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Penile carcinomas are rare tumors in Europe and need further investigations due to their inferior prognosis in late tumor stages. The presence of disparate immune cell infiltrates was observed in these tumors, which were subsequently demonstrated to give rise to divergent tumor prognoses. The objective was to further characterize this immune cell infiltrate with the use of immunohistochemistry and RNA expression. A total of twelve well-characterized cases of penile squamous cell carcinomas with known infection status by human papillomavirus (HPV) and p16 status were assessed. The cases were classified according to their morphological characteristics, including those exhibiting a pronounced peritumoral immune cell infiltrate and those with less peritumoral immune cell infiltration. The generation of RNA expression data was conducted using the nCounter ® PanCancer Immune Profiling Panel. Computational models were employed to calculate the proportions of immune cells. To corroborate the findings, an immunohistochemical analysis was conducted using antibodies against CD20, CD3, CD4, CD8, MUM1, CD68, and CD117. Our cases were clustered according to the immune cell infiltrate detected via histology in a group with less immune cell infiltrate density and in a group with increased immune cell infiltrate density. Generally, all immune cells showed an increased amount in the group with pronounced immune cell infiltrate density. The clusters were found to relate to cell functions, the complement system, cytotoxicity, pathogen defense, regulation, and T-cell functions. In cases exhibiting a pronounced immune cell infiltrate, the top three genes that exhibited the greatest upregulation were GZMA , MICB , and GNLY . No relationship to HPV infection status was demonstrated. Immunohistochemistry validated the data gained via RNA expression and showed a correlation with EPIC and Cibersort. The clustering of cases based on immune cell infiltrate density revealed significant distinctions between groups with lower and higher immune cell infiltrate density. The group with increased immune cel infiltrate density showed a greater abundance of immune cells, aligning with key functions like cytotoxicity, pathogen defense, and T-cell regulation. Among these cases, the genes GZMA , MICB , and GNLY were significantly upregulated, suggesting their involvement in an increased immune response. The role of HPV infection status in our cases with regard to the peritumoral immune cell infiltrate remains inconclusive.

PeCa is a rare entity with rising incidence rates due to increased infections with human papillomaviruses (HPV). The distinct subtypes of PeCa with an individual pathogenesis demand biomarkers for a precise patient risk assessment regarding disease progression and therapeutic susceptibility. We recently identified promising candidates associated with an HPV-instructed tumor microenvironment (TME) using HPV-positive PeCa cell lines and tissue microarrays (TMA). The capacity of HPV + p63 + PeCa cells to release neutrophil-attracting CXCL-8 provided a molecular link explaining the infiltration of CD15 + myeloid cells in PeCa specimens. The candidate biomarkers HPV, p63, CD15, DKK1, and CD147 linked a tumor-promoting TME with a higher TNM classification reflecting more aggressive and metastasizing cancers. Based on immune-reactive scores (IRS) from TMA staining for these biomarkers, we calculated correlations and conducted association analyses to assess the degree of relationship between all biomarkers. We then conducted Kaplan-Meier survival estimates and Cox regression analyses to delineate the impact on PeCa patient survival. There is a notable predictive potential regarding the survival of patients with biomarker profiles beyond the potency of the individual biomarker. From all candidate biomarkers and biomarker profiles, the combination of CD147 and infiltrating CD15 + cells linked to an active HPV-driven transformation displayed cancer-immune dynamics with dismal prognosis for patients. After deciphering relevant interdependencies, the HPV + CD147 + CD15 + status was the most potent profile predicting metastasis-free survival of PeCa patients. The results of this report underscore the need for analysis of the TME and the development of multi-parameter composite scores that reflect fundamental cancer-immune relationships to tailor therapeutic interventions based on actual cancer immune dynamics., (© 2024. The Author(s).)

This article reviews penile squamous cell carcinoma (PSCC), a rare genitourinary cancer that has been increasing in prevalence. It discusses emerging therapies, focusing on immunotherapy, vaccine therapy, and cell-based treatments, especially in the context of human papillomavirus-related PSCC. Factors influencing these therapies are discussed. These include the immune microenvironment, programmed cell death ligand-1 expression, and tumor immune cell infiltration. This article also highlights immune checkpoint inhibitors and related clinical trials. This review supports the use of personalized medicine in treating PSCC. It stresses the need for collaborative studies and data sharing to create specific treatment plans and achieve better outcomes., Competing Interests: Disclosure M.A. Assaad, H. Safa, and C. Mercinelli have no conflicts of interest that are directly relevant to the content of this article. J. Chahoud received consultation fees from Pfizer, Aveo, Exelixis, and Mycaregorythm. A. Necchi reports the following: Honoraria: Roche, MSD, AstraZeneca, Janssen, Foundation Medicine, BMS, and Astellas. Consulting or Advisory role: MSD, Roche, Bayer, AstraZeneca, Clovis Oncology, Janssen, Incyte, Seattle Genetics/Astellas, Bristol-Myers Squibb, Rainier Therapeutics, Bycicle Therapeutics, GlaxoSmithKline, Basilea Pharmaceutica, and Catalym. Research Funding (Institution): MSD, AstraZeneca, Ipsen, and Gilead. Travel, Accommodations, Expenses: Roche, MSD, AstraZeneca, Janssen, Rainer Therapeutics, and Pfizer. P.E. Spiess reports the following leadership positions: President of Global Society of Rare GU Tumors; Vice-Chair of NCCN Bladder and Penile Cancer Panel; and Member of ASCO/EAU Penile Cancer Panel., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Penile squamous cell carcinoma (PSCC) occurs more frequently in some developing countries compared to developed countries. Infection with HIV and/or high-risk human papillomavirus (hrHPV) are risk factors for penile cancer development. The tumor microenvironment of PSCC may predict prognosis and may inform on the best targets for immunotherapy. We evaluated the immune microenvironment of penile tumors histologically, and determined whether and/or how HIV and/or hrHPV infections affect this tumor microenvironment. We conducted a prospective analytical cross-sectional study in which penile cancer tumors from 35 patients presenting at the University Teaching Hospital in Lusaka, Zambia were histologically staged and assessed for presence of tumor infiltrating immune cells and expression of immune checkpoints. Immunohistochemistry was used to evaluate immune checkpoints and infiltrating immune cells, while multiplex real-time polymerase chain reaction was used for hrHPV genotyping. The median age of all participants was 55 years. About 24% had advanced histological stage, 83% were HIV+, and 63% had hrHPV detected in their tumors using multiplex real-time polymerase chain reaction. PDL1 expression was significantly higher in HIV- participants than HIV+ participants (p = 0.02). Tumors with multiple hrHPV infections had a significantly higher number of cells expressing TIM3 than those with one hrHPV (p = 0.04). High grade tumors had a significantly higher infiltrate of FoxP3+ cells (p = 0.02), CD68+ cells (p = 0.01), CD163+ cells (p = 0.01), LAG3+ cells (p = 0.01), PD1+ cells (p = 0.01) and TIM3+ cells (p = 0.03) when compared with low grade tumours. There was significant moderate to strong positive correlation of cells expressing PD1 and LAG3 (⍴ = 0.69; p = 0.0001), PD1 and TIM3 (⍴ = 0.49; p = 0.017) and TIM3 and LAG3 PDL1 (⍴ = 0.61; p = 0.001). In conclusion, the tumor microenvironment of penile squamous cell carcinoma seems to be affected by both HIV and HPV infections. TIM3 appears to be a potential therapeutic target in PSCC patients with hrHPV infections., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Mumba et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Introduction: Penile carcinomas are rare tumors throughout Europe. Therefore, little attention is drawn to this disease. That makes it important to study tumor-associated key metrics and relate these to known data on penile neoplasias., Materials and Methods: A cohort of 60 well-defined penile invasive carcinomas with known human papillomavirus (HPV) infection status was investigated. Data on tumor type, grading and staging were recorded. Additionally, data on the peri- and intratumoral immune cell infiltrate in a semiquanititave manner applying an HE stain were assessed., Results: Our study showed a significant correlation of immune cell infiltrate and pT stage with overall survival. Therefore, in a subset of tumors, PD-L1 staining was applied. For tumor proportion score (TPS), 26 of 30 samples (87%) were scored >0%. For the immune cell score (IC), 28 of 30 samples (93%) were defined as >0% and for CPS, 29 of 30 samples (97%) scored >0. PD-L1 expression was not associated with overall survival., Conclusion: PD-L1 is expressed in penile carcinomas, providing a rationale for targeted therapy with checkpoint inhibitors. We were able to show that immune reaction appears to be prognostically relevant. These data enhance the need for further studies on the immune cell infiltrate in penile neoplasias and show that PD-L1 expression is existent in our cohort, which may be a potential target for checkpoint inhibitor therapy., (© 2021. The Author(s).)

Penile cancer is a rare but highly lethal cancer, and therapeutic options for patients presenting with lymph nodal disease are very limited. Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TIL) was shown to provide durable objective response in patients with metastatic melanoma and TIL have been expanded from solid tumors at rates between 70 and 90% depending on the specific diagnosis. We evaluated whether TIL could be expanded from surgical specimens of patients with penile cancer. Tumor samples from metastatic lymph nodes obtained at the time of inguinal lymph node dissection were collected, minced into fragments, placed in individual wells of a 24-well plate, and propagated in high dose IL-2 for four weeks. The phenotype of expanded TILs was assessed by flow cytometry and their anti-tumor reactivity was assessed by IFN-γ ELISA. TIL were expanded from 11 out of 12 (91.6%) samples of metastatic lymph nodes. Expanded TIL were predominantly CD3 + (mean 67.5%, SD 19.4%) with a mean of 46.8% CD8 + T cells (SD 21.1%). Five out of 11 samples (45.4%) from expanded TIL secreted IFN-γ in response to autologous tumor. TIL expansion and phenotype of expanded T cell lymphocytes were independent of previous HPV infection and treatment with neoadjuvant chemotherapy. This is the first report demonstrating successful expansion of tumor-reactive TIL from penile cancer patients, which support development of ACT strategies using TIL for the treatment of advanced and recurrent penile cancer., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Purpose: Nearly half of penile cancers are related to human papillomavirus (HPV) infection. Investigations of tumor- and HPV-specific T cell reactivity in regional lymph nodes (LNs) from patients with penile cancer are warranted., Materials and Methods: In this study, single-cell suspensions from LNs and peripheral blood from 11 patients with penile cancer were stained with antibodies for lymphocyte markers and analyzed by fluorescence-activated cell sorting (FACS). DNA was extracted from the tumor tissue and HPV status was investigated by PCR., Results: T-cell reactivity against autologous tumor-extract and against the HPV-vaccine Gardasil® was tested by flow-cytometric assay of specific cell-mediated immune response in activated whole blood (FASCIA). CD4 + /CD8 + ratios were significantly lower in HPV positive LNs (p<0.05). Immune responses to tumor extract assessed by blast transformation and expansion in vitro , of either CD4 + or CD8 + T-cells, were found in 9 of 13 LNs (69%). 5 of 6 tested patients demonstrated T cell recognition of tumor-associated antigen(s). In HPV-positive patients, dose-dependent T cell responses against L1 (late) HPV proteins (Gardasil vaccine) were demonstrated., Conclusions: LN-derived T cells from patients with penile cancer recognize tumor antigen(s) and in HPV-positive cases, there is a response against L1 (late) HPV proteins, being constituents of the Gardasil vaccine., Competing Interests: The authors have nothing to disclose., (© The Korean Urological Association, 2021.)

Penile squamous cell carcinomas (SCCs) are common tumors in older horses, with poor prognosis mostly due to local invasion and recurrence. These tumors are thought to be mainly caused by Equus caballus papillomavirus type 2 (EcPV-2). The aim of this study is to characterize the tumor immune environment (TIME) in equine penile tumors. Equine penile epithelial tumors (17 epSCCs; 2 carcinomas in situ , CIS; 1 papilloma, P) were retrospectively selected; immune infiltrate was assessed by histology and immunohistochemistry; RT-qPCR tested the expression of selected chemokines and EcPV-2 DNA and RNA. The results confirmed EcPV-2-L1 DNA in 18/20 (90%) samples. L1 expression was instead retrieved in 13/20 cases (65%). The samples showed an increased infiltration of CD3 + lymphocytes, macrophages (MAC387; IBA1), plasma cells (MUM1), and FoxP3 + lymphocytes in the intra/peritumoral stroma when compared to extratumoral tissues ( p < 0.05). Only MAC387 + neutrophils were increased in EcPV-2 high viral load samples ( p < 0.05). IL12 / p35 was differentially expressed in EcPV high and EcPV low groups ( p = 0.007). A significant decrease of IFNG and IL2 expression was highlighted in TGFB1 -positive samples ( p < 0.05). IBA1 and CD20 were intratumorally increased in cases where IL-10 was expressed ( p < 0.005). EpSCCs may represent a good spontaneous model for the human counterpart. Further prospective studies are needed in order to confirm these preliminary results.

The incidence of penile squamous cell carcinoma (PSCC) has increased in developed countries over the past decades owing to increased human papilloma virus (HPV) exposure. Despite successful surgical treatment of locoregional PSCC, effective treatment options for advanced disease are limited. The prognosis of patients with bulky nodal and metastatic PSCC is dismal and new management approaches are urgently needed. Genomic analyses have provided transformative knowledge on the genomic and molecular landscape and tumour microenvironment of PSCC. Around one-quarter of patients with metastatic PSCC have clinically actionable genomic alterations in mechanistic target of rapamycin, DNA repair and receptor tyrosine kinase pathways. These patients might benefit from combined and sequential targeted therapies. HPV vaccination might be another therapeutic option as PSCC is genetically similar to other HPV-driven cancers. In addition, 40-60% of PSCC tumours show strong PDL1 expression, and the frequency of mutational signatures suggestive of immunotherapy resistance is low, pointing to potential utility of immunotherapy for PSCC. Finally, identification of the composition of the penile microbiota and its biological role might lead to new cancer prevention and treatment strategies.

Background: Indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan (Trp) catabolism have been demonstrated to play an important role in tumor immunosuppression. This study examined the expression and catalytic activity of IDO1 in penile squamous cell carcinoma (PSCC) and explored their clinical significance., Methods: IDO1 expression level, serum concentrations of Trp and kynurenine (Kyn) were examined in 114 PSCC patients by immunohistonchemistry and solid-phase extraction-liquid chromatography-tandem mass spectrometry. The survival was analyzed using Kaplan-Meier method and the log-rank test. Hazard ratio of death was analyzed via univariate and multivariate Cox regression. Immune cell types were defined by principal component analysis. The correlativity was assessed by Pearson's correlation analysis., Results: The expression level of IDO1 in PSCC cells was positively correlated with serum Kyn concentration and Kyn/Trp radio (KTR; both P < 0.001) but negatively correlated with serum Trp concentration (P = 0.001). Additionally, IDO1 up-regulation in cancer cells and the increase of serum KTR were significantly associated with advanced N stage (both P < 0.001) and high pathologic grade (P = 0.008 and 0.032, respectively). High expression level of IDO1 in cancer cells and serum KTR were associated with short disease-specific survival (both P < 0.001). However, besides N stage (hazard radio [HR], 6.926; 95% confidence interval [CI], 2.458-19.068; P < 0.001) and pathologic grade (HR, 2.194; 95% CI, 1.021-4.529; P = 0.038), only serum KTR (HR, 2.780; 95% CI, 1.066-7.215; P = 0.036) was an independent predictor for PSCC prognosis. IDO1 expression was positively correlated with the expression of interferon-γ (IFNγ, P < 0.001) and immunosuppressive markers (programmed cell death protein 1, cytotoxic T-lymphocyte-associated protein 4 and programmed death-ligand 1 and 2; all P < 0.05), and the infiltration of immune cells (including cytotoxic T lymphocytes, regulatory T lymphocytes, tumor-associated macrophages, and myeloid-derived suppressor cells; all P < 0.001) in PSCC tissues. Furthermore, the expression of IDO1 was induced by IFNγ in a dose-dependent manner in PSCC cells., Conclusions: IFNγ-induced IDO1 plays a crucial role in immunoediting and immunosuppression in PSCC. Additionally, serum KTR, an indicator of IDO1 catabolic activity, can be utilized as an independent prognostic factor for PSCC., (© 2020 The Authors. Cancer Communications published by John Wiley & Sons Australia, Ltd. on behalf of Sun Yat-sen University Cancer Center.)

Current chemotherapeutic treatment for advanced penile squamous cell carcinoma has substantial side effects and no randomized data to support an overall survival benefit. Immunotherapy with checkpoint blockade is currently being tested in penile cancer patients in clinical trials. The high PD-L1 expression and CD8 + T-cell infiltration in penile cancer represent a promising prospect for immunotherapy response in the treatment of locally advanced disease. For efficacious immunotherapy treatment, a better understanding of the tumor microenvironment (TME) is critical. Here we use the structure revealed by cancer immunograms to define current knowledge of the penile cancer TME as a backbone for future research. PATIENT SUMMARY: Advanced penile cancer has a poor prognosis with a need for more effective therapy. In this manuscript we describe the potential of immunotherapy as a new treatment modality in penile cancer., (Copyright © 2019 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Penile squamous cell carcinoma (PeSCC) is a rare tumor and advanced PeSCC is associated with poor survival due to the aggressiveness of the disease and lack of effective systemic therapies. We describe for the first time a case with advanced chemoradiation refractory PeSCC who had documented response to active immunotherapy with the immune checkpoint inhibitor, anti-programmed death-1 monoclonal antibody Nivolumab. The patient suffered from a poor prognosis human papillomavirus-negative PeSCC, with a somatic inactivation mutation of cyclin-dependent kinase inhibitor 2A (CDKN2A) gene in tumor cells, and treatment with Nivolumab resulted in a partial response to therapy and significant tumor shrinkage. Histology transitions and alterations in tumor-infiltrating cytotoxic CD8 T-cell lymphocytes, programmed death ligand-1 expression on tumor cells and immune cells in tumor lesion biopsies pretreatment and posttreatment with Nivolumab were observed and described. In conclusion, in patients with metastatic PeSCC active immunotherapy combinations with an anti-programmed death-1/programmed death ligand-1 agent may be beneficial and further relative clinical studies are required.

The host's immune system plays a pivotal role in many tumor types, including squamous cell carcinomas (SCCs). We aim to identify immunological prognosticators for lymph node metastases (LNM) and disease-specific survival (DSS) in penile SCC. For this retrospective observational cohort study, penile SCC patients ( n  = 213) treated in the Netherlands Cancer Institute, were selected if sufficient formalin-fixed, paraffin-embedded tumor material was available. Analysis included previously described high-risk human papilloma virus (hrHPV) status, immunohistochemical scores for classical and non-classical human leukocyte antigen (HLA) class I, programmed death ligand-1 (PD-L1) expression, and novel data on tumor-infiltrating macrophages and cytotoxic an regulatory T-cells. Clinicopathological characteristics and extended follow-up were also included. Regression analyses investigated relationships of the immune parameters with LNM and DSS. In the total cohort, diffuse PD-L1 tumor-cell expression, CD163 + macrophage infiltration, non-classical HLA class I upregulation, and low stromal CD8 + T-cell infiltration were all associated with LNM. In the multivariable model, only tumor PD-L1 expression remained a significant predictor for LNM (odds ratio (OR) 2.8, p  = 0.05). hrHPV negativity and diffuse PD-L1 tumor-cell expression were significantly associated with poor DSS and remained so upon correction for clinical parameters [hazard ratio (HR) 9.7, p  < 0.01 and HR 2.8, p  = 0.03]. The only immune factor with different expression in HPV + and HPV - tumors was PD-L1, with higher PD-L1 expression in the latter ( p  = 0.03). In the HPV - cohort ( n  = 158), LNM were associated with diffuse PD-L1 tumor-cell expression, high intratumoral CD163 + macrophage infiltration, and low number of stromal CD8 + T-cells. The first two parameters were also linked to DSS. In the multivariable regression model, diffuse PD-L1 expression remained significantly unfavorable for DSS (HR 5.0, p  < 0.01). These results emphasize the complexity of the tumor microenvironment in penile cancer and point toward several possible immunotherapy targets. Here described immune factors can aid risk-stratification and should be evaluated in clinical immunotherapy studies to ultimately lead to patient tailored treatment.

Two major pathways of penile carcinogenesis are known: human papillomavirus (HPV)-induced penile cancer and HPV-negative cancers associated with chronic dermatoses. Therefore, modern measures for prevention of penile cancer may for example include prophylactic HPV vaccination. The resulting B‑cell-mediated immunity to HPV capsid proteins is effective protection against future HPV infections. Contrarily when treating existing HPV infections or HPV-associated cancers an antigen-specific T‑cell immunity is necessary. To date, screening and treatment of precancerous lesions to prevent penile cancer are not established in the German health care program and the highly expected therapeutic HPV vaccines are still on the horizon. In this article, we focus on possible strategies to prevent HPV-related penile cancer on different levels of carcinogenesis.

Background: Evidence suggests that natural antibodies developed after HPV16 infection may protect some women but not men against subsequent HPV16 reacquisition. Less is known whether antibodies developed following HPV16 infection are protective among men who have sex with men (MSM). Methods: Four hundred seventy-five MSM from the Human Papillomavirus Infection in Men (HIM) study were tested for serum antibodies to HPV16 L1 using enzyme-linked immunosorbent assays, and for anal and genital HPV16 DNA using PCR consensus primer system (PGMY 09/11). Adjusted Cox regression was used to evaluate whether baseline HPV16 seropositivity impacts subsequent genital or anal HPV16 DNA. Results: The risk of subsequent genital HPV16 [aHR = 1.05, 95% confidence interval (CI) = 0.66-1.68] and anal HPV16 infections among MSM (aHR = 2.34, 95% CI = 0.92-5.98) was similar or nonsignificantly higher in HPV16-seropositive than HPV16-seronegative MSM. The risk of genital HPV16 was also similar between HPV16-seronegative and HPV16-seropositive MSM in the highest tertile of HPV16 antibody levels and when restricting to those with new sex partners during follow-up ( P > 0.20). Among the 118 MSM who were HPV16 seropositive, 90% remained HPV16 seropositive up to 4 years later. When tested together, MSM with the highest antibody titers (top tertile) had similar levels to females (mean = 130.3 vs. 134.5 EU/mL, P = 0.84). Conclusions: Despite years of HPV16 seropositivity persistence and antibody titers comparable with females, this study suggested no evidence of HPV16 natural antibodies protecting against subsequent genital or anal HPV16 infection in MSM. Impact: This could help partially explain the high incidence of genital and anal HPV16 infection and related anal cancer seen in middle-aged and older MSM. Cancer Epidemiol Biomarkers Prev; 27(4); 496-502. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Penile squamous cell carcinoma (SCC) is primarily treated by surgical resection. Locally advanced and metastatic diseases require a multidisciplinary treatment approach. However, mortality and morbidity remain high, and novel molecular and immunotherapeutic targets are actively being sought. We investigated the expression of immune-checkpoint markers in penile cancers. Fifty-three invasive penile SCCs diagnosed between 1985 and 2013 were retrieved from our surgical pathology archives. Representative formalin-fixed, paraffin-embedded archival blocks were used for the construction of 2 high-density tissue microarrays. Tissue microarrays were stained with immunohistochemistry for PD-L1, FOXP3, CD8, and Ki-67. PD-L1 was investigated using rabbit monoclonal anti-PD-L1 antibody (Cell Signaling, Boston, MA; E1L3N, 1:100). Overall, 21 (40%) of 53 penile SCCs had positive PD-L1 expression. PD-L1 was expressed by a significant proportion of advanced penile SCC. Forty-four percent (15/34) of stage pT2 or more SCC and 38% (6/16) of tumors with lymph node metastasis were positive for PD-L1. PD-L1 expression did not correlate with patient age, tumor location, histologic subtype, tumor stage, anatomic depth of invasion, or tumor grade. FOXP3 expression in tumoral immune cells was found in 26 (49%) of 53 cases. FOXP3 expression in stromal immune cells correlated with tumor thickness (P = .0086). The ratio of CD8/FOXP3 was greater than 1 in 62% of cases in tumor-infiltrating immune cells and 34% of cases in stromal immune cells. Our current study is the largest to assess expression of PD-L1 in a clinically well-annotated North American cohort of penile SCC. Our findings support a rationale for targeting immune-checkpoint inhibitor pathways in advanced penile SCC., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Despite aggressive multimodal therapy, locally advanced and/or metastatic penile squamous cell carcinoma (SqCC) is associated with significant morbidity and mortality, indicating a need for new therapeutic options. Given the emerging clinical utility of immunotherapeutics, we sought to assess the incidence and potential clinical significance of PD-L1 expression in penile SqCC., Patients and Methods: Using an anti-PD-L1 primary antibody (clone 5H1), immunohistochemistry was carried out on whole tumor sections from 37 patients with penile SqCC treated at our institution between 2005 and 2013. PD-L1-positive tumors were defined as those with membranous staining in ≥5% of tumor cells. Association between PD-L1 expression and clinicopathologic parameters was examined using Fisher's exact test. Correlation between PD-L1 expression in primary tumors and matched metastases was assessed using the Spearman rank correlation coefficient (ρ). The difference in cancer-specific mortality between PD-L1-positive and -negative groups was examined using the log-rank test., Results: Twenty-three (62.2%) of 37 primary tumors were positive for PD-L1 expression, and there was strong positive correlation of PD-L1 expression in primary and metastatic samples (ρ = 0.72; 0.032 < P < 0.036). Primary tumor PD-L1 expression was significantly associated with usual type histology (P = 0.040) and regional lymph node metastasis (P = 0.024), as well as decreased cancer-specific survival (P = 0.011)., Conclusions: The majority of primary penile SqCC tumors express PD-L1, which is associated with high-risk clinicopathologic features and poor clinical outcome. These data provide a rational basis for further investigation of anti-PD-1 and anti-PD-L1 immunotherapeutics in patients with advanced penile SqCC., (© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Kaposi sarcoma (KS) is a cancer with an incidence in patients after transplantation (Tx) that is 500 times greater than that in the healthy population. The risk of KS increases significantly during therapy, especially when immunosuppressive therapy with cyclosporine A (CsA) is used. Most cases of KS develop during the first 2 years after transplantation. After a KS diagnosis, it is recommended to reduce the doses of immunosuppressive medications. Conversion of immunosuppressive treatment into mammalian target of rapamycin (m-TOR) inhibitors is strongly suggested., Patients and Methods: We present the case of a 65-year-old man with end-stage renal disease (ESRD) of unknown etiology, who had kidney transplantation in 2008. Immunosuppressive protocol was based on CsA, mycophenolate mofetil (MMF) and prednisolone (PRE). In 2011, during the dermatological consultation, on the penis glans a purple stain of uneven surface was noted. Histology study revealed the presence of KS. The treatment was modified. The patient was converted from CsA to everolimus. Before converting, the creatinine concentration was 1.79 mg/dl and proteinuria less than 0.3 g/day., Results: The change in the scheme of immunosuppresion from CsA to everolimus was performed to treat the Kaposi sarcoma. Gradually, within a year, the KS was cured. However, the graft function deteriorated, and the graft was lost in one-years' time., Conclusion: We present the first documented case of KS in the genital area of a kidney patient. The reduction in the strength of immunosuppression, and the introduction of an m-TOR inhibitor, may have contributed to the deterioration of kidney function, however it was substantial in the treatment of KS., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Purpose: Loss of expression of HLA class I is a mechanism of immune evasion in various cancers that is often associated with a worse patient outcome. We analyzed HLA expression in a large cohort with penile cancer in relation to clinical outcome., Materials and Methods: We used penile cancer tissue blocks from 168 patients who underwent surgical resection between 2000 and 2009 to construct tissue microarrays. Immunohistochemical staining was done with antibodies directed against classic and nonclassic HLA molecules. HLA expression was scored semiquantitatively, divided into 3 expression groups and correlated with clinicopathological variables, including HPV and survival. Survival analysis was performed using the Kaplan-Meier method and Cox proportional hazards models., Results: Complete and partial loss of total classic HLA class I was observed in 32% and 50% of cases, and up-regulation of HLA-E and G in 16% and 13%, respectively. When corrected for relevant clinical parameters, partial HLA-A loss was significantly associated with decreased survival overall (HR 2.3, 95% CI 1.1-4.6) and in HPV negative patients alone (HR 3.4, 95% CI 1.4-8.4). Abnormal HLA-B/C, E or G expression levels were not associated with survival., Conclusions: To our knowledge this is the first study to describe a link between HLA expression and the clinical outcome of penile cancer. HLA down-regulation occurs frequently and partial loss of HLA-A is an independent predictor of poor survival in HPV negative patients. Complete understanding of the mechanisms and relevance of HLA down-regulation and immune evasion in regard to the clinical outcome will contribute to the future design of immunotherapy interventions., (Copyright © 2015 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Human papillomavirus infection (HPV) has been implicated in penile cancer, and although the annual incidence is estimated to be 1,570 in the United States, there are areas of the world in which the incidence is as much as 20-fold higher. Ample data in the literature support testing and vaccination against HPV-related cervical cancer, but for men and penile cancer, these data are lacking. However, some preliminary data would suggest that HPV not only plays an important role in a significant subset of patients with penile cancer but also may be a target for penile cancer prevention as well via initiation of a vaccination program in high-risk male populations., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Besides the well-known systemic immune deficiency, also a regional immune deficiency, labeled as "immunocompromised district" (ICD), has been documented and focused in the recent years. The objective of the study is to gain more insights into the mechanisms involved in systemic and local immune destabilization. A 35-year-old, homosexual, and drug-addicted HIV+ man presented with a single nodule of Kaposi sarcoma (KS) located on the penis, where a slow to heal herpes zoster had appeared 2 months before. It has been assumed that the unusual penile location of herpes zoster facilitated the outbreak of KS in the affected dermatome because of a viral damage to sensory nerve fibers of the same dermatome. This damage, by interfering with the immunoregulatory function of neuropeptides released by nerve endings in that area, may have caused a regional alteration of the immune control favoring the local onset of the "opportunistic" angiogenic tumor (KS). In a few words, an ICD took place in an immunocompromised patient, thus introducing a more vulnerable site in an already vulnerable subject. The present case is the second one in the literature to document an ICD in the setting of preexisting systemic immune deficiency.

Background: HPV is related to a number of cancer types, causing a considerable burden in both genders in Europe. Female vaccination programs can substantially reduce the incidence of HPV-related diseases in women and, to some extent, men through herd immunity. The objective was to estimate the incremental benefit of vaccinating boys and girls using the quadrivalent HPV vaccine in Europe versus girls-only vaccination. Incremental benefits in terms of reduction in the incidence of HPV 6, 11, 16 and 18-related diseases (including cervical, vaginal, vulvar, anal, penile, and head and neck carcinomas and genital warts) were assessed., Methods: The analysis was performed using a model constructed in Microsoft(®)Excel, based on a previously-published dynamic transmission model of HPV vaccination and published European epidemiological data on incidence of HPV-related diseases. The incremental benefits of vaccinating 12-year old girls and boys versus girls-only vaccination was assessed (70% vaccine coverage were assumed for both). Sensitivity analyses around vaccine coverage and duration of protection were performed., Results: Compared with screening alone, girls-only vaccination led to 84% reduction in HPV 16/18-related carcinomas in females and a 61% reduction in males. Vaccination of girls and boys led to a 90% reduction in HPV 16/18-related carcinomas in females and 86% reduction in males versus screening alone. Relative to a girls-only program, vaccination of girls and boys led to a reduction in female and male HPV-related carcinomas of 40% and 65%, respectively and a reduction in the incidence of HPV 6/11-related genital warts of 58% for females and 71% for males versus girls-only vaccination., Conclusions: In Europe, the vaccination of 12-year old boys and girls against HPV 6, 11, 16 and 18 would be associated with substantial additional clinical benefits in terms of reduced incidence of HPV-related genital warts and carcinomas versus girls-only vaccination. The incremental benefits of adding boys vaccination are highly dependent on coverage in girls. Therefore, further analyses should be performed taking into account the country-specific situation. In addition to clinical benefits, substantial economic benefits are also anticipated and warrant further investigation as do the social and ethical implications of including boys in vaccination programs.

Purpose: To investigate the use of ClinProt technique to identify cancer markers in plasma of patients suffering from squamous cell carcinoma of the penis (SCCP)., Materials and Methods: Plasma of 36 healthy subjects and 25 patients with penile carcinoma who underwent surgical treatment between June 2010 and June 2011 was collected and analyzed by the ClinProt/MALDI/ToF technique. Then the peptides were identified from the C8 MB eluted fraction of patients' and control subjects' plasma by LIFT MS/MS., Results: A cluster of 2 peptides (A=m/z 1897.22 ± 9 Da and B=m/z 2021.99 ± 9 Da) was able to discriminate patients from control subjects. Cross validation analysis using the whole casuistic showed 62.5 % and 86.76 % sensitivity and specificity, respectively. The cluster also showed very high sensitivity (100 %) and specificity (97%) for SCCP patients that died due to the disease. Furthermore, patients with lymph node involvement presented sensitivity and specificity of 80 % and 97 %, respectively. These two peptides were identified by the proteomic approach based on a MALDI-TOF/TOF as fragments of C3 (m/z 1896.17) and C4a/b (m/z 2021.26) complement proteins., Conclusions: The results showed that as the disease progresses, the fragments C3 and C4 A/B are less expressed in comparison with healthy subjects. These results may be useful as prognostic tools.

Human papillomavirus is responsible for common condyloma acuminata and a number of premalignant and malignant anogenital lesions. The immunocompromised population is at particular risk because of a higher incidence of malignant transformation. Lesions in this population may prove refractory to standard treatment. This is part II of a two-part review that will discuss the treatment of condyloma acuminata and vaginal, vulvar, penile, and anal intraepithelial neoplasias. This article will provide an updated review of available treatments, with a focus on recent advances and the challenges faced in successfully treating human papillomavirus lesions in the immunocompromised host., (Copyright © 2011 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.)

Human papillomavirus (HPV) is responsible for common condyloma acuminata and a number of premalignant and malignant anogenital lesions. These conditions are of particular concern in immunocompromised individuals who have higher risk of malignant transformation and are more difficult to treat. This is part I of a two-part review that will highlight the cutaneous features of condyloma acuminata and vaginal, vulvar, penile, and anal intraepithelial neoplasias, with an emphasis on presentation of these HPV-mediated diseases in the immunocompromised host. Counseling patients about these conditions requires a thorough understanding of the epidemiology, natural history of HPV, transmission and infectivity, risk of malignancy, and the role of the host immune response in clearing HPV lesions. Part II will provide an updated review of available treatments, with a focus on recent advances and the challenges faced in successfully treating HPV lesions in immunocompromised patients., (Copyright © 2011 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.)

Background: The pathogenesis of penile squamous cell carcinoma (PSCC) is not well understood, though risk factors include human papillomavirus (HPV). Disruption of HER/PTEN/Akt pathway is present in many cancers; however there is little information on its function in PSCC. We investigated HER family receptors and phosphatase and tension homolog (PTEN) in HPV-positive and negative PSCC and its impact on Akt activation using immunohistochemistry and fluorescent in situ hybridisation (FISH)., Methodology/principal Findings: 148 PSCCs were microarrayed and immunostained for phosphorylated EGFR (pEGFR), HER2, HER3, HER4, phosphorylated Akt (pAkt), Akt1 and PTEN proteins. EGFR and PTEN gene status were also evaluated using FISH. HPV presence was assessed by PCR. pEGFR expression was detected significantly less frequently in HPV-positive than HPV-negative tumours (p = 0.0143). Conversely, HER3 expression was significantly more common in HPV-positive cases (p = 0.0128). HER4, pAkt, Akt and PTEN protein expression were not related to HPV. HER3 (p = 0.0054) and HER4 (p = 0.0002) receptors significantly correlated with cytoplasmic Akt1 immunostaining. All three proteins positively correlated with tumour grade (HER3, p = 0.0029; HER4, p = 0.0118; Akt1, p = 0.0001). pEGFR expression correlated with pAkt but not with tumour grade or stage. There was no EGFR gene amplification. HER2 was not detected. PTEN protein expression was reduced or absent in 62% of tumours but PTEN gene copy loss was present only in 4% of PSCCs., Conclusions/significance: EGFR, HER3 and HER4 but not HER2 are associated with penile carcinogenesis. HPV-negative tumours tend to express significantly more pEGFR than HPV-positive cancers and this expression correlates with pAkt protein, indicating EGFR as an upstream regulator of Akt signalling in PSCC. Conversely, HER3 expression is significantly more common in HPV-positive cases and positively correlates with cytoplasmic Akt1 expression. HER4 and PTEN protein expression are not related to HPV infection. Our results suggest that PSCC patients could benefit from therapies developed to target HER receptors.

Objectives: To evaluate the role of proliferating cell nuclear antigen (PCNA) and MIB-1/Ki-67 immunohistochemical expression in predicting lymph node metastasis and survival in primary penile squamous cell carcinoma., Methods: We conducted a retrospective evaluation of 125 patients with penile squamous cell carcinoma submitted to primary tumor treatment, with information on lymph node status. Clinical and pathologic data for PCNA and MIB-1/Ki-67 expression in the primary tumor were analyzed. Correlations between these data and lymph node metastasis risk and survival were calculated., Results: In univariate analysis, low MIB-1/Ki-67 expression, the presence of lymphovascular permeation, clinically positive lymph nodes, tumor thickness greater than 5 mm, and infiltration of cavernous bodies were correlated with lymph node metastasis. However, the independent factors for lymph node metastasis risk were PCNA and MIB-1/Ki-67 immunoreactivity, lymphovascular permeation, and N clinical stage. Independent variables for disease-free survival were urethra infiltration and the presence of lymph node metastasis. For death risk evaluation the independent variables were age, lymph node metastasis, and clinical stage., Conclusions: There was a correlation between PCNA and MIB1/Ki-67 immunohistochemical expression and the presence of lymph node metastasis. However, PCNA and MIB1/Ki-67 immunohistochemical expression did not have a relationship with survival and death risk.

Objective: To investigate the early diagnosis and early treatment of primary penile malignant lymphoma., Methods: One case of rare primary penile malignant lymphoma was studied with regard to its primary clinical process and characteristics, differential diagnosis and therapeutic method. The application value of the immunohistochemical features, in clinical diagnosis was analyzed., Results: Surgical treatment of removing the penis, testes and scrotum was carried out, followed by chemotherapy went. The immunohistochemical tests showed CD56, granzyme B, perforin and cytoplasmic CD3epsilon to be positive, and surface CD3 negative., Conclusion: Primary malignant lymphoma of the penis, though rare clinically, may be treated effectively if diagnosed early. Wedge biopsy with histological examination and immunohistochemical tests is the most common method for definite diagnosis.

In a case-control study in Uganda, we examined associations between different cancer sites or types in relation to antibodies against human papillomaviruses (HPV)-16, -18 and -45. For each cancer site or type, the control group comprised all other cancers excluding those known, or thought to be associated with HPV infection (cancers of the uterine cervix, penis and eye). Among controls the seroprevalence of antibodies was 11% (68/616) against HPV-16, 5% (29/605) against HPV-18 and 6% (35/605) against HPV-45. Antibodies against HPV-16 were significantly associated with only two cancers: uterine cervix [prevalence of antibodies 27% (51/191); odds ratio (OR) 2.0, 95% confidence interval (CI) 1.2-3.1, P=0.01] and penis [prevalence of antibodies 27% (4/15); OR 6.4, 95% CI 1.7-24.3, P=0.01]. For both cancers, the risk increased with increasing anti-HPV-16 antibody titre (Ptrend=0.01 for each). No cancer site or type was significantly associated with antibodies against HPV-18 and -45.

We report a 39-year-old HIV negative man with a solitary reddish-brown papule located on the glans penis, which had developed 6 months previously. Histopathologic examination showed spindle-shaped cells scattered between collagen bundles and intermingled with small, pointed vascular-like spaces. Spindle-shaped cells stained positively for antiFactor VIII and anti-CD34 antibodies. Human herpes virus-8 DNA was detected in tumor tissue and in peripheral blood mononuclear cells. Based on clinicopathologic and molecular findings, the diagnosis of classic Kaposi's sarcoma was made. Two months after the initial observation, three additional papules developed on the glans penis. Histopathologic examination of one lesion confirmed the diagnosis of classic Kaposi's sarcoma. The remaining lesions were treated with electrodessication and curettage. After a follow-up period of 6 months no evidence of recurrence was observed. We report this case for the unusual localization of Kaposi's Sarcoma in a young, HIV-negative patient., (Copyright John Libbey Eurotext 2003)

Objective: To evaluate whether serum squamous cell carcinoma antigen (SCCAg) measurements may be of use in identifying nodal metastases in patients with SCC of the penis after treating the primary tumour., Patients and Methods: The levels of SCCAg were analysed in 11 men with penile SCC between 1994 and 2001., Results: An elevated SCCAg level had a sensitivity of 57% (95% confidence interval, CI, 18-90%) and a specificity of 100% (CI 40-100%) for nodal metastases. Levels of SCCAg increased exponentially in patients who developed nodal metastases after treatment of the primary tumour, and were elevated before clinical or radiological evidence of nodal disease., Conclusion: Either the absolute level or the rate of rise of SCCAg may be a useful tool with which to follow patients after excision of the primary tumour. It may be more sensitive than computed tomography and magnetic resonance imaging in detecting recurrence, but further evaluation is needed.

Strong evidence suggests that virtually all cases of cervical cancer are caused by infection with oncognenic types of human papillomavirus (HPV). HPV is also found frequently in neighbouring anogenital epithelia and their neoplastic lesions. This review describes the general aspects of the natural history of anogenital HPV infections and summarises the evidence for an association between HPV and cancers of the uterine cervix, vulva, anus and penis.

Human papillomavirus (HPV) DNA has been detected in the great majority of cancers of the uterine cervix and anus, whereas the association of HPV DNA with cancer at other anogenital sites has produced less consistent results. This study was designed to compare HPV exposure among anogenital cancer cases and matched controls. Cases (1782) of anogenital cancer diagnosed in the Seattle area from 1978 to 1998 were identified and interviewed. Their responses were compared with those of 2383 age- and sex-matched controls. Blood was drawn at interview from both cases and controls and tested for antibodies to HPV-16 and HPV-18. Tissue blocks were tested for HPV DNA for 649 cases. Serum antibodies to HPV-16 were associated with in situ and invasive cancer at all sites among men and women with the exception of in situ penile cancer. Anti-HPV-18 antibodies were associated with cancers at all sites among women. The increased risk of cancer associated with HPV-16 seropositivity ranged from odds ratio = 1.8 (95% confidence interval, 1.4-2.5) for adenocarcinoma of the cervix to odds ratio = 5.9 (95% confidence interval, 3.4-10.3) for anal cancer in men. Associations between seroprevalence and cancers were stronger when analyses were restricted to HPV-16- or HPV-18 DNA-positive cases. HPV DNA was detected in >80% of cancers from all sites tested. HPV-16 DNA was the type most frequently detected at all sites (range, 40.9-82.2%). HPV-18 DNA was detected in 44.7% of adenocarcinomas of the cervix but detected much less often (2.6-18.1%) at other sites. These findings support an important role for HPV infection in anogenital cancer at all sites. Differences in the proportion of seropositives among HPV-16 DNA-positive cases by site suggest either that the immune response varies by site or that cancer development may lead to changes in antibody responses in a site-specific fashion.

Impairment of natural cytotoxicity mediated by natural killer (NK) cells may play a role in the pathogenesis of penile carcinoma. The aim of this study was to examine the NK activity profile and its prognostic significance in patients with squamous cell carcinoma of the penis. The NK activity was measured in peripheral blood mononuclear cells (PBMCs) from 39 patients diagnosed histologically as having invasive squamous cell penile carcinoma and 4 patients with verrucous carcinoma of the penis. Of 39 patients with invasive squamous cell carcinoma, 4 had undergone previous penile amputation. According to the prognosis, the patients with invasive squamous cell carcinoma were divided into two groups: with metastasis and without metastasis. The patients were evaluated in relation to clinicopathologic variables using univariate analyses. NK cell activity was significantly decreased in all patients with penile carcinoma when compared with the control groups (p < 0.0001). There was no statistically significant difference between the groups with and without metastasis. We conclude that there is a decrease in NK activity in PBMCs from patients with penile carcinoma and that the presence of advanced disease or metastatic involvement is not responsible for this reduction.

This report presents the unusual occurrence of metachronous perianal and penile carcinomas in a young, immunosuppressed man. Both anogenital cancers were HPV-16-DNA-positive by the polymerase chain reaction. DNA in situ hybridization analysis of the penile carcinoma revealed HPV-16 in most neoplastic cells. HPV-16 appears to have played a central role in both anogenital cancers in this patient, suggesting that, like in immunologically susceptible women, a carcinogenic 'field effect' may exist in the anogenital area of the immunosuppressed male.

The ultrastructural localization of Brazilian pemphigus foliaceus (BPF) (fogo selvagem) antigen(s) in cultured human squamous cell carcinoma cells was studied using immunogold electron microscopy. Five of six BPF sera, which showed positive cell-surface reactivity on immunofluorescence, bound to the cell-cell contact area of cytoplasmic projections. This binding pattern was apparently different from that of non-endemic pemphigus foliaceus and pemphigus vulgaris sera, and mouse monoclonal anti-human E-cadherin antibody. The results suggest that BPF autoantibodies recognize a molecule(s) which is different from non-endemic pemphigus antigens, or different epitope(s) of a molecule identical with non-endemic pemphigus antigens, and that the epitope(s) to which BPF autoantibodies bind is expressed on cell-cell contact areas at a relatively early stage of cell-cell adhesion formation.

Langerhans' cells could have an important role in the immune surveillance for the malignant transformation associated with certain viral infections. A planimetric study of Langerhans' cells was performed on epithelial sheets obtained from male and female patients who presented with human papillomavirus-induced condylomata. Preliminary epidemiological studies have indicated that after a human papillomavirus infection the risk of malignant transformation is higher in the cervix than in the penis. Our study was designed in such a way that the Langerhans' cell density observed in condylomata could be compared to that detected in adjacent normal areas from the same patients. The results showed that a highly significant decrease in Langerhans' cells occurred in male and female human papillomavirus infected genital tracts. In the penis the local treatment with 5-fluorouracil restored the normal Langerhans' cell density. The significance of these findings in relationship with malignant transformation is discussed.

Background: Two unusual cases of cutaneous angiocentric T-cell lymphoma were found to be associated with Epstein-Barr virus infection., Objective: The objective was to study the clinical course and the response of the disease to conventional chemotherapy., Methods: Histologic specimens from both patients were studied. Clonal proliferation was assessed by Southern blot hybridization., Results: The disease in both patients was rapidly progressive and responded poorly to aggressive treatment. Biopsy specimens showed infiltration of atypical lymphoid cells with angiocentricity and angiodestruction, which probably resulted in the observed tissue necrosis. Clonal proliferation of Epstein-Barr virus DNA was detected in tissue from primary skin lesions and disseminated nasal lesions., Conclusion: Epstein-Barr virus-associated angiocentric T-cell lymphoma in our patients was characterized by an aggressive course and resistance to conventional chemotherapy. A search for Epstein-Barr virus and the human T-lymphotropic virus should be performed in patients with atypical features of cutaneous T-cell lymphoma.

We report a 42-year-old white bisexual man with disseminated Kaposi's sarcoma limited to the skin and gastrointestinal tract. Results of several serum tests for human immunodeficiency virus (HIV) antibodies have been negative. The CD4/CD8 ratio has remained normal, and his Kaposi's sarcoma has had a benign clinical course during 30 months of follow-up. Similar reports of disseminated Kaposi's sarcoma with a benign clinical course in homosexual or bisexual men without demonstrable HIV infection are reviewed. Some cellular immune impairment that might be more prevalent in the homosexual population may be implicated in the pathogenesis of this type of Kaposi's sarcoma.

TA-4 antigen, originally isolated from women with squamous cell carcinoma of the cervix, is elevated in the sera of patients with squamous cell carcinomas of several sites, including esophagus, lungs, and head and neck. In this study, we compared the serum levels of TA-4 in normal volunteers, patients with resected penile squamous cell carcinoma, and patients with metastatic penile squamous cell carcinoma. TA-4 values were elevated in 5 of 11 patients (45%) who had metastatic disease. In 2, TA-4 was normal the first time metastasis was clinically detected but rose as the disease progressed. Moreover, in 3 patients in whom serial determinations were made, serum TA-4 values correlated well with disease progression and response to treatment. We conclude that TA-4 values are elevated in some patients with metastatic squamous cell carcinoma of the penis and may become a useful marker for monitoring response to therapy.

In a study on 129 patients with penile condylomata acuminata we recognised an incidence of 32% penile yeast affection. Candida was found in 54%, Torulopsis in 30% and Rhodotorula in 17% of all cases. The high rate of yeasts not belonging to the candida species is remarkable. There was no correlation between our test results regarding the cell-mediated immunity against candida albicans and the local yeast infection.

Penile condylomata were eradicated from 22 (54%) of 41 men whose lesions were painted twice (with a 72-hr interval) by the investigator with 8% podophyllotoxin in ethanol and from 83 (48%) of 173 men who self-administered either 0.5 to 1.0% topical preparations twice or thrice daily for three subsequent days. All regimens had identical efficacy; a higher frequency of mild local irritation in the self-medicating group may be outweighed by a relatively lower risk for hazardous systemic absorption. The rate of cure was higher when tumors afflicted the preputial cavity than the urinary meatus or penile skin and was lower when there were more than five warts, lesions grew in a plaque-like pattern, or duration of warts exceeded six months. Sixty-six men were sensitized with 2,4-dinitrochlorobenzene; the degree of response to subsequent challenge did not correlate to number or growth pattern of lesions or to cure rate.

To evaluate the prognostic significance of host immunocompetence in urologic cancer patients, the subsequent clinical course of 95 patients was determined a year after skin testing with dinitrochlorobenzene. A close correlation was demonstrated between dinitrochlorobenzene reactivity and prognosis among 38 transitional carcinoma patients. Of 19 patients with impaired reactivity 13 had tumor recurrences and 11 of these died of cancer within 1 year. Only 5 of 19 patients with normal dinitrochlorobenzene reactivity had recurrences and none died during the same interval. Although not statistically significant, similar results were observed among 10 renal cell carcinoma patients of whom 3 of 5 with impaired dinitrochlorobenzene reactivity had tumor recurrences, while 4 of 5 with normal reactivity remained free of tumor. One testis tumor patient with impaired dinitrochlorobenzene reactivity died of cancer, while 3 of 4 with normal reactivity remained free of tumor. Similarly, 1 patient with carcinoma of the penis with impaired dinitrochlorobenzene reactivity died of cancer, while 2 of 3 with normal reactivity remained free of tumor. In contrast, reactivity to dinitrochlorobenzene did not correlate with the clinical course of 38 prostatic carcinoma patients. Ten of 19 patients with normal dinitrochlorobenzene reactivity and 9 of 19 with impaired reactivity were dead or had symptomatic recurrences within 1 year, while 9 of 19 with normal reactivity and 10 of 19 with impaired reactivity were either free of tumor or asymptomatic. However, a trend toward a correlation between dinitrochlorobenzene reactivity and tumor progression was observed among patients not receiving endocrine therapy. The differences with respect to the prognostic significance of host immunocompetence between transitional carcinoma patients and those with prostatic carcinoma may be explained by fundamental differences in the biologic properties of these tumors, especially the endocrine sensitivity of prostatic carcinoma.

It is stated that a general final evidence is not yet possible from the existing results of immunological investigations and it may be possible only when taking into consideration the extensive furthering controls mentioned. On the basis of the therefore further existing uncertainty in the evaluation of the immunological valency of the cryotherapy, which is expressed also in literature, the originally optimistic suggestions concerning an increased immune response to the cryotherapy must be judged critically. Even when the clininically favourable courses after cryotherapy, above all in the treatment of the penis carcinoma, may be impressible--a cryospecific immune reaction was not to be proved by the test systems at our disposal.

World-wide incidences of penile cancer are reviewed and epidemiologic factors including ciecumcision, hygiene, phimosis, smegma, irritation, infection, veneral disease, viruses, environment, race, immune response, trauma, and age are discussed. The lowest rates appear in groups practicing infant circumcision and in areas where standards of sexual hygiene are high.

A squamous cell carcinoma-related antigen (SCC-Ag), which has been recognized as a tumor marker of cervical cancer of the uterine, was detected in the serum with a radioimmunoassay and its clinical usefulness in penile cancer was evaluated. Seven serum samples of penile cancer, one of Paget's disease and two of condyloma acuminatum were analyzed for the SCC-Ag level. The mean +/- standard deviation of serum SCC-Ag level and positive rate (greater than 2.0 ng/ml) were 1.6 +/- 1.75 ng/ml and 14%. Neither pathological staging nor cell grading of penile cancer showed any relation to the serum SCC-Ag level. When the tumor of the penis has been recognized and a cut-off value of 1.0 ng/ml used, the positive rate of penile cancer was 71.4% and false positive rate of other benign penile tumors was 0%. Serum SCC-Ag values were changed parallel in to the clinical course in three patients. These results suggest that the detection of the serum SCC-Ag value may be of use for detection of penile cancer and monitoring of these patients.

To detect the presence of Herpes Simplex Virus Type 2 (HSV-2) and Human Papilloma Virus (HPV), common structural antigens in penile cancers, 20 squamous cell carcinomas were studied by immunohistochemical methods. All specimens were from Singaporeans ranging in age from 44 to 69 years. None of the specimens contained HSV-2 and HPV common structural antigens. The reasons for the absence of HPV common antigen were discussed. The significance of the association of HPV with penile cancers is uncertain. The role of HPV in the carcinogenesis of penile cancer is far from clear. Further studies need to be done and other possible causes have to be explored.