unterschiedliches Ausmaß an invertierter epithelialer Hyperplasie, multiple, endophytische, papilläre epidermale Projektionen, eine Tassen-förmige Basis mit einer zentralen Hyperkeratose und aktive virale pathologische Befunde (Koilozyten) zeigten. Die überweisenden TierärztInnen wurden kontaktiert und ein Follow-Up bezüglich eines Wiederauftretens und der Verabreichung begleitender Medikation wurde festgehalten.CIP wird selten beschrieben, typischerweise als einzelne Veränderung ohne einen Vorbericht eines Wiederauftretens, obwohl eine Gruppe von Hunden mit schwerer Immundefizienz invasive Malignitäten entwickelt hatte. In sieben von acht retrospektiven Fällen wurde nicht von einem Wiederauftreten der CIP berichtet. Die Autoren spekulieren, dass das Wiederauftreten bei diesem Deutschen Schäferhund im Zusammenhang mit der chronischen (wenn auch niedrig-dosierten) Glukokortikoidbehandlung gestanden haben dürfte.背景: 本論文は、ジャーマン・シェパード・ドッグに発生した多発性、再発性反転性乳頭腫 (CIP) の1例を、8例の回顧的追跡調査と合わせて報告する。 方法: 3歳、黒色、ジャーマン・シェパード・ドッグの雌犬が、CIPと思われる急速に成長する脱毛したドーム状の色素沈着した光沢のある4つの小結節を呈した。本症例はアトピー性皮膚炎に伴う掻痒のためプレドニゾロンの長期投与を受けており、外科的切除後もプレドニゾロン治療を継続した。初診時から12ヶ月後、本症例は2つの新しいCIP病変のために来院したが、これはアレルギーの再燃期間中にプレドニゾロンの投与量を増やしたことと一致していた。 結果: 症例の初期病変およびその後の再発病変の両方について、病理組織学的評価を実施した。病理組織学的所見に基づいて、過去2年間に著者の診断病理サービスから遡って8例のCIPを同定した。9例すべての病変は、程度の差こそあれ、反転した上皮過形成、複数の、内生した、乳頭状の表皮突起、中央に過角化を伴うカップ状の底部、活発なウイルスの病理学的所見 (koilocytes) を示していた。提出した獣医師に連絡を取り、再発や併用薬に関するフォローアップを受けた。 結論と臨床上の重要性: CIPはまれにしか報告されず、典型的には単一の病変として報告され、過去に再発の報告はないが、重度の複合免疫不全症の犬の1グループは浸潤性の悪性腫瘍を発症した。回顧的調査を実施した8症例のうち7症例では、CIPの再発は記録されていない。著者らは、ジャーマン・シェパード・ドッグのCIP再発は、慢性的な (低用量ではあるが) グルココルチコイド投与と関連しているのではないかと推測している。.背景: 本文描述了一例德国牧羊犬多发性、复发性皮肤内翻性乳头状瘤(CIPs), 并结合8个病例的回顾性随访评估。 方法: 一只3岁黑色雌性德国牧羊犬出现了4个快速生长、脱毛、圆顶、色素沉着、有光泽的结节, 与CIP一致。该犬长期进行泼尼松龙治疗以管理特应性皮炎的瘙痒, 并在手术切除后继续该治疗。初次就诊后12个月, 犬出现2处新的CIP病变, 与过敏发作期间泼尼松龙剂量增加同步发生。 结果: 对复发病例的原发和后续病灶进行组织病理学评价。回顾两年来的组织病理学结果, 据此确定了8例CIP, 这些结果来自作者所在的病理学诊断服务机构。9例均存在不同程度的内翻性上皮增生、多发性、内生性、乳头状表皮突起、杯状底伴中央角化过度和活动性病毒病理表现(koilocytes)的病变。联系了送检兽医, 并获得了关于复发和同时用药的随访。 结论和临床重要性: CIP不常被报告, 通常为单一病变, 之前未报告复发, 尽管一组并发联合免疫缺陷的患犬发生了侵袭性恶性肿瘤。在8个回顾性病例的7例中, 无CIP复发记录。作者推测, 德国牧羊犬的复发可能与长期 (尽管剂量低) 给予糖皮质激素相关。.Este artigo descreve um caso de papilomas cutâneos invertidos (PCIs) múltiplos e recorrentes em um cão pastor alemão, combinado com uma avaliação de acompanhamento retrospectivo de oito casos. MÉTODOS: Uma cadela pastor alemão de 3 anos de idade, preta, apresentou quatro nódulos alopécicos, abaulados, hiperpigmentados e brilhantes de crescimento rápido, compatíveis com PCI. O cão foi tratado para prurido associado a dermatite atópica com prednisolona a longo prazo e esta terapia foi continuada após a excisão cirúrgica. Doze meses após a apresentação inicial, o cão foi apresentado por duas novas lesões PCI, coincidindo com um aumento da dosagem de prednisolona durante um período de crise alérgica.A avaliação histopatológica foi realizada nas lesões originais e subsequentes do caso com recidiva. Oito casos de PCI foram identificados retrospectivamente com base em achados histopatológicos do serviço de patologia diagnóstica dos autores nos últimos dois anos. Todos os nove casos tinham lesões que exibiam vários graus de hiperplasia epitelial invertida, múltiplas projeções epidérmicas papilares endofíticas, uma base em forma de copo com hiperceratose central e achados patológicos virais ativos (coilócitos). Os veterinários foram contatados e o acompanhamento com relação à recorrência e medicamentos simultâneos foi obtido. CONCLUSÕES E IMPORTÂNCIA CLÍNICA: A PCI é raramente relatada, geralmente como uma lesão única sem relatos anteriores de recorrência, embora um grupo de cães com imunodeficiência combinada grave tenha desenvolvido malignidades invasivas. Em sete dos oito casos retrospectivos, nenhuma recorrência de PCI foi registrada. Os autores especulam que a recorrência no cão pastor alemão pode ter sido associada à administração crônica (embora em baixa dosagem) de glicocorticoides.

Objectives/Hypothesis To evaluate outcomes for patients with pathological N3 (pN3) neck disease from human papillomavirus (HPV)–related oropharyngeal squamous cell carcinoma (OPSCC) and determine variables predictive of survival. Study Design Retrospective case series with chart review. Methods This study was conducted between 1998 and 2013 and included patients with HPV-related OPSCC treated with surgery with or without adjuvant therapy and who had pN3 nodal disease. The primary outcome was disease-specific survival (DSS). Secondary outcomes included overall survival (OS), disease-free survival (DFS), adverse events, and gastrostomy tube rates. Results Thirty-nine patients were included, of whom 36 (90%) underwent adjuvant therapy. Median follow-up was 39 months (range, 2–147 months). Mean age was 56 years, and 87% were male. Seventeen patients (44%) underwent selective neck dissection, whereas six (15%) underwent radical (n = 2) or extended radical (n = 4) neck dissection. Ninety-two percent had extracapsular extension. Five-year Kaplan-Meier estimated DSS, OS, and DFS were 89% (95% confidence interval [CI]: 79%–99%), 87% (95% CI: 75%–99%), and 84% (95% CI: 72%–96%), respectively. The disease recurrence rate was 10% (5% regional, 5% distant metastasis). Patients with less than 5 pathologically positive lymph nodes (P = .041) had improved DFS. Conclusions Patients with HPV-related OPSCC and pN3 nodal disease treated with surgery and adjuvant therapy have very favorable long-term survival and regional control. Patients with five or more pathologically positive lymph nodes may be at higher risk for recurrence. Level of Evidence 4. Laryngoscope, 127:2033–2037, 2017

We performed a systematic review and meta-analysis to explore the optimum management strategy for women with atypical squamous cells of undetermined significance (ASCUS/borderline) or low-grade squamous intra-epithelial lesions (LSIL/mild dyskaryosis) cytological abnormalities at primary screening in the absence of HPV DNA test. We searched MEDLINE, EMBASE and CENTRAL and included randomised controlled trials comparing immediate colposcopy to cytological surveillance in women with ASCUS/LSIL. The outcomes of interest were occurrence of different histological grades of cervical intraepithelial neoplasia (CIN) and default rates during follow-up. Pooled risk ratios (RR) and 95% confidence intervals (CI) were calculated using a random-effect model and with inverse variance weighting. Interstudy heterogeneity was assessed using I2 statistics. Six RCTs were included. Immediate colposcopy significantly increased detection of unimportant abnormalities as opposed to repeat cytology (koilocytosis: 32 vs. 21%, RR: 1.49, 95% CI = 1.17–1.90); CIN1: 21 vs. 8%, RR: 2.58, 95% CI = 1.69–3.94). Although immediate colposcopy detected CIN2, CIN2+, and CIN3+ earlier than cytology, the differences were no longer observed at 24 months (CIN3+: 10.3 vs.11.9%, RR: 1.02, 95% CI = 0.53–1.97), with significant interstudy heterogeneity (p

Background Human papillomavirus (HPV)-related oropharyngeal squamous cell carcinomas (OPSCC) are clinically, epidemiologically and prognostically distinct from other OPSCCs. The incidence of HPV-related OPSCCs has increased significantly worldwide over the past few decades. However, no studies of OPSCC with direct molecular HPV testing has been conducted in New Zealand. Aims To estimate the proportion of OPSCCs attributable to HPV infections in a New Zealand population with a validated HPV testing algorithm. Methods HPV-status was determined by p16 immunohistochemistry and polymerase chain reaction (PCR) of both L1 and E6/7 genes on 55 OPSCCs diagnosed in 2010 and 2011 in Central and South Auckland. Baseline and survival analyses were performed according to HPV status. Results Forty-one (75%) of OPSCC tumours had HPV infections. There was 98% concordance between p16 immunohistochemistry and real-time E6/E7 PCR. After a median follow-up period of 2.6 years, patients with OPSCC of HPV aetiology had more favourable outcomes compared to patients with HPV-negative OPSCC (hazard ratio 0.14, P = 0.02) after adjustment for other variables. Conclusion This study highlights the significant role that HPV plays in the aetiology of OPSCC in New Zealand, and confirms the high rate of accuracy of p16 immunostaining.

A 58-year-old, postmenopausal, multiparous woman presented with a chief complaint of abnormal vaginal bleeding. Endometrial cytology was evaluated twice, revealing only squamous epithelial cells both times. Degenerated leiomyoma or uterine sarcoma was suspected from imaging findings, and total abdominal hysterectomy and bilateral salpingo-oophorectomy were therefore performed. However, histopathological examination revealed no signs of malignancy, and the patient was diagnosed as having ichthyosis uteri with uterine leiomyoma. No koilocytosis was evident, and immunostaining for p16 was also negative. Ichthyosis uteri is an extremely rare disease of unknown origin in which squamous metaplasia of the endometrium occurs across a wide area. Although regarded as a benign condition, cases have been reported in which the underlying condition was squamous cell carcinoma or endometrial adenocarcinoma. If ichthyosis uteri is present, a comprehensive approach is required, and the possibility of uterine malignancy should be considered. However, there may be no direct association between the malignant lesions and ichthyosis uteri.

BACKGROUND Whether higher grade cervical intraepithelial neoplasia (CIN grade 2 or greater [CIN ≥ 2]) that develops because of human papillomavirus (HPV) genotypes not included in vaccines may progress to cervical cancer is largely unknown. The objectives of this study were to document expression of the cyclin-dependent kinase inhibitor 2A (p16) tumor-suppressor protein p16INK4A as a biomarker of cervical carcinogenesis or of malignant potential and to evaluate whether its expression differs between lesions associated with vaccine and nonvaccine high-risk (HR) human papillomavirus (HPV) genotypes. METHODS The study population consisted of 371 women who had not received HPV vaccines. Women were categorized into vaccine and nonvaccine HR-HPV genotypes and lesions associated with those types. Logistic regression analyses were used to determine the association between positive expression p16INK4A and the risk of being diagnosed with CIN 2 or CIN 3. Differences in the proportion of CIN ≥2 lesions that were positive for p16INK4A expression by vaccine-related or nonvaccine-related HR-HPV genotype were determined using the Pearson chi-square test. RESULTS Specimens that were positive for p16INK4A expression were 5.3 and 16.6 times more likely to be diagnosed as CIN 2 and CIN 3 lesions, respectively, compared to CIN 1 lesions. CIN ≥ 2 lesions that were negative for the bivalent and 9-valent HR-HPV genotypes had similar rates of positive p16INK4A expression compared with lesions that were positive for those HR-HPV genotypes. CONCLUSIONS Lesions that may develop because of HR-HPV genotypes not included in HPV vaccines are likely to have similar malignant potential, suggesting that well developed screening programs combined with nonvaccine-based approaches may be needed to manage the residual risk of developing cervical cancer in the post-HPV vaccination era. Cancer 2016;122:3615-23. © 2016 American Cancer Society.

Background. Comorbidity and anemia strongly influence treatment and outcome of oropharyngeal squamous cell carcinomas (SCCs), but respective data are frequently lacking in clinical studies. We evaluated 149 cases of oropharyngeal SCC primarily treated with surgery regarding the impact of these factors on disease-free survival (DFS) and overall survival (OS). Methods. Data were recorded during treatment and follow-up visits. Human papillomavirus (HPV) association of oropharyngeal SCC was detected by p16 immunohistochemistry. Results. Patients with p16-positive disease were significantly less comorbid and anemic, and treated more aggressively. Comorbidity and anemia, but not p16 status, significantly influenced DFS and had more impact on OS than p16 status. Conclusion. In our study, p16-positive seems a good surrogate marker for healthier patients. Patients with p16-positive disease showed improved survival, but this was limited to none/mild comorbid and/or nonanemic individuals in this group. On the basis of our results, we strongly suggest the inclusion of these factors in risk stratification for clinical studies. (C) 2016 Wiley Periodicals, Inc.

Background Precancerous high-grade squamous intraepithelial lesion (HSIL), the current consensus terminology for anogenital squamous cell carcinoma in situ (SCCIS), often presents with distinctive histopathologic findings that may be a function of anatomic site or associated human papillomavirus infection. Methods Fifty-six specimens of anogenital HSIL were compared with an equal number of specimens of SCCIS from non-anogenital sites in regard to the presence of parakeratosis, flag sign in the stratum corneum, compact stratum corneum, hypergranulosis, koilocytes, small blue cells, clonal populations of keratinocytes, pagetoid scatter of atypical keratinocytes, clear cell change, glassy red cytoplasm, pigmentation, nuclear/cytoplasmic(N/C) ratio >2/1, nuclear hyperchromasia, pleomorphic nuclei, mitotic figures, abnormal mitotic figures, dyskeratotic keratinocytes, involvement of skin appendages, acantholysis and amyloid deposition. Results Hypergranulosis, koilocytes, small blue cells, pigmentation, nuclear hyperchromasia, dyskeratotic keratinocytes and amyloid deposition were more frequently noted in anogenital HSIL. Parakeratosis, clear cell change, pleomorphic nuclei, skin appendages involvement and acantholysis were strongly associated with non-anogenital location. There was no significant difference in the incidence of the remaining features. Conclusion The strongest predicators of an anogenital location included hypergranulosis, koilocytes, small blue cells and nuclear hyperchromasia. Pigmentation and amyloid deposition were also strongly associated with an anogenital location.

The study aimed to detect the variants of human papillomavirus (HPV) type 16 E6 and E7 in patients with cervical high-grade squamous intraepithelial lesion (HSIL), and to determine the existence and recurrence of persistent infection after treatment with loop electrosurgical excision procedure (LEEP). Preoperatively collected cervical exfoliated cells from 100 HPV 16 positive HSIL patients enrolled in the study were used to test for E6 and E7 variants. Follow-ups which included TCT, HPV test, and colposcopy were performed every 3 months after the operation, and colposcopic biopsy and endocervical curettage were performed for patients with abnormalities. Patients were followed for 2 years, and recurrence was defined as detecting low-grade squamous intraepithelial lesion (LSIL) or relapse of HSIL in 1 year. In 81% of patients, the E6 variant was the Asian prototype (As.P), 14% of patients had the European variant, 2% had the European prototype (EP), and 3% had the African 1 variant (Af1). The HPV16 could be easily cleared by LEEP in patients with As.P. Persistent infection or recurrence was very rare in this group. The patients with European variants T350G or A442C had a significantly higher incidence of persistent and recurring HPV16 infection. In conclusion, (i) in most cases, As.P caused HSIL. (ii) The European variant E6 T350G/A442C may be associated with higher rates of recurring and persistent HPV16 infection after the LEEP. (iii) The E7 gene mutation may not be a risk factor for recurring HSIL caused by HPV16 or persistent infection. J. Med. Virol. 88:1982-1988, 2016. © 2016 Wiley Periodicals, Inc.

In our previous study of the etiologic role of oncogenic human papillomavirus (HPV) types other than HPV16 and 18, we observed a significantly higher risk of cervical intraepithelial neoplasia Grades 2-3 (CIN2/3) associated with certain lineages of HPV types 31/33/45/56/58 [called high-risk (HR) variants] compared with non-HR variants. This study was to examine whether these intra-type variants differ in persistence of the infection and persistence-associated risk of CIN2/3. Study subjects were women who had any of HPV types 31/33/45/56/58 newly detected during a 2-year follow-up with 6-month intervals. For each type, the first positive sample was used for variant characterization. The association of reverting-to-negativity with group of the variants and CIN2/3 with length of positivity was assessed using discrete Cox regression and logistic regression, respectively. Of the 598 newly detected, type-specific HPV infections, 312 became undetectable during follow-up. Infections with HR, compared with non-HR, variants were marginally more likely to become negative [adjusted hazard ratio = 1.3; 95% confidence interval (CI), 0.9-1.8]. The adjusted odds ratio associating with the development of CIN2/3 was 3.0 (95% CI, 1.2-7.4) for persistent infections with HR variants for 6 months and 10.0 (95% CI, 3.8-38.0) for persistent infections with HR variants for 12-18 months as compared with the first positive detection of HR variants. Among women with non-HR variants, there were no appreciable differences in risk of CIN2/3 by length of positivity. Findings suggest that the lineage-associated risk of CIN2/3 was not mediated through a prolonged persistent infection, but oncogenic heterogeneity of the variants.

In this prospective cohort study, we compared the performance of human papillomavirus (HPV) mRNA and DNA testing of women with atypical squamous cells of undetermined significance (ASC-US) during cervical cancer screening. Using a nationwide Danish pathology register, we identified women aged 30-65 years with ASC-US during 2005-2011 who were tested for HPV16/18/31/33/45 mRNA using PreTect HPV-Proofer (n = 3,226) or for high-risk HPV (hrHPV) DNA using Hybrid Capture 2 (HC2) (n = 9,405) or Linear Array HPV-Genotyping test (LA) (n = 1,533). Women with ≥1 subsequent examination in the register (n = 13,729) were followed for up to 9.5 years for high-grade cervical intraepithelial neoplasia (CIN) or cancer. After 3 years' follow-up, mRNA testing had higher specificity for CIN3 or worse (CIN3+) than HC2 testing (88.1% [95% confidence interval (CI): 86.8-89.6%] versus 59.3% [95% CI: 58.1-60.4%]) and higher positive predictive value (PPV) (38.2% [95% CI: 33.8%-43.1%] versus 19.5% [95% CI: 17.8-20.9%]). However, the sensitivity of mRNA testing was lower than that of HC2 testing (66.7% [95% CI: 59.3-74.5%] versus 97.0% [95% CI: 95.5-98.4%]), and women testing mRNA negative had higher 3-year risk for CIN3+ than those testing HC2 negative (3.2% [95% CI: 2.2-4.2%] versus 0.5% [95% CI: 0.3-0.7%]). Patterns were similar after 18 months and 5 years'; follow-up; for CIN2+ and cancer as outcomes; across all age groups; and when comparing mRNA testing to hrHPV DNA testing using LA. In conclusion, the HPV16/18/31/33/45 mRNA test is not optimal for ASC-US triage due to its low sensitivity and the substantial risk for precancer following a negative test.

BackgroundWhile human papillomavirus (HPV) is an accepted risk factor for oropharyngeal squamous cell carcinoma (SCC), its aetiological role in oral cavity SCC remains unclear. This study aimed to determine the HPV prevalence in an Australian population.

Assessment of Human papillomavirus (HPV) prevalence and genotype distribution is important for monitoring the impact of prophylactic HPV vaccination. This study aimed to demonstrate the HPV genotypes predominating in pre-malignant and cervical cancers in Northern Ireland (NI) before the vaccination campaign has effect. Formalin fixed paraffin embedded tissue blocks from 2,303 women aged 16-93 years throughout NI were collated between April 2011 and February 2013. HPV DNA was amplified by PCR and HPV genotyping undertaken using the Roche(®) linear array detection kit. In total, 1,241 out of 1,830 eligible samples (68.0%) tested positive for HPV, with the majority of these [1,181/1,830 (64.5%)] having high-risk (HR) HPV infection; 37.4% were positive for HPV-16 (n = 684) and 5.1% for HPV-18 (n = 93). HPV type-specific prevalence was 48.1%, 65.9%, 81.3%, 92.2%, and 64.3% among cervical intraepithelial neoplasias (CIN) Grades I-III, squamous cell carcinomas (SCC) and adenocarcinoma (AC) cases, respectively. Most SCC cases (81.3%) had only one HPV genotype detected and almost a third (32.0%) of all cervical pathologies were HPV negative including 51.9% of CIN I (n = 283), 34.1% CIN II (n = 145), 18.7% of CIN III (n = 146), 7.8% of SCC (n = 5), and 35.7% of AC (n = 5) cases. This study provides important baseline data for monitoring the effect of HPV vaccination in NI and for comparison with other UK regions. The coverage of other HR-HPV genotypes apart from 16 and 18, including HPV-45, 31, 39, and 52, and the potential for cross protection, should be considered when considering future polyvalent vaccines.

Background Human papillomavirus (HPV) are responsible for a broad spectrum of mucocutaneous infections and may cause squamous cell carcinoma following long-standing infection . Oncogenic HPV, most commonly HPV 16, are detectable in over 90% of cervical intraepithelial neoplasia and anal intraepithelial neoplasia (AIN). Human immunodeficiency virus (HIV) infection is strongly associated with a higher prevalence of chronic HPV infection, a higher incidence of AIN and an increased risk for anal cancer (AC). In September 2013, guidelines concerning prevention, screening and treatment of AIN for patients affected by HIV were issued by the German AIDS society. Objective In order to validate the suggested screening procedure, we analysed data from 123 male and female patients with HIV infection that regularly present in our outpatient clinic. Methods Anal cytology, HPV typing and high-resolution anoscopy (HRA) were performed. Results Our results show that screening by anal cytology only identifies a minority of patients with high grade AIN (AIN 3) histology. Patients with normal cytology (NILM, cytology graded negative for intraepithelial lesion or malignancy; n = 5, 29.4%), atypical squamous cells of undetermined significance (ASCUS; n = 5, 71.4%) and low grade squamous intraepithelial lesion (LSIL; n = 8, 44.5%) showed highly dysplastic lesions (AIN 2 and 3) in the histological workup more frequently than expected. Additionally, high-grade squamous intraepithelial lesion (HSIL) was strongly associated with detection of high-risk oncogenic HPV. Conclusion Anal cytology as the solitary screening tool for anal cancer fails to detect anal dysplasia in a considerable number of patients. Additionally, HPV typing and possibly further biomarkers might be applied to identify those patients with a higher risk of developing anal carcinoma, in order to monitor them more closely or directly transfer them to HRA.

Although anal cancer remains a relatively uncommon tumour its frequency is rising, especially in high-risk groups. It is now well recognized that anal squamous cell carcinoma, the largely predominant tumour type, shares many similarities with cancer of the uterine cervix, with a major role for oncogenic human papilloma viruses in both tumours. Anal squamous precancerous lesions have now to be classified with the same criteria and terminology as their cervical counterparts, by using the Lower Anogenital Squamous Terminology (LAST) proposal. Only p16 protein is a useful marker in this setting at the present time. As most cases of anal cancer are treated by non-surgical procedures, pathology has a limited role in the staging of the disease, except for early lesions treated by local excision, and when the sentinel lymph node procedure is undertaken that is still under evaluation. A variety of other tumour types can occur more rarely, with difficult diagnostic issues, solved in most cases by immunohistochemistry.

Objective Laryngeal cancer is the most common type of cancer in the head and neck. Human papillomavirus (HPV) represents a group of >150 related viruses. Infection with certain types of HPV can cause some types of cancer. This study aimed to evaluate the sociodemographic and histopathologic characters of squamous cell carcinoma of the larynx and its relationship to HPV subtype 16 (HPV-16). Study design Cross-sectional. Setting Tertiary university hospitals at 5 districts in Egypt (Minia, Cairo, Giza, Qaluobia, and Bani Seuif). Subjects and Methods This cross-sectional study was conducted on 50 adult patients with laryngeal cancer who were admitted at 5 tertiary care hospitals in Egypt from January 2014 through December 2014. All patients were subjected to a comprehensive preoperative assessment, histopathologic assessments of tumor biopsies, and immunohistochemical staining for HPV-16. Results HPV-16 immunostaining was positive in 9 patients (18%). A significant correlation between HPV-16 immunoreactivity and tumor grade ( P < .001) was detected, with no significant correlation between HPV-16 immunoreactivity and other clinical and pathologic variables. Conclusion The frequency of HPV-16 in laryngeal carcinoma is 18%, and there is significant correlation between HPV-16 and tumor grade.

Basaloid squamous cell carcinoma is a biologically aggressive neoplasm mainly found in the head and neck region. Recently, four cases of basaloid squamous cell carcinoma of the bladder have been reported, and three of them occurred in patients with neurogenic bladder, repeated catheterizations and human papillomavirus infection of the urinary tract. To the best of our knowledge, none of the patients affected by basaloid squamous cell carcinoma of the bladder described in the literature had documented genital involvement by human papillomavirus. Herein, we describe the case of a woman with neurogenic bladder affected by basaloid squamous cell carcinoma of the bladder and by a concomitant genital tract human papillomavirus infection.

To predict the impact of current vaccines on cervical cancer and for the improvement of screening programs, regional data on distribution of human papillomavirus (HPV) types in women with or without cervical cancer is crucial. The present meta-analysis intend to comprehensively evaluate the HPV burden in women with invasive cervical cancer, high-grade squamous intraepithelial lesion (cervical intraepithelial neoplasia 2 and 3), low-grade squamous intraepithelial lesion (cervical intraepithelial neoplasia 1), atypical squamous cells of undetermined significance and normal cytology, as these data will help decision making in regards with screening programs and HPV vaccination in Iran. To determine the HPV prevalence and type distribution in Iranian women with or without cervical cancer, 20 published studies were included in this meta-analysis. In total, 713, 124, 104, 60, and 2577 women invasive cervical cancer, high-grade squamous intraepithelial lesion (cervical intraepithelial neoplasia 2 and 3), low-grade squamous intraepithelial lesion (cervical intraepithelial neoplasia 1), atypical squamous cells of undetermined significance and normal were reviewed, respectively. Overall HPV prevalence in women with invasive cervical cancer, high-grade squamous intraepithelial lesion (cervical intraepithelial neoplasia 2 and 3), low-grade squamous intraepithelial lesion (cervical intraepithelial neoplasia 1), atypical squamous cells of undetermined significance and normal cytology were 77.4%, 71.8%, 65.3%, 61.7%, and 8.4%, respectively. The six most common types were HPV 16, 18, 6/11, 31, and 33; among them HPV 16 was the most frequent type in all five different groups. According to this study, it was estimated that HPV vaccines could have a great impact on prevention of cervical cancer in Iran. In conclusion, this meta-analysis highlights the necessity of introducing vaccination program in Iran.

To understand the potential role in cervical cancer development of the three most common high-risk human papillomavirus (HR-HPVs) in Thai women, HPV genotypes and viral genome statuses in different cervical lesions were investigated. Cervical tissues consisting of no cervical intraepithelial neoplasia (84 cases), grade I cervical intraepithelial neoplasia (176 cases), grade II–III cervical intraepithelial neoplasia (91 cases), and squamous cell carcinoma (66 cases) were subjected for HPV genotyping by polymerase chain reaction (PCR) and reverse line blot hybridization assay and for HPV genome status determination by amplification of papillomavirus oncogene transcripts (APOT) assay. HPV prevalence was 28.6% in no cervical intraepithelial neoplasia, 40.3% in grade I cervical intraepithelial neoplasia, 70.3% in grade II–III cervical intraepithelial neoplasia and 86.4% in squamous cell carcinoma cases. The three most common HR-HPV types were HPV 16, 58, and 18 which were distributed in all cervical lesions. HPV physical statuses could be investigated in 4 no cervical intraepithelial neoplasias, 2 grade I cervical intraepithelial neoplasias, 28 grade II–III cervical intraepithelial neoplasias and 31 squamous cell carcinomas. The integrated-derived transcripts were found 3.6% in grade II–III cervical intraepithelial neoplasia and 48.4% in squamous cell carcinoma, whereas no viral genome integration was found in the group of no cervical intraepithelial neoplasia or grade I cervical intraepithelial neoplasia samples. The frequencies of HR-HPV integration in squamous cell carcinoma were found 40%, 100%, 20% of HPV 16, 18, and 58. This study indicates the oncogenic potential ability of the three most common HR-HPVs associated with cervical cancer progression. J. Med. Virol. 86:1911–1919, 2014. © 2014 Wiley Periodicals, Inc.

Studies about cervical carcinogenesis have demonstrated the increased expression of matrix-metalloproteinase (MMP) according to the grade of cervical intraepithelial lesions. Considering the importance of innovative techniques to introduce noninvasive and rapid diagnoses for patients, this study aimed to perform MMP-9 immunocytochemistry in cervical smears according to the cytopathological diagnoses, in order to monitor MMP activity in cervical smears. This cross-sectional study investigated the expression of MMP-9 in normal cervical smears, inflammatory cervical smears, squamous intraepithelial lesions, and cervical carcinoma. Cervical smears from 630 women were collected for cytopathological diagnoses and immunocytochemistry. Women with squamous intraepithelial lesions showed an increase in MMP-9 expression, with moderate to intense staining occurring with increasing cervical lesion grade. The prevalence of moderate to intense MMP-9 staining was 9% in normal cervical smears, 12% in cervical inflammation, 24% in low-grade squamous intraepithelial lesion (LSIL), 92% in high-grade squamous intraepithelial lesions (HSIL) and 100% in cervical carcinoma cases. In the specific case of LSIL, we found that association with MMP-9 is more evident when there is the simultaneous presence of an infectious agent. Thus, the expression of MMP-9 in cervical smears increases according to the grade of cervical lesion and LSIL in the presence of infectious agents showed higher MMP-9 expression than women with LSIL without infectious agents. Diagn. Cytopathol. 2014;42:827–833. © 2014 Wiley Periodicals, Inc.

Human papillomavirus (HPV) infection is involved in cervical lesion development. It interferes with host immune response and modifies the expression of human leukocyte antigen-G (HLA-G), a nonclassical HLA-I antigen with immune-inhibitory functions. We analyzed the frequencies of two HLA-G 3' untranslated region polymorphisms (14 bp ins/del, +3142C>G), involved in HLA-G modulation, in 33 condyloma acuminatum, 14 low grade squamous intraepithelial lesion and 100 invasive cervical cancer (ICC) HPV infected patients. We showed the involvement of HLA-G polymorphisms in HPV infection and lesion development, and suggested that 14 bp del allele promotes high-risk HPV infection, with del/C haplotype associated with ICC development. On the basis of these evidences, HLA-G polymorphisms could represent a risk factor in HPV positive subjects.

Human papillomavirus (HPV)-related oropharyngeal carcinoma is a distinct form of head and neck squamous cell carcinoma (HNSCC) at the morphologic, epidemiologic, and molecular levels. In contrast to nonHPV–related HNSCC, HPV-related oropharyngeal carcinoma has had a dramatic, increasing incidence in the United States over the past 3 decades. In many institutions, including ours, greater than 80% to 90% of oropharyngeal squamous cell carcinomas (SCCs), which occur primarily in the palatine tonsil and base of tongue, are associated with high risk-HPV (HR-HPV) types, predominantly HPV type 16 (HPV16). Cancer in these patients is driven by the production of the HPV E6 and E7 oncoproteins, which interfere with p53 and pRb tumor-suppressor pathways. A consequence of this includes the overexpression of p16, which, in selected clinical contexts, can be used as an immunohistochemical surrogate marker of HR-HPV infection. HPVrelated HNSCCs often are associated with an improved response to therapy; therefore, the diagnosis of HPVrelated HNSCC has potentially important therapeutic and prognostic implications. Because of the tendency of HPV-related HNSCC to metastasize to cervical lymph nodes, fine-needle aspiration (FNA) is frequently used for its initial evaluation and diagnosis. In this context, accurate and efficient testing methods for HR-HPV are needed for the evaluation of HNSCCs in cytologic preparations. The article by Guo et al in this issue of Cancer Cytopathology addresses the validity of using the Cervista HPV16/18 and Cervista HPV HR assays [Hologic, Inc., Marlborough, Mass], 2 of several US Food and Drug Administrationapproved methods for testing HPV in cervical cytology specimens, for the detection of HR-HPV in FNA specimens of HNSCC. The availability of valid methods, such as that described by Guo et al, for detecting HRHPV in FNA specimens of HNSCC is important for multiple reasons. First, as alluded to previously, the demonstration of HR-HPV in HNSCC has significant implications for patient prognosis, because many of these patients will have improved outcomes in terms of overall survival, progression-free survival, and disease-specific survival compared with patients who have non-HPV–related HNSCC. The typical patient with HPVrelated HNSCC is a middle-aged man, nonsmoker, and nondrinker with sexual risk factors for oral HPV infection, and low T and high N in the TNM staging system. That being said, a group of HR-HPV-related HNSCCs remains in which the prognosis appears to be further modified by other features, such as TP53 mutations and expression of Bcl-2. Biomarkers like these are currently the subject of much research, because they have the potential to influence the therapeutic approach in patients with HPV-related HNSCC. Although changes in the management of patients with HPV-related HNSCC, such as de-escalation therapies, are currently limited to clinical trials, in the very near future, the demonstration of HPV positivity is likely to

Anal cancer is one of the most common non-AIDS-defining malignancies in the era of combination antiretroviral therapy. Its precursor lesion, anal intraepithelial neoplasia (AIN), is highly prevalent in HIV-infected populations. More than 90% of anal squamous cell cancers are attributable to human papillomavirus (HPV). While the biology of HPV-related intraepithelial neoplasia is consistent across lower anogenital sites, the natural history of AIN is not well established and cannot be assumed to be identical to that of cervical intraepithelial neoplasia. Screening strategies to prevent anal cancer should be developed based on robust natural history data in HIV-infected and uninfected populations. Likewise, treatments need to be tested in randomized clinical trials, and reserved for those at significant risk of progression to cancer. This review covers the epidemiology, pathogenesis and immunology of HPV infection, AIN and anal cancer, and summarizes the current diagnosis, screening and treatment strategies in HIV-infected adults.

Objective To analyse the association between high-risk human papillomavirus (HR-HPV) and other risk factors in the aetiology of head and neck squamous cell carcinoma (HNSCC) in an Asian population. Study Design This study is a cross-sectional analysis of 80 patients who were diagnosed with HNSCC. Patients' demographics, dietary habit, medical and social history were obtained. Surgical specimens from these patients were then histologically analysed using H&E stain and immunohistochemistry (IHC) for the presence of HR-HPV primary antibody. Results High-risk human papillomavirus was detected in 41 patients, representing 51.3% of the 80 paraffin-embedded tissues of HNSCC; 27.5% of these were weak positive, 10.0% medium positive and 13.8% were strongly positive for the HR-HPV on IHC. The tongue lesions had the highest HR-HPV infection of 72.2%. No association existed between HR-HPV and patient's demographics, dietary habit and other predisposing factors. Conclusion The place of HR-HPV as a possible aetiological factor for HNSCC has further been established from this study.

In our study, we for the first time assessed the association of galectin-7 and S100A9 with clinicopathological variables and survival outcomes in cervical squamous carcinoma patients and explored the underlying molecular mechanisms in cervical squamous carcinoma cell lines. Immunohistochemical analysis of 243 patient samples showed that the positive staining rate for galectin-7 and S100A9 gradually decreased from normal cervical tissue to intraepithelial neoplasia and to cervical squamous carcinoma. Both galectin-7 and S100A9 showed significant negative association with lymph node metastasis and staging of cervical squamous carcinoma. Cervical squamous carcinoma patients with negative staining of galectin-7 or S100A9 showed significantly lower 5-year overall survival rate than those with positive staining. Multivariate analysis with the Cox's proportional hazards model indicated that both galectin-7 and S100A9 had significant protective effect on cervical squamous carcinoma patients. Subsequent in vitro study in SiHa and C-33A human cervical squamous carcinoma cell lines revealed that knocking down galectin-7 or S100A9 enhanced tumor cell invasion and tumor cell viability against paclitaxel-induced apoptotic stress, likely through increasing the matrix metalloproteinase-9 expression and activating the phosphatidylinositol 3-kinase/Akt signaling pathway, respectively. Knocking down both galectin-7 and S100A9 produced a synergistic effect, with galectin-7 displaying more significant and consistent protective effects than S100A9 on cervical squamous carcinoma cells. In summary, our study for the first time provides clinicopathological and in vitro evidence showing that both galectin-7 and S100A9 play important protective roles in cervical squamous carcinoma, which provides fresh insights into the biology of cervical squamous carcinoma.

Infection with a high-risk human papillomavirus (HPV) is established as a major risk factor for cervical cancer. In Japan, eight HPV genotypes (16, 18, 31, 33, 35, 45, 52 and 58) confer a much higher risk of cervical cancer and its immediate premalignant lesions (cervical intraepithelial neoplasia grade 3 [CIN 3]) than do other high-risk and the low-risk HPV types. However, only a small fraction of infected women develop CIN 3 or invasive cervical cancer, suggesting the involvement of additional cofactors in cervical carcinogenesis. A multicenter prospective cohort study of Japanese women with low-grade cervical abnormalities has demonstrated that tobacco smoking is significantly associated with an increased risk of persistent low-grade cervical lesions, while the presence of human leukocyte antigen Class II DRB1*1302 protects against progression to CIN 3. Understanding the epidemiology of HPV infections and cervical cancer may improve prevention and lead to novel clinical management strategies for cervical precursor lesions. Viral and host factors that affect the risk of cervical cancer are discussed in this review.

INTRODUCTION The purpose of this study is to determine if high risk human papillomaviruses (HPV) and Epstein Barr virus (EBV) are both present in the same prostate cancer specimens. METHODS We used a range of analytical techniques including in situ polymerase chain reaction (IS-PCR) and standard liquid PCR followed by sequencing of the product to seek to identify HPV and EBV in normal, benign, and malignant prostate tissues. RESULTS Both HPV type 18 and EBV gene sequences were identified in a high and approximately equal proportion of normal, benign, and prostate cancer specimens. These sequences were located in the nuclei of prostate epithelial cells. HPV associated koilocytes were identified in 24% of prostate cancer specimens. CONCLUSIONS The presence of both HPV and EBV gene sequences in most of the same normal, benign, and malignant prostate specimens is particularly noteworthy because of recent experimental evidence demonstrating that EBV and HPV can collaborate to increase proliferation of cultured cervical cells. Because the presence of EBV and HPV in normal, benign, and malignant prostate tissues appears to be ubiquitous, it is possible that they are harmless. On the other hand HPV type 18 in particular, has high oncogenic potential and may be associated with some prostate cancers. The identification of HPV associated koilocytes in prostate cancer specimens is an indication of HPV infection and potential oncogenic influences of human papillomavirus in prostate cancer. Prostate 73: 236–241, 2013. © 2012 Wiley Periodicals, Inc.

BACKGROUND: The incidences of genital human papillomavirus (HPV) infection associated squamous intraepithelial lesions and cervical squamous cell carcinoma are significantly increased in HIV-positive women. The role of other cervicovaginal infections in the acquisition of the HPV infection cervical carcinogenesis and genital HIV infection remains largely speculative. METHODS: A retrospective study was conducted including 1087 HIV-positive women in rural Mpumalanga province South Africa for the period 1 May 2009 to 31 August 2010. For each patient the age at first presentation cervical cytological diagnosis subsequent follow-up cytology and histology and microscopically visible infections (including endemic Bilharzia) were tabulated and statistically analysed. RESULTS: The prevalence of low-grade squamous intraepithelial lesion (LSIL) high-grade squamous intraepithelial lesion (HSIL) squamous cell carcinoma atypical squamous cells of undetermined significance (ASC-US) and atypical squamous cells cannot exclude HSIL (ASC-H) in the study population were 22.1% 30.9% 0.6% 13.5% and 4.0% respectively. LSIL HSIL and squamous cell carcinoma were diagnosed respectively at the average ages of 35.7 37.9 and 37.2 years. Four patients with cervical intraepithelial neoplasia grade 1 (CIN1) 32 with CIN2/CIN3 and two with cervical squamous cell carcinoma were also diagnosed with Bilharzia. Of the other infections only bacterial vaginosis had a positive statistical correlation with HPV-induced cervical abnormalities (LSIL HSIL or squamous cell carcinoma). CONCLUSION: This study confirms the high prevalence of progressive HPV-associated cervical disease in a rural Southern African HIV-positive population which is at least equal to or worse than in other African HIV-positive studies. The high incidence of Bilharzia infection in those cases that underwent cervical cone excision suggests a possible relationship with progressive HPV disease and cervical carcinogenesis. Bacterial vaginosis (perhaps in combination with Bilharzia) may compromise the normal barriers against HPV and HIV infection. (c) 2012 John Wiley & Sons Ltd.

Objective We evaluated the distribution of histological diagnoses in pregnant women with atypical cytology or cervical malignancy signs, as well as the usefulness of the Swede score colposcopic scoring system to reduce the need for diagnostic cervical biopsy. Design Prospective clinical study. Setting and population The study comprised 261 pregnant women undergoing colposcopic investigation because of atypical cervical cytology, dysplastic biopsy changes, recurrent non-obstetric bleeding or pathological appearance of the cervix. Methods Five colposcopic variables (acetowhiteness, margins plus surface, vessel patterns, lesion size and iodine staining) were scored with 0, 1 or 2 points. Colposcopically directed biopsies or loop electrosurgical excision biopsies were taken from all lesions. Histology was compared with the colposcopic score. Sensitivity and specificity were calculated for each variable, and the combination of all five variables, with high-grade lesions (i.e. cervical intraepithelial neoplasia (CIN2, CIN3 or adenocarcinoma-in-situ (AIS)) as endpoints. Main outcome measures Colposcopic score (Swede score) and histology (CIN1, 2, 3; AIS; cancer). Results The specimens consisted of normal tissue in 19.5% of cases, low-grade lesions (i.e. CIN1, koilocytosis, glandular dysplasia of lower grade than AIS) in 26.1%, high grade lesions in 52.9% and cancer in 1.5%. All high grade lesions and cancers had total Swede scores of ≥ 5 and ≥ 8, respectively. Vessel patterns, lesion size and margins plus surface were most important for high grade lesion detection. Conclusion The Swede score seems to be a useful tool in evaluating atypical cervical cytology in pregnant women and may reduce the need for diagnostic biopsies.

N. Gupta, N. Dudding, J. Crossley, S.J. Payyappilly and J.H.F. Smith Outcome of SurePath™ cervical samples reported as borderline nuclear changes by cytological subtype and high-risk HPV status Background: The average borderline rate in cervical cytology samples for English laboratories was 3.8% with the range being 2.0–6.8% at the time of the present study, which was undertaken in order to determine the association between different subtypes of borderline nuclear change (BNC), high-grade cervical intraepithelial neoplasia (CIN) and high-risk human papillomavirus (hrHPV) status. Materials and methods: Of 68 551 SurePathTM cervical samples reported in one laboratory over a period of 2 years, 2335 (3.4%) were reported as BNC. hrHPV status was known in 1112 cases (47.6%). The outcome was known only for women with hrHPV-positive BNC, who were recommended for colposcopy under the National Health Service Cervical Screening Programme sentinel site protocol. Women with hrHPV-negative BNC were returned to 3-yearly recall. The cases were subdivided into BNC, high-grade dyskaryosis cannot be excluded (B-HG; 105 cases); BNC with koilocytosis (B-K; 421 cases); BNC with other features of HPV (B-HPV; 160 cases); and BNC, not otherwise specified (B-NOS; 426 cases) and were correlated with the histological outcome where available. Results: The study population age ranged from 23 to 65 years. Cases that tested positive for hrHPV by Qiagen HCII assay comprised 78.1%, 81.0%, 73.1% and 67.8% of B-HG, B-K, B-HPV and B-NOS categories, respectively. CIN2 or worse (CIN2+) was found in 64.6%, 10.0%, 19.7% and 20.1% of hrHPV-positive cases of B-HG, B-K, B-HPV and B-NOS, respectively, which was significantly higher in the B-HG category (P

Neuroendocrine carcinoma (NEC) of the anal canal is exceedingly rare and its histogenesis is poorly understood. We present a case of small-cell NEC of the anal canal in a 70-year-old woman. The NEC appeared as a submucosal tumor at the dentate line and was associated with squamous intraepithelial neoplasia (SIN). The NEC was positive for neuroendocrine markers including synaptophysin, chromogranin A and CD56, whereas the SIN component did not express any of these markers. Both components exhibited p16 overexpression. A PCR analysis revealed that both the SIN and NEC components were positive for human papillomavirus (HPV) 18 DNA. Our observations imply that SIN may be a precursor of anal canal NEC and that HPV18 may play an important role in the histogenesis of anal canal NEC, similar to its role in cervical NEC.

Lewis J S Jr, Ukpo O C, Ma X-J, Flanagan J J, Luo Y, Thorstad W L & Chernock R D (2012) Histopathology 60, 982–991 Transcriptionally-active high-risk human papillomavirus is rare in oral cavity and laryngeal/hypopharyngeal squamous cell carcinomas – a tissue microarray study utilizing E6/E7 mRNA in situ hybridization Aims: Human papillomavirus is well established in oropharyngeal squamous cell carcinoma as both causative and prognostic, but its significance in non-oropharyngeal tumours is unclear. In particular, the significance of finding viral DNA is not known. We sought to evaluate nonoropharyngeal squamous cell carcinomas for transcriptionally-active human papillomavirus and to compare this with the presence of viral DNA. Methods: We evaluated an 87 patient tissue microarray cohort of oral cavity and laryngeal/hypopharyngeal squamous cell carcinomas for high risk human papillomavirus DNA and E6 and E7 mRNA transcripts by in situ hybridization, and for p16 expression by immunohistochemistry. Results: We found only two of the 73 (2.7%) evaluable cases to harbour transcriptionally-active human papillomavirus. Both of these tumours were from the larynx, one was positive for human papillomavirus DNA by in situ hybridization, and both were extensively positive for p16. All oral cavity and hypopharyngeal tumours were negative for human papillomavirus. Conclusions: Transcriptionally-active human papillomavirus appears to be rare in laryngeal, hypopharyngeal, and oral cavity squamous cell carcinomas. As such, it appears unlikely to be a ‘driver’ or to be clinically significant in most established tumours.

Schneiderian papilloma (SP) is classified into three types: inverted, oncocytic, and exophytic. Malignant transformation occurs in 10% of SP; most are inverted and oncocytic types. Malignant transformation of polypoid exophytic SP is exceptional; only two cases have been reported in the English literature. A 58-year-old man consulted our hospital because of nasal obstruction. Nasal endoscopy and imaging modalities showed a polyp in the right nasal cavity. Biopsy findings showed compatibility with SP. However, since fludeoxyglucose positron emission tomography (FDG-PET) showed signals, polypectomy was performed. Grossly, the polyp was reddish white and measured 2 cm. Histologically, the polyp consisted of a non-invasive squamous cell carcinoma (SCC) component (70%), a mature squamous component (20%), and Schneiderian epithelium (10%). Vague koilocytosis was present in the SCC component. The three components were arranged in an exophytic papillary pattern. Immunohistochemically, the non-invasive SCC component was positive for cytokeratins (AE1/3, CAM5.2, CK5/6), p63, p53, and Ki67 (labeling 50%). The mature squamous component was positive for cytokeratins (AE1/3, CAM5.2 and CK5/6), p63, and Ki67 (labeling 6%). The Schneiderian component was positive for cytokeratins (AE1/3, CAM5.2, and CK5/6), p63, and Ki-67 (labeling 4%). The tumor was HPV negative in the three components. The polyp was diagnosed as exophytic Schneiderian carcinoma arising from exophytic SP. The patient is now free from tumor 4 years after the operation.

A 9-year-old gelding presented with approximately 100 papillomas that covered about 75% of the distal penis. Biopsy was performed, and histology showed evidence of viral cytopathic change and koilocytosis. Polymerase chain reaction using DNA extracted from biopsied tissue amplified equine papillomavirus type 2 (EcPV-2) DNA sequences. Sixteen months later, the horse was re-examined and the appearance of the papillomas was unchanged. Equine papillomavirus type 2 DNA sequences were again amplified from both biopsied tissue and swabs of the penis. Papillomavirus was localized to the lesions by immunohistochemistry and in situ hybridization. An examination 2 years after the initial presentation revealed no detectable change in the appearance of the penis. The large number of papillomas and their failure to regress over an extended period support a clinical classification of papillomatosis. To the authors' knowledge, this is the first report of papillomatosis of the equine penis. This novel clinical manifestation suggests that persistent EcPV-2 infection is possible in horses. As there is evidence that EcPV-2 may promote development of equine penile squamous cell carcinoma, understanding the natural history of EcPV-2 infections may be important in preventing equine penile neoplasia.

J Oral Pathol Med (2012) 41: 9–15 Background: Betel nut chewing, cigarette smoking and alcohol drinking are thought to be major environmental risk factors responsible for the development of oral squamous cell carcinomas. Oncogenic human papillomavirus infections have a well-established association with uterine cervical carcinoma. However, little is known about the exact role of human papillomavirus infections in oral squamous cell carcinomas. This study is designed to elucidate the role of human papillomavirus infections in cancer development and prognosis of oral squamous cell carcinomas. Methods: Molecular techniques including in situ hybridization and immunohistochemistry of p16INK4A and p53 for evidences of human papillomavirus in tissue micro-arrays were investigated. Results: Twenty-four of 65 cases of oral squamous cell carcinomas were found positive for in situ hybridization and 14 were found positive for p16INK4A. The majority of cases without the evidence of human papillomavirus were related to p53 over-expression. There were statistically significant correlations between the results of human papillomavirus test and size or extent of the tumor (P = 0.003) or the stage of oral squamous cell carcinomas (P = 0.015). Kaplan–Meier plot analysis demonstrated a tendency of longer survival in cases of oral squamous cell carcinomas with the evidence of human papillomavirus or positive p16 INK4A. Conclusions: Human papillomavirus infections may play a unique role in oral carcinogenesis. Our data strongly suggest that human papillomavirus-positive oral squamous cell carcinomas comprise a distinct clinical and pathological disease entity that appears related to a better outcome with longer survival and bears a causally associated relationship different from other carcinogenic mechanisms.

Cytopathic effects related to the human papillomavirus (HPV) infection are more frequently found in cervical intraepithelial neoplasia (CIN) 1; however, there are indications that at least half the histological diagnoses of CIN2 and CIN3 include koilocytosis areas. The objective of this study was to evaluate the frequency of the cytological criteria suggestive of HPV infection in the cervical smears of women with a histological diagnosis of CIN. One hundred and sixty-two women with abnormal cervical smears and a diagnosis of CIN confirmed by histopathology were selected, including 46 cases of CIN 1, 42 of CIN 2 and 74 cases of CIN 3. Koilocytosis was found in 63% of the smears from women with a histopathological diagnosis of CIN 1. This sign was observed in 26.2% and 25.7% of smears of women with a diagnosis of CIN 2 and CIN 3, respectively. Cytomegaly also was frequent in cervical smears of women with histopathological diagnosis of CIN 1 (71.8%). On the other hand, spindle cells and atypical metaplasia were more frequent in women with CIN 2 and CIN 3. Atypical parakeratosis showed similar frequency in all grades of CIN diagnosis. Koilocytois and cytomegaly were inversely correlated with the diagnosis of CIN2 or CIN 3, with OR values respectively of 0.30 (95%CI 0.13-0.68) and 0.26 (95%CI 0.11-0.58). The others signs analyzed did not show any significant association. Koilocitosis and cytomegaly can provides good reassurance that a patient with atypical cervical smear have CIN 1.

R. G. Blanks Estimation of disease severity in the NHS cervical screening programme. Part I: artificial cut-off points and semi-quantitative solutions Objective: Current cytology and histology classifications are based on ordered categories and have a strong emphasis on providing information that decides a woman's management rather than the best estimate of disease severity. This two-part paper explores the use of a quantitative approach to both cytology and histology disease severity measurements. Methods: In Part I the problem of artificial cut-off points is discussed and a simple semi-quantitative solution to the problem is proposed. This closely relates to the revised British Society for Clinical Cytology (BSCC) terminology. The estimates of disease severity are designed as extensions of the existing methods, with an emphasis on probability rather than certainty, as a more natural way of approaching the problem. Borderline changes are treated as categorical variables, but koilocytosis, mild, moderate and severe dyskaryosis, and ?invasive as quasi-continuous and the disease severity estimated as a grade number (GN) with any value between 0–4 and the margin of error as a calculated grade range (CGR). Results: As an example, if the reader is unsure between moderate dyskaryosis (HSIL favouring CIN2) and mild dyskaryosis (LSIL favouring CIN1) they can register this uncertainty as a probability, such as 60%/40% moderate/mild. With 2 and 1 as the mid-points of the grade numbers for moderate and mild dyskaryosis the GN value is ((60 × 2) + (40 × 1))/100 = 1.6. The CGR is 1.5 − 0.4 to 1.5 + 0.6 = 1.1 to 2.1. The GN (CGR) estimate of disease severity is therefore 1.6 (1.1–2.1). In a similar manner the disease severity from all slides showing koilocytosis or dyskaryosis can be estimated as a number between 0 and 4 with an associated error. Histology can be treated in a similar way. Conclusions: This semi-quantitative approach provides a framework more suitable for research and audit of disease severity estimates. It avoids the paradox inherent in the current systems using artificial cut-points to produce categories whereby increasing agreement can only be achieved by losing information.

Canine viral plaques are uncommon skin lesions that are induced by papillomaviruses (PVs). Plaques are usually of little clinical significance in dogs, although they have been reported rarely to progress to squamous cell carcinoma (SCC). Here is described a 7-year-old mixed-breed dog that developed numerous darkly pigmented plaques up to 8 cm in diameter. Multiple ulcerated nodular masses were visible within plaques on the ventrum and axilla. The dog showed no clinical evidence of immunodeficiency and appeared otherwise healthy. Over the next 2 years, five surgeries were performed to remove 23 ulcerated masses that ranged in size from 2 to 5 cm in diameter. Five masses were submitted for histology, and all were SCCs. Each was surrounded by epidermis that contained histological features consistent with those described in canine plaques. Suggestive of a PV aetiology, massive numbers of large keratohyaline granules were present throughout the thickened epidermis. Additionally, koilocytes were focally present, and one sample contained a band of keratinocytes within the superficial epidermis that contained pale cytoplasm and marginated chromatin. From two samples, DNA sequences from a previously unreported PV were amplified, and immunohistochemistry confirmed the presence of PV antigen in both. The PV DNA sequences were most similar to those of canine PVs previously associated with plaque formation. The plaques observed in this case were unusual owing to their rapid growth, large size and frequent malignant transformation. It is unknown whether this unusual behaviour was due to the specific PV detected in this case or to host factors within the dog.

Warty (condylomatous) carcinoma (WC) is a rare specific variant of invasive squamous cell carcinoma that shows hybrid features of condyloma with invasive cell carcinoma. As compared with conventional squamous cell carcinoma, WC tends to run a less aggressive clinical course. A case is presented here in which squash smears of a penile foreskin tumor in a 65-year-old male revealed small cohesive clusters and sheets of tumor cells in papillary configurations. The neoplastic cells were polygonal to elongated and contained oval nuclei, coarse chromatin pattern, and distinct nucleoli. Nuclear pleomorphism and loss of nuclear polarity were observed. Characteristically, there were also many koilocytes demonstrating mild to moderate nuclear atypia and perinuclear cytoplasmic halos. A cytologic diagnosis of a verruciform penile tumor was suggested. Histologic examination of the tumor showed a hyper-parakeratotic arborizing papillomatous growth with thin fibrovascular cores and the tips were variably rounded or tapered. Obvious koilocytic cytopathic change, nuclear pleomorphism, and focal stromal invasion were observed. Immunohistochemically, the tumor cells showed diffuse and strong membranous staining for cytokeratin (AE1/AE3) while the MIB-1 and p53 immunoreactive cells were confined to the basal areas of the papillae. No lymphovascular invasion was detected in D2-40 or elastic Van-Gieson stains. On the basis of the overall features, we confirmed a final diagnosis of penile WC. We demonstrated here for the first time the cytopathological features of penile WC with emphasis on differential diagnostic considerations. Diagn. Cytopathol. 2010;38:841–845. © 2010 Wiley-Liss, Inc.