A Modified Histopathologic Staging in Penile Squamous Cell Carcinoma Predicts Nodal Metastasis and Outcome Better Than the Current AJCC Staging.

Recently, the American Joint Committee on Cancer (AJCC) updated the staging system for penile squamous cell carcinoma. According to it, unlike its previous version, the involvement of urethra does not upstage the tumor; however, the involvement of corpora cavernosa (CC) does. The tumors involving CC are now staged pT3, whereas those involving corpora spongiosa (CS) are staged pT2, irrespective of the involvement of the urethra. In the current study, we sought to validate these recent modifications and in-process also attempted to improvise upon it. The histopathology slides were reviewed in 142 cases of penile squamous cell carcinoma. The histopathologic variables noted were tumor grade, anatomic level of invasion (CC/CS), lymphovascular invasion (LVI), and perineural invasion (PNI). Metastases to the lymph nodes were confirmed. Tumors were staged pT2/pT3 according to AJCC 8th edition and this staging system was further improvised by incorporating histopathologic variables similar to pT1 tumors in AJCC 8th edition. Accordingly, pT2 tumors invaded CS/CC without LVI or PNI and were not grade 3, whereas pT3 tumors invaded CS/CC, showed LVI and/or PNI, or were grade 3. Both the staging models were then correlated with nodal metastasis and disease-free survival. The new staging model (P=0.001) and not the AJCC pT2/pT3 stages (P=0.2) showed a statistically significant correlation with nodal metastasis. Similarly, only the proposed model significantly impacted disease-free survival (P=0.011). To conclude, we were unable to validate the prognostic difference between the pT2/pT3 stages according to AJCC 8th edition. The staging system can be improvised by incorporating histopathologic variables similar to pT1 tumors.

Human papillomavirus genotypes and P16INK4A expression in squamous penile carcinoma in Mexican patients.

BACKGROUND: Approximately 50% of cases of penile carcinoma (PeCa), a rare neoplasm worldwide, are associated with human papillomavirus (HPV). However, the detection of HPV-DNA is not sufficient to consider it the etiological factor in the development of this type of cancer. Currently, the overexpression of P16INK4A is used as a surrogate biomarker of HPV carcinogenesis. Information on PeCa in Mexico is scarce, particularly regarding cases related to HPV and genotype frequency. OBJECTIVE: To evaluate the presence of HPV, its genotypes, and the presence of multiple genotypes, and the expression of P16INK4A, as well as its clinical and histopathological parameters. METHODS: For HPV-DNA detection and P16INK4A expression, we used the INNO-LiPA® test and immunohistochemistry, respectively. RESULTS: Sixty cases of PeCa were evaluated, of which 75% were HPV-non-related histological variants. We found that 58.9% (33/56) of PeCa cases were HPV-DNA positive, while 30.9% of the cases evaluated (17/55) were positive for P16INK4A. HPV16 was the main genotype in 42.9% of the cases, followed by HPV52 in 7.1% and HPV18 in 5.4%. Within the HPV-positive cases, 27.3% had multiple genotypes. All HPV-positive patients under the age of 45 years were positive only for HPV16. CONCLUSIONS: HPV16 was the most commonly detected genotype in PeCa. HPV 31, 35 and 39 were infrequent; however, they were related to a single infection and P16INK4A overexpression; thus, they seem to be relevant in PeCa carcinogenesis. Our results suggest that P16INK4A overexpression could be useful for the classification of HPV-related PeCa. The role of multiple HPV genotypes in the development and prognosis of PeCa is still not completely understood. Thus, it is necessary to define criteria to establish reliable ways to classify HPV-related PeCa that could lead to optimal therapeutic approaches.

Pathology of Invasive and Intraepithelial Penile Neoplasia.

Since 1995 it has been known that tumors harboring human papillomavirus (HPV) preferentially show basaloid or condylomatous histological features, while HPV-negative tumors have a different morphology. New classification models separate subtypes of penile squamous cell carcinomas in two groups, non-HPV- and HPV-related. It is purported that HPV-related tumors have better prognosis. Other features such as inflammatory cell-rich medullary, clear-cell, and lymphoepithelioma-like patterns are also strong predictors of the presence of HPV. These tumors are morphologically distinctive and with some experience, pathologists may recognize them after routine hematoxylin and eosin staining. Occasionally, p16 immunostaining may aid in differential diagnosis. The gold standard for HPV detection is polymerase chain reaction, but this technique is expensive and not available in most pathology laboratories. In situ hybridization is useful and p16 immunostaining can detect HPV in approximately 85% of cases. There is correlation between morphology and outcome. PATIENT SUMMARY: This mini review provides an overview of the latest classification for penile invasive carcinoma and penile intraepithelial neoplasia.

Challenging the prognostic impact of the new WHO and TNM classifications with special emphasis on HPV status in penile carcinoma.

The evidence concerning prognostic parameters for clinical decision-making in penile cancer is either weak or missing. We therefore analysed the prognostic value of the revised TNM and WHO classification systems on relapse and survival with special emphasis on HPV status. We collected clinical data and tissue samples of 121 patients from centres in Germany and Russia. HPV genotyping and p16INK4a immunostaining were performed. The histological subtype and TNM were reclassified by two experienced uropathologists. Survival analyses were performed by Kaplan-Meier estimator and log-rank test. Uni- and multivariable analyses were performed by Cox proportional hazard model and Fisher's exact test for contingency analysis. HPV status was not found to be an independent prognostic factor. Histological subtypes differ in prognosis with the best outcome found in warty and the worst in basaloid carcinomas. Patients with pT1b defined by poor differentiation or lymphovascular invasion (LVI) had the shortest metastasis-free survival compared with pT1a (log-rank, p = 0.02). Lymph node metastasis and LVI were significantly associated with poor metastasis-free, cancer-specific and overall survival and could be identified as the only independent prognostic parameters. Prognostic value of TNM could not be improved using the 8th versus the 7th edition. In contrast to HPV status, histological subtypes are of prognostic value and should be an essential part of pathologic reports. The impact of the HPV status needs to be analysed in a subtype-specific manner. Parameters describing lymphatic dissemination have the highest impact on prognosis. Inclusion of tumour grade and LVI into a single T-category (pT1b) seems questionable.

Malignant Tumors of the Penis - Dia-gnostics and Therapy.

BACKGROUND: Penile cancer belongs to group of relatively rare malignancies. It represents, on average, 0.5-1% of all tumours in males globally and occurs predominantly in older individuals (> 65 years). The geographical distribution of malignant cancer of the penis is reported. A higher incidence is observed in less developed parts of the world, particularly in South America, Southeast Asia, and some areas of Africa (> 2.0/100,000). In Slovakia, there has been a recent increase in incidence (1.1/100,000 in 2011). Mortality has stabilized at 0.3/100,000 in recent years. Significant risk factors for malignant cancers include social and cultural habits and hygienic and religious practices. Important risk factors are inadequate hygiene of the foreskin sac, phimosis, human papillomavirus infection, sexual promiscuity, smoking, genital infections, and a low socio-economic and educational status. PURPOSE: The present paper provides an overview of pathology, symptomatology, diagnostic approaches, and classification of the extent of the disease. Treatment of the primary tumour depends on the extent of the disease and includes topical treatment, photodynamic treatment, cryoablation, laser photocoagulation, conservative surgical treatment, especially circumcision, and even radical treatment - penile amputation with perineal urethrostomy. An important part of the management of this malignancy is surgical treatment of metastases in inguinal lymph nodes. The article devotes more attention to non-surgical treatment modalities, in particular radiotherapy (external and brachytherapy) and systemic therapy (chemotherapy and biologic therapy), offering an overview of the indications and regimens in the adjuvant, neoadjuvant and palliative approaches, with and without concomitant chemoradiotherapy, and describes possible adverse effects of the treatments.  Conclusion: Patients with penile cancer should be concentrated in centres that have abundant experience in the diagnosis and treatment of this disease. Key words penile cancer - surgical treatment - radiotherapy - chemotherapy - biologic therapy The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 12. 11. 2018 Accepted: 12. 12. 2018.

Penile intraepithelial neoplasia: Nomenclature, incidence and progression to malignancy in the Netherlands.

OBJECTIVE: To determine the incidence of penile intraepithelial neoplasia in the Netherlands using a nationwide histopathology registry and to discuss the nomenclature of premalignant penile lesions. METHODS: Data from patients in the Netherlands diagnosed with a premalignant penile lesion between January 1998 and December 2007 were collected from the nationwide histopathology registry (PALGA); this database covers all pathology reports of inhabitants in the Netherlands. The premalignant lesions included were erythroplasia of Queyrat; Bowen's disease; bowenoid papulosis; mild, moderate and severe dysplasia; and carcinoma in situ of the penis. The terminology used in the pathological reports was translated to penile intraepithelial neoplasia. The grading was made analogous to that of vulvar premalignant lesions. RESULTS: The PALGA database enrolled 380 patients with premalignant penile lesions. Severe premalignant lesions, penile intraepithelial neoplasia III, were found in 254 patients (67%), penile intraepithelial neoplasia II in 84 (22%) and penile intraepithelial neoplasia I in 42 patients (11%). Most lesions were located on the prepuce (45%), followed by glans (38%) and shaft (3%). The median age of patients with penile intraepithelial neoplasia was 58 years. Progression to malignant disease occurred (2% for penile intraepithelial neoplasia I vs 7% for penile intraepithelial neoplasia III) in 26 patients. CONCLUSIONS: Penile intraepithelial neoplasia is a rarely diagnosed condition. Because of the wide variation of terms used for premalignant intraepithelial neoplasia of the penis, we recommend restricting this nomenclature to penile intraepithelial neoplasia.

Pathologic Nodal Involvement in Patients With Penile Cancer With Cavernosal Versus Spongiosal Involvement.

BACKGROUND: The American Joint Committee on Cancer recently proposed new TNM staging for penile cancer, with proposed T2 as spongiosal invasion and T3 as cavernosal invasion. We sought to validate the proposed staging system for predicting pathologic nodal involvement using the National Cancer Data Base. PATIENTS AND METHODS: Invasive penile cancer cases from 2010 to 2012 were identified. Differences in demographic and pathologic factors between T2 and T3 tumors were compared using χ2 and t tests. Logistic regression was performed to determine the odds of pathologically involved lymph nodes (pN+) by T classification. RESULTS: There were 378 T2 and 524 T3 patients with penile cancer. Compared with T2 tumors, T3 tumors were larger (mean size, 5.8 cm vs. 4.3 cm), had higher positive surgical margin rates (12% vs. 9%), and were more likely to have lymphovascular invasion (42% vs. 31%) (all P < .05). In multivariable analysis, both T2 (odds ratio [OR], 2.0; 95% confidence interval [CI], 1.2-3.3) and T3 (OR, 2.3; 95% CI, 1.4-3.6) remained significantly associated with risk of positive lymph nodes compared with T1 disease, but there was no increase in risk between T2 and T3 disease (OR, 1.1; 95% CI, 0.7-1.8; P = .56). CONCLUSION: The proposed new American Joint Committee on Cancer staging system for the penile cancer distinguishes spongiosal (T2) from cavernosal (T3) involvement. There does not appear to be a difference in positive lymph node status between the 2 grades when other clinical and pathologic variables are considered.

Estudio Descriptivo: Experiencia en el Manejo Quirúrgico del Cáncer de Pene en el Servicio de Urología del Instituto Oncológico Nacional Dr. Juan Tanca Marengo. Enero del 2010 a Diciembre del 2015. Guayaquil ­ Ecuador / Descriptive Research: Experience in the Surgical Management of Penile Cancer in the Urology Department of the National Oncological Institute Dr. Juan Tanca Marengo. January 2010 to December 2015. Guayaquil - Ecuador

INTRODUCCIÓN: El cáncer de pene en todo el mundo tiene una incidencia del 0.51- 8.3 por 100 000 varones. Su tratamiento puede ser quirúrgico, conservador o radical, con tratamiento adyuvante radioterapia y quimioterapia. Los objetivos fueron determinar histológicamente el tipo de cáncer de pene más común, el lugar de afectación, y el tratamiento quirúrgico más empleado. MÉTODOS: Es un estudio descriptivo, retrospectivo realizado en el Instituto Oncológico Nacional Dr. Juan Tanca Marengo, en el período de enero del 2010 a diciembre del 2015. Se incluyó a los pacientes con diagnóstico histopatológico de cáncer de pene; las variables estudiadas fueron edad, localización, presencia de ganglios, histopatología, recidiva, metástasis y cirugía realizada; se obtuvo la media y desviación estándar. Para el análisis estadístico se utilizó Excel 2016 y SPSS. RESULTADOS: Los pacientes estudiados fueron 58 con cáncer de pene; se evidenció, en relación a la edad se obtuvo una media de 59 años y desviación estándar +/-14.74. La lesión se localizó con mayor frecuencia en el glande 41 %, seguido de una afectación total del pene con un 38 %; en el caso de los ganglios fueron palpables en 24 pacientes. El tipo histológico más frecuente fue el carcinoma epidermoide 67 %. El tratamiento más empleado fue la penectomía subtotal en el 62 %. CONCLUSIONES: Se determinó que el carcinoma epidermoide fue el tipo histológico más prevalente, localizándose principalmente en el glande; la técnica más empleada fue penectomía subtotal. Se recomienda acudir precozmente cuando se evidencia una lesión a nivel del pene, el tratamiento precoz de estas lesiones mejoran el pronóstico del paciente.

BACKGROUND: Penis cancer worldwide has an incidence of 0.51- 8.3 per 100 000 males. It is treatment can be surgical, conservative or radical, with adjuvant treatment radiotherapy and chemotherapy. The objectives were: to determine histologically the most common type of penile cancer, the place of involvement, and the most used surgical treatment. METHODS: It is a descriptive, retrospective study realized in Dr. Juan Tanca Marengo National Oncological Institute, between the periods of January 2010 to December 2015. Patients with a histopathological diagnosis of penile cancer were included; the variables studied were age, location, presence of lymph nodes, histopathology, recurrence, metastasis and surgery performed; the mean and standard deviation were obtained. For the statistical analysis Excel 2016 and SPSS were used. RESULTS: The patients studied were 58 with penile cancer; it was evidenced, in relation to age, an average of 59 years and standard deviation was obtained +/- 14.74. The lesion was located more frequently in the glans 41 %, followed by a total involvement of the penis with 38 %; in the case of the nodes they were palpable in 24 patients. The most frequent histological type was squamous cell carcinoma 67 %. The most used treatment was subtotal penectomy in 62 % CONCLUSIONS: It was determined that squamous cell carcinoma was the most prevalent histological type, being located mainly in the glans; the technique most used was subtotal penectomy. It is recommended to pay attention early when there is evidence of a lesion at the level of the penis, the early treatment of these lesions improves the patient's prognosis.

[Pathology and histopathological evaluation of penile cancer]. / Pathologie und histopathologische Begutachtung des Peniskarzinoms.

BACKGROUND: Penile cancer is rare in Germany and in western European countries. Our understanding of the pathogenesis and pathology of this malignancy has increased considerably in recent years. OBJECTIVES: Clinical management has become more complex, with organ-preserving strategies being increasingly favored. Associated with these developments, the demands on the pathology reports of biopsies and surgical specimens from the penis have also increased. MATERIALS AND METHODS: According to guidelines and the relevant literature, this review outlines the most important aspects that must be considered in the classification and pathological reporting of penile cancer. RESULTS: Correct histological subtyping of penile cancer is important for prognostic and therapeutic considerations. There are also some peculiarities with the current TNM classification system of this tumor compared to other entities. CONCLUSION: Handling of specimens and histopathological typing must be performed by experienced pathologists according to recent developments in the pathogenesis, classification, and therapeutic strategies of penile cancer.

The World Health Organisation 2016 classification of penile carcinomas: a review and update from the International Society of Urological Pathology expert-driven recommendations.

The International Society of Urological Pathology (ISUP) held an expert-driven penile cancer conference in Boston in March 2015, which focused on the new World Health Organisation (WHO) classification of penile cancer: human papillomavirus (HPV)-related tumours and histological grading. The conference was preceded by an online survey of the ISUP members, and the results were used to initiate discussions. Because of the rarity of penile tumours, this was not a consensus but an expert-driven conference aimed at assisting pathologists who do not see these tumours on a regular basis. After a justification for the novel separation of penile squamous cell carcinomas into HPV-related and non-HPV-related-carcinomas, the histological classification of penile carcinoma was proposed; this system was also accepted subsequently by the WHO for subtyping of penile carcinomas (2016). A description of HPV-related neoplasms, which may be recognised by their histological features, was presented, and p16 was recommended as a surrogate indicator of HPV. A three-tier grading system was recommended for penile squamous carcinomas; this was also adopted by the WHO (2016). Many of the distinctive histological subtypes of squamous cell carcinoma of the penis are associated with distinct grades, based on the squamous cell carcinoma subtype histological features.

Proposal for reclassification of N staging system in penile cancer patients, based on number of positive lymph nodes.

In the present study, we aim to compare the rationality of proposed N classification based on the number of metastatic lymph nodes (LNs) with the current one. A total of 509 penile cancer patients at our institute were analyzed. Univariable and multivariable statistical analyses were used to assess cancer-specific survival (CSS) in 2 staging systems. Harrell's concordance index was applied to evaluate predictive accuracy of the current and proposed N classification in predicting CSS. We propose a new classification: pN1 (metastasis in 1-2 regional LNs), pN2 (metastasis in 3 regional LNs, or 3 or fewer regional lymph nodes with extranodal extension), and pN3 (metastasis in 4 or more regional LNs). According to the current and proposed N classification, the 5-year CSS of penile cancer patients with pN1, pN2 and pN3 was 85.8%, 39.0%, and 19.7%; and with pN1, pN2 and pN3 was 79.8%, 39.3% and 15.3%, which almost all showed significant difference (P < .001, P = .259) (P < .001, P < .001). Multivariable predictive accuracy of the proposed and current N staging was 76.48% and 70.92% (5.56% gain; P < .001). With a multivariable model of clinical features, both current (hazard ratio [HR], 7.761, 10.612; P < .001, P < .001) and proposed N stages (HR, 3.792, 3.971; P < .001, P < .001) exhibited independent effects on survival. The proposed N classification is superior to the current one, which is simpler and provides more accurate prognosis.

Subclassification of pN3 staging systems for penile cancer: Proposal for modification of the current TNM classification.

OBJECTIVE: To validate the clinical and prognostic significance of our proposed pN3 subclassification in penile cancer. MATERIALS AND METHODS: A retrospective analysis of 509 patients with penile cancer undergoing partial, total penectomy or inguinal lymphadenectomy or pelvic lymphadenectomy at Sun Yat-sen University Cancer Center was reevaluated by pathologists. pN3 stage was subclassified into pN3a (extranodal extension of any inguinal lymph node [LN] metastasis only) and pN3b (pelvic LN metastasis). The t test and chi-square test were applied to assess the comparability of pN3a and pN3b with clinicopathologic features. Univariable and multivariable statistical analyses were used to evaluate prognostic effect with cancer-specific survival. RESULTS: Among 509 patients, 71 patients with pN3 stage cancer were divided into 39 with pN3a and 32 with pN3b. The median number of LNs removed and the number of positive LNs were 27 and 3, respectively. The 3-year cancer-specific survival in pN3a and pN3b groups was significantly different at 47.9% and 28.6% (P = 0.003). In multivariable analysis, pN3 subclassification was an independent predictor for cancer-specific mortality (hazard ratio = 2.77; 95% CI: 1.170-6.558; P = 0.02). Adding pN3 subclassification to a multivariable model including pT stage, tumor grade, side involvement, lymphovascular invasion, number of positive LNs, and adjuvant therapy increased predictive accuracy for cancer-specific mortality from 0.665 to 0.695 (P<0.001). CONCLUSIONS: Subclassification helps better distinguish patients with pN3 penile cancer with increased risk of disease progression and cancer-related mortality.

The 2016 WHO Classification of Tumours of the Urinary System and Male Genital Organs-Part A: Renal, Penile, and Testicular Tumours.

UNLABELLED: The fourth edition of the World Health Organization (WHO) classification of urogenital tumours (WHO "blue book"), published in 2016, contains significant revisions. These revisions were performed after consideration by a large international group of pathologists with special expertise in this area. A subgroup of these persons met at the WHO Consensus Conference in Zurich, Switzerland, in 2015 to finalize the revisions. This review summarizes the most significant differences between the newly published classification and the prior version for renal, penile, and testicular tumours. Newly recognized epithelial renal tumours are hereditary leiomyomatosis and renal cell carcinoma (RCC) syndrome-associated RCC, succinate dehydrogenase-deficient RCC, tubulocystic RCC, acquired cystic disease-associated RCC, and clear cell papillary RCC. The WHO/International Society of Urological Pathology renal tumour grading system was recommended, and the definition of renal papillary adenoma was modified. The new WHO classification of penile squamous cell carcinomas is based on the presence of human papillomavirus and defines histologic subtypes accordingly. Germ cell neoplasia in situ (GCNIS) of the testis is the WHO-recommended term for precursor lesions of invasive germ cell tumours, and testicular germ cell tumours are now separated into two fundamentally different groups: those derived from GCNIS and those unrelated to GCNIS. Spermatocytic seminoma has been designated as a spermatocytic tumour and placed within the group of non-GCNIS-related tumours in the 2016 WHO classification. PATIENT SUMMARY: The 2016 World Health Organization (WHO) classification contains new renal tumour entities. The classification of penile squamous cell carcinomas is based on the presence of human papillomavirus. Germ cell neoplasia in situ of the testis is the WHO-recommended term for precursor lesions of invasive germ cell tumours.

What is new in Genitourinary Pathology? Recent developments and highlights of the new 2016 World Health Organization classification of tumors of the urinary system and male genital organs

The recently published 2016 World Health Organization (WHO) Classification of Tumors of the Urinary System and Male Genital Organs stems from the accumulated knowledge and data collected during the last 12 years, since the previous edition of the WHO "blue book" 2004. The major changes in prostate pathology include the introduction of a novel grading system for prostate cancer (Grade Groups/International Society of Urological Pathology (ISUP) grades 1­5), the recognition of intraductal carcinoma as a new entity, and the terminological changes regarding the neuroendocrine prostatic neoplasms. In bladder and urothelial tract, within the spectrum of flat and non-invasive lesions, a newly introduced term "urothelial proliferation of uncertain malignant potential" replaced the term "urothelial hyperplasia", and the term "urothelial dysplasia" was better defined. A category of "invasive urothelial carcinoma with divergent differentiation" was introduced for tumors showing a component of "usual type" urothelial carcinoma combined with other morphologies. A new WHO/ISUP renal tumor grading system was recommended (Grade 1­4). The definition of renal papillary adenoma was modified and expanded to include papillary neoplasms measuring up to 1.5 cm. Several new epithelial renal tumors were recognized as new entities including: hereditary leiomyomatosis and renal cell carcinoma (RCC) syndrome­associated RCC, succinate dehydrogenase­deficient RCC, tubulocystic RCC, acquired cystic disease­associated RCC, and clear cell papillary RCC. In testis pathology, intratubular proliferations of testicular germ cell tumors were renamed as "germ cell neoplasia in-situ" (GCNIS), and the testicular neoplasms were divided into two main groups: derived from or unrelated to GCNIS. A major change in penile pathology was the introduction of a new classification of penile squamous cell carcinoma, based on the presence of human papillomavirus (HPV), which characterizes penile tumor subtypes as HPV-related or non-HPV-related. A similar distinction was introduced for the preneoplastic penile intraepithelial precursor lesion (PeIN) into non-HPV related (differentiated PeIN) and HPV-related types (undifferentiated PeIN). In this review, we provide a summary and highlight the changes in the genitourinary pathology introduced by the 2016 WHO blue book, and we also discuss some recent developments that may impact the practice of genitourinary pathology in the near future (AU)

Review of in situ and invasive penile squamous cell carcinoma and associated non-neoplastic dermatological conditions.

Penile carcinoma is a rare genitourinary malignancy in North America and Europe with highest rates recorded in South America, Africa and Asia. Recent classifications have refined the terminology used in classifying intraepithelial/in situ lesions and additionally newer entities have been recognised in the invasive category. While increasing recognition of a bimodal pathway of penile carcinogenesis has facilitated understanding and classification of these tumours, handling and subtyping of penile malignancies presents a challenge to the reporting pathologist, in part due to their rarity. This article reviews the terminology and classification of in situ and invasive carcinomas and their relationship to human papilloma virus status. In addition, associated non-neoplastic dermatological conditions of relevance and appropriate ancillary investigations will be addressed.

Pathological factors, behavior, and histological prognostic risk groups in subtypes of penile squamous cell carcinomas (SCC).

Pathologists' contribution in the determination of prognosis in invasive penile squamous cell carcinoma is crucial. The TNM staging system is based on the identification of pathological data. There are multiple pathologically based factors believed to be important in relation to the rates of regional inguinal lymph node and specific cancer death. Among them are tumor site, size, histological subtypes, thickness or anatomical level of invasion, tumor front, and vascular or perineural invasion. The identification of these factors determines the prognostic profile of patients with penile cancer. These factors are used for the construction of pathological risk groups, prognostic index, or nomograms and are helpful in the prediction of nodal metastasis or patients' outcome. This review will describe in detail the influential pathological prognostic factors present in each tumor category emphasizing the impact of especial histological subtypes in tumor spread and final outcome. There are few studies comprehensibly addressing the relation of tumor morphology and prognosis according to histological types. We are summarizing findings of prognostic factors in 3 different series for the most common types and individual series in more recently described tumor entities. We had found a broad correlation of special subtypes of penile squamous cell carcinomas that made regional nodal status and final outcome predictable according to histological features of the tumor. These findings permitted grouping special subtypes of squamous cell carcinomas into prognosis risk groups of low, intermediate, and high. In the first category of excellent prognoses are the usual grade I, verrucous, papillary NOS, pseudohyperplastic and cuniculatum carcinomas. In the second group, there are the grade II usual, mixed and warty carcinomas. The third category of tumors, with the worst prognosis is composed of high grade usual, basaloid, warty-basaloid, papillary basaloid, and sarcomatoid carcinomas. We found that subtyping of penile squamous cell carcinoma is important to determine risk for nodal metastasis and patients' survival.

HPV- and non-HPV-related subtypes of penile squamous cell carcinoma (SCC): Morphological features and differential diagnosis according to the new WHO classification (2015).

The majority of penile carcinomas are squamous cell carcinomas originating in the squamous mucosa covering the glans, coronal sulcus, or inner surface of the foreskin, the 3 latter sites comprising the penile anatomical compartments. There is a variegated spectrum of subtypes of penile squamous cell carcinomas according to recent classification schemes. Currently, because of etiological and prognostic considerations, 2 morphologically and molecularly distinctive groups of subtypes of penile SCCs based on the presence of HPV were delineated. The predominant cell composition of tumors associated with HPV is the basaloid cell, which is the hallmark and best tissue marker for the virus. Tumors negative for the virus, however, are preferentially of lower grade and keratinizing maturing neoplasms with the exception of sarcomatoid carcinoma. HPV is detected in research studies by PCR or in situ hybridization (ISH) technologies, but p16 immunohistochemical stain is an adequate and less-expensive surrogate that is useful in the routine practice of pathology. The aim of this review is to demonstrate the variable morphological phenotypic expression of penile tumors separating non-HPV- and HPV-related neoplasms and to add morphological information that will justify subclassifying squamous cell carcinomas in a number of special subtypes. A brief discussion of the differential diagnosis in each category is also provided.

Reconstructive strategy and classification of penoscrotal defects.

OBJECTIVE: To classify defects in the penoscrotal region according to their specific anatomic sites. METHODS: From January 2002 to December 2012, 20 male patients underwent reconstruction for penoscrotal defects. The causative factors were Fournier's gangrene in 12 patients, extramammary Paget's disease in 4, skin tumors in 3, and deformity after a burn injury in 1. The defects were categorized according to their anatomic location: penis (P), and right (r) and left (l) scrotum (Sr and Sl), inguinal area (Ir and Il), and perianal area (Ar and Al). RESULTS: Seven patients with defects in the penis received skin grafts. Defects affecting more than 2 anatomic regions or extensive defects (>100 cm(2)) were reconstructed by free tissue transfer. Other defects were reconstructed by perforator-based island flap coverage. All of the flaps survived without complications. CONCLUSION: We introduce a classification that provides a simple way to specify the anatomic location and extent of a defect. This classification will permit more effective and straightforward reconstruction in the penoscrotal region.

Reproducibility of histopathologic tumor grading in penile cancer--results of a European project.

Since reliable molecular prognostic parameters for inguinal lymph metastases in penile cancer are not available, tumor grading is often used as a surrogate prognostic tool for the indication of inguinal lymphadenctomy and has been integrated into the current TNM classification for penile cancer. The reliability of tumor grading is under discussion. We examined interobserver grading variability in 90 primary penile carcinomas, assessed by 12 different uropathologists from five European countries. Tumor grading, following the CAP scheme, was compared, and interobserver variability was calculated using kappa statistics. The interobserver variability was high as reflected by an overall low kappa coefficient (mean k = 0.34) and reached a moderate level only in 26.4 % of the cases (range 0.02-0.67). The percentage of G1 tumors assigned ranged from 8.6 to 52.5 %, G2 tumors from 27.1 to 72.6 % and G3 tumors from 11.7 to 48.7 %. Only some observers assigned G4 with a range of 0.6-21.9 %. Subdivision into low and high grade according to UICC and EAU classifications differed significantly (P < 0.001). Low reproducibility of grading in penile carcinomas with the favored method does not allow a reliable prognostication of tumor aggressiveness. Inclusion of histological grading into the TNM classification currently seems not to be a benefit.

Two major pathways of penile carcinogenesis: HPV-induced penile cancers overexpress p16ink4a, HPV-negative cancers associated with dermatoses express p53, but lack p16ink4a overexpression.

BACKGROUND: Penile squamous cell carcinomas (SCC) arise either through transforming infections with human papillomavirus (HPV) or independent of HPV, often in the background of lichen sclerosus (LS) and lichen planus (LP). Despite impact on therapy and prognosis, etiologic stratifications are missing in most histological diagnoses and publications about penile cancers/precursors. OBJECTIVE: Classification of penile lesions into HPV-induced or HPV-negative via immunohistochemical demonstration of p16(ink4a) overexpression, a surrogate marker for transforming HPV-high-risk infections, and p53 expression in the absence of p16(ink4a) overexpression. METHODS: Archival formalin-fixed material of 123 invasive penile cancers and 43 pre-invasive lesions was evaluated for the presence of LS, LP, 28 HPV genotypes, and expression of p53 and p16(ink4a). RESULTS: Seventy-two of 123 SCCs and 33 of 43 pre-invasive lesions showed p16(ink4a) overexpression independent of HPV-HR genotypes involved; 66 of 72 SCCs and 29 of 43 precursor lesions revealed a single HPV-high-risk-genotype (HPV-HR16 in 76% followed by HPV33, HPV31, HPV45, HPV18, HPV56); 5 of 72 SCCs and 4 of 43 precursor lesions revealed multiple HPV-HR-genotypes. One SCC revealed HPV-LR and HR-DNA. Fifty-one of 123 SCCs and 10 precursor lesions were p16(ink4a) negative, but showed nuclear p53 expression in tumor cells and basal keratinocytes. Forty-nine of 51 SCCs and 10 of 10 precursor lesions lacked HPV DNA. Two of 51 SCCs contained HPV18 and HPV45 DNA, respectively, but p16(ink4a) negativity classified them as non-HPV-induced. Twenty-seven of 51 SCCs showed peritumoral LS, 13 of 51 SCCs showed peritumoral LP, and 11 SCCs revealed no peritumoral tissue. Histologically, HPV-negative precursors showed hyperkeratotic, verrucous, atrophic, and basaloid differentiation. LIMITATIONS: This was a retrospective study. CONCLUSIONS: p16(ink4a) overexpression identifies HPV-HR-induced penile carcinogenesis independent of HPV-HR genotype. p53 expression along with p16(ink4a) negativity identifies HPV-negative cancers. Correct etiologic classification of penile lesions during diagnostic work-up allows optimal therapy decisions.