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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.

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.

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 p16 INK4a 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.

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 χ 2 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., (Copyright © 2018 Elsevier Inc. All rights reserved.)

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., (© 2017 John Wiley & Sons Ltd.)

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.

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., (Copyright © 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

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., (Copyright © 2015 Elsevier Inc. All rights reserved.)

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., (Copyright © 2015 Elsevier Inc. All rights reserved.)

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., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

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., (Copyright © 2013 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.)

Penile squamous cell carcinoma (SCC) is uncommon in Europe, where it accounts for approximately 0.7% of all malignant tumors in men. The main risk factors are poor hygiene, lack of circumcision, human papillomavirus (HPV) infection, and certain chronic inflammatory skin diseases. HPV infection is detected in 70% to 100% of all penile in situ SCCs and in 30% to 50% of invasive forms of the disease, mainly basaloid and warty SCCs. In situ tumors can be treated conservatively, but close monitoring is essential as they become invasive in between 1% and 30% of cases. The treatment of choice for penile SCC is surgery. Inguinal lymph node irradiation is no longer recommended as a prophylactic measure, and it appears that selective lymph node biopsy might be useful for reducing the morbidity associated with prophylactic inguinal lymph node dissection. Survival is directly related to lymph node involvement. Improving our knowledge of underlying molecular changes and their associated genotypes will open up new therapeutic pathways., (Copyright © 2011 Elsevier España, S.L. and AEDV. All rights reserved.)

We are presenting the morphological features of 121 cases of atypical penile intraepithelial lesions. The term penile intraepithelial neoplasia (PeIN) was used to encompass all of them, and lesions were classified into 2 major groups, differentiated and undifferentiated. The latter was further divided in warty, basaloid, and warty-basaloid subtypes. Ninety-five cases were associated with invasive squamous cell carcinomas. Differentiated lesions predominated (68%), followed by warty-basaloid (14%), basaloid (11%), and warty (7%) subtypes. Multifocality was found in 15% of the cases. Differentiated lesions were preferentially located in foreskin, whereas warty and/or basaloid subtypes were more prevalent in the glans. The former lesions were preferentially seen in association with keratinizing variants of squamous carcinoma, whereas the latter subtypes were found mostly in conjunction with invasive warty, basaloid, and warty-basaloid carcinomas. Lichen sclerosus was present in 51% of cases of differentiated lesions and absent in warty and/or basaloid subtypes. In summary, PeIN can be classified into 4 distinctive morphological subtypes. The proper pathological characterization of these lesions may provide important clues to the understanding of the pathogenesis and natural history of penile cancer., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: Metastatic involvement of the inguinal lymph nodes is associated with decreased survival and is a strong prognostic factor in penile squamous cell carcinoma. The aim of the current systematic review was to evaluate the accuracy of (18)F-FDG PET/CT for inguinal lymph node staging in penile squamous cell carcinoma and possible influential factors., Materials and Methods: Medline, SCOPUS, Springer, Science Direct, and Google Scholar were searched using the key words "(penile or penis) and PET," with no date or language limitation. The meeting abstracts were not excluded either. Statistical pooling was performed using the random-effects model., Results: Seven studies were included in the meta-analysis. One article had 2 different subgroups of patients, and each subgroup was considered as a separate study. Pooled sensitivity and specificity were 80.9% (95% confidence interval [CI]: 69.5%-89.4%) and 92.4% (95% CI: 86.8%-96.2%), respectively. Pooled sensitivity was 96.4% (95% CI: 81.7%-99.9%) for cN+ and 56.5% (95% CI: 34.5%-76.8%) for cN0 patients., Conclusions: (18)F-FDG PET/CT imaging has relatively low sensitivity (especially in cN0 patients) for detection of inguinal lymph node involvement in penile cancer patients, which does not justify its routine use. However, patients with clinically palpable lymph nodes may benefit from (18)F-FDG PET/CT because the sensitivity in this subgroup of patients is high.

Inguinal lymph node metastasis is the single most important factor for predicting survival in patients with penile squamous cell carcinomas. To estimate the likelihood of this event, investigators have combined pathologic features of the primary tumor in the form of stratification systems. In this article we review 3 such systems (Solsona et al, J Urol 2001;165:1506; Hungerhuber et al, Urology 68:621, 2006; and Chaux et al, Am J Surg Pathol 2009;33:1049) built upon histologic grade, extent and depth of tumor invasion, and perineural invasion. We evaluate their usefulness, limitations, and possible implications for the management of patients with penile cancer. We also provide clues for the proper identification and interpretation of these pathologic features. Inguinal metastases were observed in 64% to 83% of patients in high-risk groups, 20% to 33% of intermediate groups, and 0% to 8% of low-risk groups. The results of these studies suggest that patients in high-risk groups could benefit from prophylactic bilateral groin dissection. In addition, patients in low-risk groups might be managed by surveillance alone. Finally, the authors suggest that additional approaches, such as sentinel lymph node biopsy, should be used for the intermediate-risk group. The identification of other pathologic features, such as vascular and perineural invasion, could tip the scales in problematic or paradoxical cases. The fate of these risk groups would be better defined by the identification of molecular biomarkers and genetic profiling.

Most primary malignant tumors of the penis are squamous cell carcinomas (SCC) of the usual type. In recent years several variants, each with distinctive clinicopathologic features, have been described. Pseudohyperplastic carcinoma and carcinoma cuniculatum are both low-grade, extremely well-differentiated SCC variants characterized by an indolent clinical course and good prognosis. The former, which may be confused with pseudoepitheliomatous hyperplasia, preferentially affects the inner foreskin mucosa of elderly men and the latter is a verruciform tumor with an endophytic, burrow-like pattern of growth. Pseudoglandular carcinoma (featuring solid tumor nests with extensive central acantholysis simulating glandular lumina) and clear cell carcinoma (human papillomavirus [HPV]-related tumors composed of periodic acid-Schiff positive clear cells) are aggressive tumors with a high incidence of inguinal nodal metastases. Papillary carcinomas are HPV-unrelated verruciform tumors composed of complex papillae with acanthosis, hyper- and parakeratosis, absence of koilocytes, irregular fibrovascular cores, and jagged tumor base. Finally, in warty-basaloid carcinomas areas of warty (condylomatous) and basaloid carcinomas coexist in the same tumor, either separated or intermingled, giving the tumor a variegated appearance. In this review special emphasis is given to the differential diagnosis of these special variants with a discussion of the possible implications for clinical management.

Objectives: The aim of this study was to validate recently proposed modifications to the current TNM classification of penile squamous cell carcinoma (PSCC) by using data from four German urological centers., Methods: We identified 89 patients treated for histologically confirmed PSCC between 1996 and 2008 and reclassified them according to the proposed TNM staging revisions. The proposed changes restricted T2 to tumoral invasion of the corpus spongiosum, whereas invasion of the corpus cavernosum was considered as T3. No changes were made to T1 and T4. Furthermore, N1 was limited to unilateral and N2 to bilateral inguinal lymph node involvement regardless of their number. Pelvic lymph node involvement and fixed lymph node were considered as N3 tumors. The range of follow up after initial treatment was 1-142 months (mean 38)., Results: Node-negative cases following the current classification were 65.2% (30/46), 48.5% (16/33) and 87.5% (7/8) for T1, T2 and T3, respectively. According to the proposed classification, N0 cases were markedly reduced in the T3 group (55.5%, 10/18) and relatively changed in the T2 group (56.5%, 13/23). T4 patients had no negative disease status. The 3-year disease-specific survival (DSS) rates for the proposed categories were 85.4%, 71.6% and 62.4% for T1, T2 and T3, respectively. For the current categories, the 3-year DSS rates were 85.4%, 66.9% and 100% for T1, T2 and T3, respectively. The 3-year DSS of the current N categories was 78.7%, 51% and 13.3% for N1, N2 and N3, respectively. According to the newly proposed categories, the 3-year DSS was 70%, 50% and 13.3% for N1, N2 and N3, respectively., Conclusion: Tumor and nodal staging of the newly proposed TNM classification show a more distinctive survival compared to the current one. However, a multi-institutional validation is still required to further corroborate the proposed modifications., (© 2011 The Japanese Urological Association.)

Several classification schemes for penile precancerous lesions have been proposed, but none of them seems to correlate with the current understanding of penile cancer pathogenesis. Recently, a system, which takes into account morphologic features and purported etiopathogenesis, was proposed, separating penile intraepithelial neoplasia (PeIN) in differentiated and warty/basaloid subtypes. This study was designed to seek an immunohistochemical profile that can be helpful in the classification and differential diagnosis of penile epithelial abnormalities and precancerous lesions using the aforementioned system. The immunohistochemical panel included stains for p16, p53, and Ki-67. For p16 immunostaining, only full-thickness positivity in all epithelial cells was considered as positive; for p53 and Ki-67 immunostaining, patchy or diffuse nuclear positivity above the basal layer was considered as positive. Seventy-four lesions in 59 patients were selected and classified as follows: differentiated PeIN, 34 cases; squamous hyperplasia (SH), 21 cases; basaloid PeIN, 15 cases; and warty PeIN, 4 cases. The mean age of patients was 64 years. Forty-two lesions (56.8%) were located in the glans and 32 (43.2%) in the foreskin. Overexpression of p16 was useful for distinguishing SH from warty/basaloid PeINs (0% vs. 94.7%, P<0.0001) but not SH from differentiated PeINs (0% vs. 5.9%, P=0.519). In addition, p16 allowed the distinction of differentiated and warty/basaloid PeINs (5.9% vs. 94.7%, P<0.0001). Immunohistochemistry results for p53 allowed the separation of SH and differentiated PeIN (9.5% vs. 44.1%, P=0.0078) and SH and warty/basaloid PeIN (9.5% vs. 55.6%, P=0.0042). Ki-67 immunostain was useful for distinguishing SH from differentiated PeIN (52.6% vs. 89.7%, P=0.0062) and SH from PeIN with warty and/or basaloid features (52.6% vs. 100%, P=0.0011). There seems to be a distinctive immunohistochemical profile for associated and precursor epithelial lesions of the penis. SH was p16 and p53 negative, with variable Ki-67 positivity. Differentiated PeIN was p16 negative and Ki-67 positive, with variable p53 positivity. Basaloid and warty PeINs were consistently p16 and Ki-67 positive, with variable p53 positivity. The use of a triple p16/p53/Ki-67 immunohistochemical panel was found to be helpful in the classification, differential diagnosis, and morphologic standardization of penile intraepithelial lesions.

From the pathogenic point of view, penile cancers may be grouped in human papillomavirus-related and unrelated tumors, each one of them with distinctive morphologic features. The former are predominantly composed of small, undifferentiated basaloid cells, with more or less prominent koilocytic changes, and the latter of keratinizing differentiated squamous cells. The same cellular types are observed in precancerous lesions. On the basis of these observations, we constructed a novel nomenclature for penile precancerous lesions and classified them as penile intraepithelial neoplasia (PeIN) of differentiated, warty, basaloid, and warty-basaloid types. The aim of this study was to test the usefulness of immunohistochemical p16 overexpression, considered as a surrogate for high-risk human papillomavirus infection, using this classification system. We pathologically evaluated 141 patients with PeIN, associated (123 cases) and unassociated (18 cases) with invasive cancer. Distribution of PeIN types was: differentiated, 72%; basaloid, 9%; warty-basaloid, 7%; warty, 4%; and mixed, 7%. There was a striking similarity in the morphology of in situ and invasive squamous cell carcinomas. Differentiated PeIN was commonly associated with usual, verrucous, papillary, and other low-grade keratinizing variants of squamous cell carcinoma whereas in basaloid and warty carcinomas the presence of in situ lesions with similar morphology was habitual. We evaluated p16 overexpression using a 4-tiered (0, 1, 2, and 3) pattern-based system. To properly distinguish differentiated PeIN from in situ lesions with warty and/or basaloid features only pattern 3, which requires full-thickness staining in all epithelial cells, was considered positive. Using this approach, there was a significant association of the negative patterns and differentiated PeIN and of the positive pattern and warty, basaloid, and warty-basaloid PeIN (P<0.0001). Basaloid variant had the strongest association. The sensitivity rate of p16 positivity for discriminating types of PeIN was of 82%, with a specificity of 100% and an accuracy of 95%. Lichen sclerosus was identified in 42 cases and their epithelial component was p16 negative in all cases. Although more studies are necessary to confirm these observations, p16 overexpression seems to be a useful tool for discriminating differentiated from warty, basaloid, and warty-basaloid PeIN.

A heterogeneous spectrum of epithelial alterations and atypical lesions affect the squamous epithelium of penile mucosal anatomical compartments. Analogous to other genital sites, the terminology utilized to define the lesions is variable. The few pathologic studies of penile precancerous lesions are mostly related to carcinoma in situ and human papilloma virus (HPV), and the information on low-grade atypical lesions is limited. The objective of this study was to comprehensively describe the morphologic features of all epithelial alterations, benign and atypical, low grade and high grade, associated with invasive squamous cell carcinoma of the penis and to investigate their relation with each other and with subtypes of invasive carcinoma. We also propose herein a simple and reproducible nomenclature for penile precancerous abnormalities until more biological, molecular, or epidemiologic information on the lesions is available. Two hundred and eighty-eight penectomy and circumcision specimens with invasive squamous cell carcinoma were pathologically evaluated. Carcinomas were classified as usual, verrucous, papillary not otherwise specified, warty (condylomatous), basaloid, and mixed. Associated lesions were classified as squamous hyperplasia and squamous intraepithelial lesions of low and high grade (LGSIL and HGSIL). In LGSIL, atypia was confined to the lower third, and in HGSIL, atypical cells affected at least two thirds of the squamous epithelium. Subtypes of SIL were squamous, warty, basaloid, warty-basaloid, and papillary. Squamous hyperplasia, the most common lesion, was found in 83% of the cases, followed by LGSIL (59%) and HGSIL (44%). In 62% of the cases more than 1 associated lesion was present per specimen. A sequence from squamous hyperplasia to low-grade to high-grade SIL was seen frequently. Squamous hyperplasia was more commonly associated with usual squamous, papillary, and verrucous than with warty and basaloid invasive carcinomas. LGSIL was associated with all types of squamous cell carcinoma but was rarely present adjacent to basaloid or verrucous tumors. HGSIL was present in two thirds of invasive warty, basaloid, and mixed warty-basaloid tumors, in about half of usual squamous cell carcinomas, and was absent in papillary and verrucous carcinomas. Correlation of special types of invasive carcinomas with subtypes of SIL revealed morphologic correspondence of invasive tumor and the associated intraepithelial lesion. Squamous LGSIL was preferentially associated with verrucous, papillary, and usual squamous cell carcinomas; warty LGSIL, with invasive warty and mixed warty-basaloid carcinomas. High-grade SIL of the squamous type was frequently found in squamous cell carcinoma of usual type but was rarely present with warty or basaloid carcinomas. Basaloid HGSIL was associated with basaloid carcinoma, and HGSIL of warty type, with either warty or mixed warty-basaloid carcinomas. The high frequency of squamous hyperplasia and LGSIL and preferential association with usual, verrucous, and papillary carcinomas plus the subtle morphologic differences of the 2 lesions suggest that, despite its benign appearance, squamous hyperplasia is a precursor of the aforementioned carcinomas. The association and histologic similarities between high-grade SIL of the basaloid, warty, or mixed forms with their invasive counterparts indicate these lesions are their likely precursors.

Surgeons often perform small or superficial penile biopsies that are difficult to classify definitely with regard to a benign or malignant nature, and if malignant, cannot always be accurately subclassified. Staging and therapeutic decisions rely on the identification, in these materials, of pathologic parameters related to prognosis. In this study, we evaluated the accuracy and completeness of pathologic information obtained from biopsies of 57 consecutive patients with squamous cell carcinoma (SSC) of the penis, and compared it with the information obtained from penectomies. Diagnostic accuracy was determined by recording discordances of critical factors in biopsies and penectomies. The evaluated parameters were as follows: cancer diagnosis, histologic type, tumor grade, depth of invasion (anatomical levels), and vascular invasion. Histologic subtypes of SCC were the following: usual 37, verruciform 11, mixed 7, pseudohyperplastic 1, and sarcomatoid 1. Grades were 1, 2, and 3 (well, moderately and poorly differentiated). Levels of invasion were lamina propria, corpus spongiosum, and corpus cavernosum in the glans; and lamina propria, dartos, and skin in the foreskin. In 2 patients with well-differentiated tumors a diagnosis of cancer could not be established in biopsy material. In 17 cases (30%) there was a biopsy-penectomy discordance of histologic types, especially of verruciform and mixed carcinomas. Biopsies failed to identify the correct histologic grade in 30% of the cases. A higher grade was usually identified in penectomy specimens. Because biopsies were superficial, the deepest point of invasion could not be determined in 91% of the cases. Vascular invasion was identified in biopsies in only 1 of 8 patients. In summary, biopsies were useful for cancer diagnosis except in 2 differentiated variants of penile squamous cell carcinoma. However, important pathologic parameters related to prognosis were missed on biopsy materials, and they were more accurately evaluated in penectomy specimens. We conclude that clinical and pathologic staging of penile cancer, at least in our material, cannot depend on biopsy information alone. Data from biopsies may be insufficient to make a decision whether to perform a groin dissection, or for prognostic evaluation in those patients in whom other treatment modalities (such as radiotherapy or chemotherapy) are being considered.

Within the spectrum of penile squamous cell carcinomas, those that we descriptively refer to collectively as the "verruciform" lesions are particularly difficult to subclassify. In a review of 50 such tumors, we found 11 distinctive neoplasms with condylomatous features conforming to the appearance of so-called "warty (condylomatous) carcinoma." The average patient age was 55 years and the average duration of disease was 19 months. The primary tumor involved multiple anatomic sites (glans, coronal sulcus, and foreskin) in seven cases and a single site (glans or foreskin) in four cases. Grossly, white to gray cauliflower-like tumors typically measuring approximately 5 cm were noted. Histologically the tumors were mainly papillomatous with acanthosis and hyperkeratosis. The papillae had prominent fibrovascular cores. The most conspicuous microscopic findings were striking nuclear atypia of koilocytotic type and clear cytoplasm. The interface between tumor and stroma was irregular in the majority of cases; deep invasion of corpus cavernosum was noted in five cases. The differential diagnosis included verrucous carcinoma, low-grade papillary squamous cell carcinoma, not otherwise specified, and giant condyloma acuminatum. Among other differences, the first two lesions show no koilocytotic changes and the last lacks malignant features and irregular stromal invasion. Metastatic spread occurred in two patients; both are alive with evidence of recurrent disease 12 and 72 months after initial diagnosis. A third patient was alive with recurrent disease 12 months after diagnosis. Five patients were free of disease 8, 12, 24, 52, and 108 months after diagnosis. Three patients were lost to follow up. Warty (condylomatous) carcinomas of the penis are morphologically distinctive verruciform neoplasms with features of human papillomavirus-related lesions and should be distinguished from other verruciform tumors so that differences in behavior, if any, between these tumors will become established.

Objectives: To examine the histologic features of p21 in penile tumors and to determine the role of p21 and p53 in the pathogenesis of this group of tumors., Methods: The clinicopathologic features of 87 patients with penile tumors were studied. The expression of p53 and p21 proteins in 49 cases was investigated by immunohistochemistry., Results: Of the 87 tumors studied, 84 represented primary penile tumors (72 malignant and 12 benign) and 3 represented secondary tumors (2 from bladder, 1 from nasopharynx). The primary malignant penile tumors included 66 surface carcinomas with squamous differentiation (92%), 3 cases of Paget disease (4%), 1 case of Bowen disease (1%), and 2 penile urethral squamous cell carcinomas (3%). The former group was subdivided into squamous cell carcinoma (n = 50), verrucous carcinoma (n = 8), basaloid squamous cell carcinoma (n = 3), adenoid squamous cell carcinoma (n = 3), spindle cell carcinoma (n = 1), and adenosquamous carcinoma (n = 1). The benign tumors were squamous cell papillomas (n = 10) and fibromatoses (n = 2). Expression of p21 and p53 was noted in 40% and 89%, respectively, of the 47 patients with primary surface penile carcinoma with squamous differentiation. Positive p21 and p53 expression was also seen in 2 cases of Paget disease. Staining for p21 was often weak and was found in the suprabasal region of carcinomas with squamous differentiation, while p53 expression was seen in the basal region of squamous cell carcinomas. Preinvasive lesions also showed p21 and p53 expression. An inverse correlation between p53 and p21 expression (p53(+)/p21(-) or p53(-)/p21(+)) was noted in half of the squamous cell carcinomas, 4 of 5 verrucous carcinomas, 2 of 3 basaloid squamous cell carcinomas, and in 1 spindle cell carcinoma. The other cases did not show this correlation., Conclusions: Penile tumors had different histologic variants and p21/p53 expression patterns. Expression of p21 did play a role in some tumors and could be dependent or independent of p53 expression.

Penile tumors, although not frequent, represent a difficult diagnostic and therapeutic challenge. Of the malignant penile neoplasms, the most frequent is penile carcinoma, which includes squamous cell carcinoma and its well-differentiated variant, verrucous carcinoma. Current concepts about classification, epidemiology, pathogenesis, histopathology, diagnosis, staging, prognosis, and treatment are presented.

Between 1974 and 1985, 16 patients (7 men, 9 women) with a diagnosis of genital verrucous carcinoma were identified from the cancer registry of the Tom Baker Cancer Centre in Calgary. All the men had lesions on the penis. In the women, five lesions were on the vulva, four were on the cervix and two were on the vagina (two women each had two involved sites). The histologic slides from the surgically excised specimens were reviewed, and, by applying strict criteria, all cases could be reclassified as giant condyloma (five cases), intraepithelial neoplasia with or without condylomatous features (eight cases) or invasive squamous cell carcinoma (five cases). The authors believe that, in genital lesions associated with the human papillomavirus, a diagnosis of verrucous carcinoma is nonspecific and may lead to inappropriate clinical management.