Penile intraepithelial neoplasia (PeIN) and penile squamous cell carcinoma (PeSCC) are both thought to be associated with male genital lichen sclerosus and human papillomavirus (HPV) infection through dichotomous pathways: (i) undifferentiated PeIN and warty/basaloid PeSCC are thought to be HPV related, whereas (ii) differentiated PeIN and usual PeSCC are considered HPV independent. Tissue arrays were constructed from male genital lichen sclerosus, undifferentiated and differentiated PeIN, usual-type PeSCC, and unaffected tissues. Staining for p16 and for high-risk and low-risk HPV subtypes through RNAscope was performed. The expression of HPV RNA and p16 were quantified, and appropriate statistical comparisons were undertaken. High-risk HPV was prevalent in undifferentiated PeIN (77%) and less so in PeSCC (46%) and was exiguous or absent in all other tissues. LR HPV was only observed in 2 tissue cores. Strong p16 staining exhibited 96.15% sensitivity and 100% specificity for high-risk HPV. Transcriptionally active HPV is unlikely to be implicated in male genital lichen sclerosus and differentiated PeIN, although it is clearly important in undifferentiated PeIN. The high prevalence of high-risk HPV in usual PeSCC challenges the existing paradigm. Strong p16 positivity was a reliable surrogate marker for the detection of transcriptionally active high-risk HPV.

INTRODUCTION:Frozen section examination (FSE) of the tumor resection margins is important during penile-preserving surgery (PPS) in penile cancer. The margin status will impact on how much penile or urethral tissue is excised. We aim to evaluate the outcomes of intraoperative FSE of resection margins in PPS. PATIENTS AND METHODS:A retrospective analysis of patients with penile squamous cell carcinoma (SCC) who underwent a FSE of resection margins between 2010 and 2022 was conducted. FSEs were compared with the final histopathological analysis and the Diagnostic Testing Accuracy (DTA): sensitivity, specificity, positive (PPV) and negative predictive values (NPV) were calculated. RESULTS:Overall, 137 FSE were performed. The median (IQR) age was 65 (53-75) years. 118 (86.1%) patients had negative FSE margins, 16 (11.7%) had positive FSE margins and 3 (2.2%) had equivocal (atypical cells) results. The sensitivity, specificity, PPV, NPV and diagnostic accuracy of penile FSE were 66.7%, 100%, 100%, 93.2% and 94% respectively. 18 patients underwent further resection in the same episode due to a positive or equivocal FSE and 12 (66.7%) achieved negative margins. Limitations include the retrospective nature of the study and lack of control arm to compare with. CONCLUSIONS:Intraoperative FSE performed at our center for the assessment of penile SCC margins is 66.7% sensitive and 100% specific. FSE should be considered in PPS, as it's an essential and a reliable diagnostic tool in minimizing over-treatment.

We present a case of a 70-year-old gentleman who was referred to our tertiary 2-week-wait penile cancer clinic with a penile mass that was ulcerated, painful and discharging. This was suspicious for penile cancer and a radical circumcision was performed to remove the diseased foreskin en bloc with the lesion that was arising from the inner foreskin. Histopathology did not reveal cancer; however, we identified spirochaetes in keeping with syphilis. This was confirmed on serology. The patient was referred to the genitourinary medicine team and treated with antibiotics. This case demonstrates a rare presentation of genital syphilis in an elderly gentleman initially referred with concerns of penile cancer. Although, rare, especially in this age group, syphilis should be considered as a differential diagnosis in a patient presenting with an ulcerated, discharging, firm penile mass, especially given that the incidence of syphilis has been rising in recent years.

MGLSc is an acquired, chronic skin disease that can lead to sexual dysfunction and urological morbidity. Although both MGLSc and HPV are considered risk factors for penile cancer, no clear link has been found between the two. To further investigate the possibility of an association we correlated the presence of MGLSc and HPV across the prepuce. Preputial fresh frozen samples were collected from nine patients with clinically diagnosed MGLSc. The specimens were divided into a grid and biopsies were obtained to determine the spatial distribution of MGLSc and for HPV DNA sequencing. A total of 80 samples underwent HPV sequencing;47 from MGLSc-affected skin, 19 from unaffected skin, and 14 from indeterminate areas. A variety of both mucosal and beta HPV samples were detected, including some oncogenic types(18, 31, 51, 51, 66, 68). The most frequently encountered HPV subtypes were 24, 23, 36, and 9. Overall, 81.25% of the samples harbored HPV (74.46% in MGLSc-affected skin, 89.47% in MGLSc-unaffected skin and 92.85% in indeterminate areas). The variety of HPV ranged from a minimum of three, to a maximum of eight subtypes per patient, and from no HPV to a maximum of seven HPV subtypes per 0.79mm2area. We examined the distribution and diversity of HPV across the prepuce and detected a wide array of HPV types, most of which are considered to be of no clear clinical significance. Unlike previous publications, all our patients harbored HPV of multiple subtypes. No meaningful differences could be detected in the tropism of HPV between MGLSc-affected and unaffected skin, or between the proximal and distal anatomical aspects of the prepuce. The presence of HPV in MGLSc is likely an epiphenomenon.

Background High variability in prostate MRI quality might reduce accuracy in prostate cancer detection. Purpose To prospectively evaluate the quality of MRI scanners taking part in the quality control phase of the global PRIME (Prostate Imaging Using MRI ± Contrast Enhancement) trial using the Prostate Imaging Quality (PI-QUAL) standardized scoring system, give recommendations on how to improve the MRI protocols, and establish whether MRI quality could be improved by these recommendations. Materials and Methods In the prospective clinical trial (PRIME), for each scanner, centers performing prostate MRI submitted five consecutive studies and the MRI protocols (phase I). Submitted data were evaluated in consensus by two expert genitourinary radiologists using the PI-QUAL scoring system that evaluates MRI diagnostic quality using five points (1 and 2 = nondiagnostic; 3 = sufficient; 4 = adequate, 5 = optimal) between September 2021 and August 2022. Feedback was provided for scanners not achieving a PI-QUAL 5 score, and centers were invited to resubmit new imaging data using the modified protocol (phase II). Descriptive comparison of outcomes was made between the MRI scanners, feedback provided, and overall PI-QUAL scores. Results In phase I, 41 centers from 18 countries submitted a total of 355 multiparametric MRI studies from 71 scanners, with nine (13%) scanners achieving a PI-QUAL score of 3, 39 (55%) achieving a score of 4, and 23 (32%) achieving a score of 5. Of the 48 (n = 71 [68%]) scanners that received feedback to improve, the dynamic contrast-enhanced sequences were those that least adhered to the Prostate Imaging Reporting and Data System, version 2.1, criteria (44 of 48 [92%]), followed by diffusion-weighted imaging (20 of 48 [42%]) and T2-weighted imaging (19 of 48 [40%]). In phase II, 36 centers from 17 countries resubmitted revised studies, resulting in a total of 62 (n = 64 [97%]) scanners with a final PI-QUAL score of 5. Conclusion Substantial variation in global prostate MRI acquisition parameters as a measure of quality was observed, particularly with DCE sequences. Basic evaluation and modifications to MRI protocols using PI-QUAL can lead to substantial improvements in quality. Clinical trial registration no. NCT04571840 Published under a CC BY 4.0 license. Supplemental material is available for this article. See also the editorial by Almansour and Chernyak in this issue.

Although HPV infection is clearly implicated in the pathogenesis of undifferentiated PeIN and PeSCC, the role of HPV in MGLSc and differentiated PeIN remains unclear. Whilst the prevalence of HPV in MGLSc in most studies is reported as ≥20%, this number largely reflects HPV latency and not transcriptional activity. Formalin-fixed, paraffin-embedded blocks of penile tissue from 94 patients with MGLSc, PeSCC, differentiated (MGLSc-related) and undifferentiated (HPV-related) PeIN, as well as disease-adjacent unaffected penile skin were used to create microarrays. RNAscope® in situ hybridization was used for the detection of transcriptionally active HPV using high-risk (HR: pool of 10) and low-risk (LR: pool of 18) probes. This technology has been demonstrated to offer higher sensitivity and specificity for HPV status determination than other existing methods. The six microarrays contained a total of 204 tissue cores, of which 148 (72.54%) remained intact for analysis of LR HPV, and 146 (71.56%) for analysis of HR HPV. Only 3.4% of PeSCC and 6.25% of differentiated PeIN cores were positive for LR HPV, whereas 7.1% of MGLSc, 39.3% of PeSCC, 77.3% of undifferentiated PeIN, and 8.3% of PeSCC-adjacent unaffected cores were positive for HR HPV. Compared with the literature that shows variable amounts of latent HPV, this work has shown very little transcriptionally active HPV in MGLSc and none in differentiated PeIN, supporting the notion that HPV is a passenger phenomenon in MGLSc and not pathogenic, nor directly carcinogenic.

La surveillance active (SA) des stades précoces des cancers de prostate (CaP) permet d'éviter le sur-traitement et ses effets secondaires associés. L'IRM multiparamétrique (IRMmp) est recommandée en standard au Royaume-Uni dans cette population. L'objectif de cette étude est de caractériser l'association des changements moléculaires avec la progression radiologique afin de trouver le moment optimal pour traiter les patients. Il s'agit d'une cohorte anglaise unicentrique prospective, observationnelle et longitudinale. Les critères d'inclusion sont un CaP récemment diagnostiqué, ISUP 2, PSA ≤ 15 ng/ml, biopsies concordantes avec lésion IRM Likert 4 ou 5 et longueur maximale de cancer biopsique de 10 mm. La durée est de 12 mois : chaque patient entre en SA et bénéficie de biopsies et IRMmp de contrôle à 1 an. Les participants réalisent un don de tissu frais prostatique (biopsies ciblées), sanguin et urinaire à l'entrée et sortie d'étude. La puissance statistique d'association signal IRMmp et changement moléculaire fixe un recrutement à 60 participants. La référence est le score IRM de progression PRECISE. Le recrutement a débuté en juillet 2020 et s'est terminé en août 2022. Soixante-huit patients ont signé le consentement. 5 patients se sont retirés de l'étude. 8 patients sont sortis de SA pour découverte d'une maladie finalement plus agressive aux biopsies de confirmation. Le reste de la cohorte est éligible pour l'analyse de la comparaison des marqueurs radiologiques et moléculaires à l'entrée et à un an de suivi. À ce jour, 44 participants ont donné au moins 6 carottes de tissus frais pour analyse moléculaire (entrée et sortie). Tous ont eu une IRMmp au suivi, dont plus de 85 % sur la même machine IRM. Le dernier épisode clinique de l'étude est attendu en septembre 2023. Les analyses moléculaires et de radiomiques sont en cours. Les patients acceptent et adhèrent de plus en plus à la SA dans ce type de cancer. Identifier les paramètres pronostiques de progression en imagerie et au niveau moléculaire permettrait d'établir un nouveau modèle de soins personnalisés.

Purpose: University College London Hospital (UCLH) is a large cystectomy centre in the UK. Prior to cystectomy, neoadjuvant chemotherapy should be offered to all suitable patients with muscle-invasive bladder cancer as per the NICE guidelines. In this study, we looked at the outcomes of patients receiving neoadjuvant chemotherapy, with particular focus on patients with variant histology. Bladder cancer encompasses heterogenous pathological entities and patients with rare histological subtypes are typically excluded from trials, so outcome data are limited.

You have accessJournal of UrologyCME1 Apr 2023MP44-06 TUMOR CHARACTERISTICS OF MULTIPARAMETRIC MRI-DETECTED AND -UNDETECTED LESIONS IN PATIENTS WITH SUSPECTED RADIORECURRENT PROSTATE CANCER: AN ANALYSIS FROM THE FOCAL RECURRENT ASSESSMENT AND SALVAGE TREATMENT (FORECAST) TRIAL Alexander Light, Abi Kanthabalan, Menelaos Pavlou, Rumana Omar, Sola Adeleke, Francesco Giganti, Chris Brew-Graves, Amr Emara, Athar Haroon, Arash Latifoltojar, Harbir Sidhu, Alex Freeman, Clement Orczyk, Ashok Nikapota, Tim Dudderidge, Richard G. Hindley, Heather Payne, Anita Mitra, Jamshed Bomanji, Mathias Winkler, Gail Horan, Shonit Punwani, Hashim U. Ahmed, and Taimur T. Shah Alexander LightAlexander Light More articles by this author , Abi KanthabalanAbi Kanthabalan More articles by this author , Menelaos PavlouMenelaos Pavlou More articles by this author , Rumana OmarRumana Omar More articles by this author , Sola AdelekeSola Adeleke More articles by this author , Francesco GigantiFrancesco Giganti More articles by this author , Chris Brew-GravesChris Brew-Graves More articles by this author , Amr EmaraAmr Emara More articles by this author , Athar HaroonAthar Haroon More articles by this author , Arash LatifoltojarArash Latifoltojar More articles by this author , Harbir SidhuHarbir Sidhu More articles by this author , Alex FreemanAlex Freeman More articles by this author , Clement OrczykClement Orczyk More articles by this author , Ashok NikapotaAshok Nikapota More articles by this author , Tim DudderidgeTim Dudderidge More articles by this author , Richard G. HindleyRichard G. Hindley More articles by this author , Heather PayneHeather Payne More articles by this author , Anita MitraAnita Mitra More articles by this author , Jamshed BomanjiJamshed Bomanji More articles by this author , Mathias WinklerMathias Winkler More articles by this author , Gail HoranGail Horan More articles by this author , Shonit PunwaniShonit Punwani More articles by this author , Hashim U. AhmedHashim U. Ahmed More articles by this author , and Taimur T. ShahTaimur T. Shah More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003290.06AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: The interpretation of multiparametric MRI (mpMRI) post-radiotherapy can be challenging due to factors like glandular atrophy and diffuse T2 low signal. Using data from the FORECAST paired validation study, we compared the characteristics of mpMRI-detected and -undetected radiorecurrent disease. METHODS: The prospective FORECAST study (NCT01883128) recruited men from 6 UK centers with suspected radiorecurrent cancer who underwent prostate mpMRI followed by systematic transperineal template mapping and MRI-targeted biopsies. MRI visibility was defined as a Likert score 3-5. 3 cancer definitions were studied: any cancer; Grade Group ≥3 and/or maximum cancer core length (MCCL) ≥6mm (PROMIS definition 1); and Grade Group ≥2 and/or MCCL ≥4mm (PROMIS definition 2). Characteristics of MRI-detected vs -undetected tumors were compared. Analyses were performed at the prostate quadrant level using cluster bootstrapping with 10,000 resamples. RESULTS: 578 quadrants (147 men) were included. 88/261 quadrants (33.7%) with any cancer were MRI-undetected, compared to 62/198 quadrants (31.3%) for definition 1, and 80/238 quadrants (33.6%) for definition 2. Sensitivity of MRI for any cancer was 0.66 (95%CI 0.60-0.73), comparable to definition 1 (0.69, 95%CI 0.61-0.76) and definition 2 (0.66, 95%CI 0.60-0.73). Specificity was poorer (any cancer 0.54, 95%CI 0.46-0.62; definition 1: 0.54, 95%CI 0.46-0.62; definition 2: 0.54, 95%CI 0.46-0.62;). MRI-detected cancer comprised more Grade Group 5 tumors (difference 13.5%, p=0.01) (Table 1). MRI-detected tumors also had longer MCCL (median difference 3mm, p<0.001), and yielded more positive cores (median difference 2 cores, p=0.003). CONCLUSIONS: Of mpMRI-undetected tumors, there were fewer Grade Group 5 tumors, MCCL was shorter, and number of positive cores were fewer. At the prostate quadrant level, mpMRI had modest sensitivity and specificity, and may miss over 30% of radiorecurrent tumors across cancer definitions. mpMRI alone is therefore insufficient in localizing radiorecurrent prostate cancer. Source of Funding: Funded by the Pelican Cancer Foundation, the US National Institutes of Health, and the UK Medical Research Council © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e612 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Alexander Light More articles by this author Abi Kanthabalan More articles by this author Menelaos Pavlou More articles by this author Rumana Omar More articles by this author Sola Adeleke More articles by this author Francesco Giganti More articles by this author Chris Brew-Graves More articles by this author Amr Emara More articles by this author Athar Haroon More articles by this author Arash Latifoltojar More articles by this author Harbir Sidhu More articles by this author Alex Freeman More articles by this author Clement Orczyk More articles by this author Ashok Nikapota More articles by this author Tim Dudderidge More articles by this author Richard G. Hindley More articles by this author Heather Payne More articles by this author Anita Mitra More articles by this author Jamshed Bomanji More articles by this author Mathias Winkler More articles by this author Gail Horan More articles by this author Shonit Punwani More articles by this author Hashim U. Ahmed More articles by this author Taimur T. Shah More articles by this author Expand All Advertisement PDF downloadLoading ...

We write to express our reservations about the article ‘Does routine histology alter management post-circumcision?’ by Kerr et al.1, recently published in the Journal of Clinical Urology. The stated aims were ‘to confirm that routine histology for circumcision is not required and that clinical diagnosis is largely accurate. . . and whether histological confirmation of [lichen sclerosus] does alter patient management’. We contend that these aims are not properly addressed by the study undertaken and that the stated conclusions are of limited validity. We also contest some other statements that are made in the article. Essentially, the authors have compared retrospective data from two groups of adult male patients circumcised for a variety of indications at their institution. The groups are (a) so-called ‘controls’, i.e. patients under the care of some clinicians (n unspecified) at their institution who ‘did not send samples for histology unless malignancy was suspected’; and (b) the ‘study group’ comprising all the patients who had circumcisions i.e. both those under the care of the former clinicians (inferentially) where malignancy was suspected and those circumcised, for whatever clinical reason, by another group of surgeons (n again unstated). The absence of histological analysis in the purported control group is problematic and the effective consequence is a diagnostic vacuum. To compare outcomes, the authors rely solely on follow-up. However, the information provided on follow-up is limited, with only the range (1–6 years) and mean (40 months) described and no information on the distribution within this range, nor the frequency. No information is provided to explain the clinical necessity for such lengthy follow-up, and thus the question of whether patients required it for ongoing symptomatology in the area remains open. The authors do not provide information on how they established that there is no difference in the outcomes or re-referral rates of patients between the two groups, or accounted for patients that may have been referred to other centres, and they do not consider confounding factors that could influence re-referral, such as death or severe comorbidity. Although we appreciate the efforts that our colleagues have made to scrutinise the retrospective data available to them, the imperfections in this approach are muddling because the groups are different in several key regards. Also, we are not told the descriptive statistics of the ages of the groups; in fact no information is provided on whether the study group and control group were matched. A better way to test the hypothesis that histology is not necessary is, arguably, to submit all specimens by all surgeons for histology, compare the clinical diagnosis with the histology and, having those surgeons who would not routinely have requested histology flag those cases where that would not have been their clinical decision outside the investigative circumstances of such a study, and compare the outcomes. That would be a prospective endeavour of course. We recognise that the clinicians who did not routinely send foreskins for histology did not miss any cancers (happily), but we have other misgivings about this clinical attitude and the potential consequent endorsement of it that might ensue following a publication such as this. Reply to: 'Does routine histology alter management post-circumcision?'

Il est communément admis que la macrodissection de cellules cancéreuses spécifiques améliore le résultat de l'analyse des omiques. Cependant, cela nécessite une contribution importante de pathologistes expérimentés qui ne sont pas toujours facilement accessibles à tous les groupes de recherche. La pathologie numérique et l'intelligence artificielle (IA) pourraient fournir un outil utile. Notre étude pilote visait à déterminer quantitativement et qualitativement si l'identification des tumeurs avec Paige Prostate, un système d'IA avec détection, gradation de Gleason et fonctionnalité bêta de mesure, était applicable à un flux de travail transcriptomique. Une cohorte de 192 images de biopsies prostatiques de patients diagnostiqués avec un cancer a été évaluée par (1) deux uro-pathologistes expérimentés (gold standard), (2) un chercheur sans formation en uro-pathologie utilisant Paige, et (3) un pathologiste en formation utilisant Paige, qui ont contourné toutes les zones tumorales pour la macrodissection. Les contours produits par les trois approches ont été comparés. Le chercheur utilisant Paige s'accordait avec 95 % (182/192) des décisions des uro-pathologistes pour la sélection des échantillons. Lorsqu'un pathologiste en formation était impliqué, les 7/192 cas qui auraient été envoyés par erreur pour analyse par le chercheur utilisant Paige ont été réduits à seulement 1/192. Le chercheur et le pathologiste en formation ont contourné tous les cas en respectivement 6 et 11 heures, tandis que les uro-pathologistes ont simultanément dessiné les contours et évalué le grade de Gleason en 15 heures au total. Les uro-pathologistes ont également donné leur avis sur l'utilisation du système de détection de Paige dans un sous-ensemble de 102 images. Celle-ci a été notée comme « précise à plus de 70 % » dans 88 % des cas (90/102), y compris tous les cas bénins et ≥ Gleason 4 + 3. Pour la macrodissection de biopsies prostatiques, Paige Prostate est un outil prometteur. Comme la vérification anatomopathologique est essentielle pour la recherche, cela permettrait d'économiser le temps dédié par le pathologiste, d'impliquer les internes dans la recherche et la pathologie numérique au début de leur formation et d'accélérer la recherche qui nécessite une contribution anatomopathologique (Fig. 1, Fig. 2).

Introduction Penile intraepithelial neoplasia (PeIN) is a histological term for precancerous penile lesions. PeIN is important due to the high morbidity and mortality associated with progression to penile squamous cell carcinoma (PSSC). But PeIN is rare, contributing to a limited evidence-base for the relative efficacy of available treatment options. Objectives & methods To consolidate and expand knowledge about PeIN and its treatment, we describe the clinical and histological characteristics, treatments and outcomes of 345 patients with PeIN, managed by our multidisciplinary team. Our results are compared and contrasted with those in the literature, following comprehensive review. Results 8.7% of patients had concomitant, invasive PSCC, whilst 91.3% demonstrated PeIN alone. 84% hadundifferentiatedPeIN, and 10.7%differentiatedPeIN (5.2%, not specified). Clinical or histological evidence of HPV alone was present in 58%; features of lichen sclerosus alone in 12%; features of both in 29.4%. Only 14.4% of patients could be treated solely with topical agents or cryotherapy, whereas the remaining 85.6% underwent some form of surgical intervention, circumcision being the mainstay. Just 2.6% progressed to PSCC. Conclusions Clinical management of PeIN can be rationally optimized with excellent outcomes. Circumcision is important. Topical treatments alone are disappointing.

BACKGROUND:Male genital lichen sclerosus (MGLSc) can lead to significant sexual dysfunction and urological morbidity, and is also a risk factor for premalignant disease (penile intraepithelial neoplasia and penile cancer), particularly squamous cell carcinoma. Although the precise aetiopathogenesis of MGLSc remains controversial, accumulated evidence indicates that it is related to chronic, intermittent, occluded exposure to urine.AIM:To perform spatial mapping of MGLSc across the human prepuce and assess how this supports the urinary occlusion hypothesis.METHODS:Preputial samples were collected from 10 patients with clinically diagnosed MGLSc undergoing circumcision. The samples were then divided into a grid pattern and 10 punch biopsies were obtained from each section to determine the extent and distribution of the disease process across each prepuce.RESULTS:All 10 patients reported having urinary microincontinence, and all were histologically confirmed as having MGLSc. The most proximal aspect of the prepuce was found to be universally affected by MGLSc in all patients, whereas the most distal part was overwhelmingly shown to be the least affected area. Of the 63 MGLSc-affected regions, 62 were in direct physical contiguity with one another. The histological extent of the disease was not found to be congruent with either the severity of the symptoms reported by the patients or the clinical examination.CONCLUSION:In uncircumcised men with urinary microincontinence, after the prepuce has been replaced post micturition, small amounts of urine can pool between the juxtaposed epithelial surfaces. The proximal aspect of the prepuce is subjected to the maximum amount of occlusion and maximal contact with accumulated urine, whereas the distal prepuce is subjected to the least. Our findings suggest that accentuated contact between urine and susceptible penile epithelium due to occlusion can lead to MGLSc. Furthermore, contiguity data suggest that once established, it is possible that MGLSc advances across tissues by physical contact. This is the first study examining the changes in the preputial landscape in patients with LSc and contributes to our understanding of disease aetiology and progression.