Human papillomavirus infection affects treatment outcomes and the immune microenvironment in patients with advanced penile squamous cell carcinoma receiving programmed cell death protein 1 inhibitor-based combination therapy.

BACKGROUND: Penile squamous cell carcinoma (PSCC) is a human papillomavirus (HPV)-associated malignancy. Immunotherapy is emerging as a potential treatment for advanced PSCC. In this study, the authors analyzed the association of HPV status with outcomes and the immune microenvironment in patients with advanced PSCC undergoing programmed cell death protein 1 (PD1) inhibitor-based combination therapy (PCT). METHODS: HPV status was assessed using quantitative polymerase chain reaction in 87 patients with advanced PSCC treated with PCT. Objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) in the HPV+ and HPV- groups were compared. Additionally, bulk RNA sequencing was performed to investigate the potential impact of HPV on the immune microenvironment in advanced PSCC. RESULTS: Among patients receiving first-line PCT, ORR (91.7% vs. 64.6%, p = .014) and DCR (100.0% vs. 79.2%, p = .025) in the HPV+ group were higher compared to the HPV- group. Kaplan-Meier curves demonstrated that the HPV+ group exhibited superior PFS (p = .005) and OS (p = .004) for patients in the first-line setting. However, these advantages of HPV infection were not observed in multi-line PCT (p > .050). HPV status remained an independent prognostic factor for predicting better ORR (p = .024), PFS (p = .002), and OS (p = .020) in the multivariate analyses. Landmark analyses showed that the HPV-induced superiority of PFS occurred at an early stage (within 3 months) and OS occurred at a relatively late stage (within 9 months). Bioinformatic analyses identified potential immune-activated genes (GLDC, CYP4F12, etc.) and pathways (RAGE, PI3K/AKT, etc.), antitumor immune cell subtypes, and lower tumor immune dysfunction and exclusion scores in HPV+ tissues. CONCLUSIONS: HPV infection may confer treatment efficacy and survival benefits in patients with advanced PSCC receiving first-line PCT because of the possible stimulation of the antitumor immune microenvironment. PLAIN LANGUAGE SUMMARY: Human papillomavirus (HPV) infection may induce better objective response rate, progression-free survival (PFS), and overall survival (OS) for advanced penile squamous cell carcinoma (PSCC) patients receiving first-line programmed cell death protein 1 inhibitor-based combination therapy (PCT) instead of multi-line PCT. HPV infection-induced PFS advantage occurs at an early stage (within 3 months) whereas OS superiority occurs at a relatively late stage (within 9 months). Antitumor immune microenvironment could be stimulated by HPV infection in advanced PSCC tissues.

Fluorescence-guided surgery using cetuximab-800CW in patients with penile carcinoma.

OBJECTIVE: To investigate the feasibility of fluorescence molecular imaging (FMI), using cetuximab-800CW, as an intraoperative tool to determine surgical margins in penile squamous cell carcinoma (PSCC). PATIENTS AND METHODS: A total of 11 patients with PSCC received 75 mg cetuximab followed by 15 mg cetuximab-800CW 2 days before surgery. FMI of the whole excision specimen and tissue slices was performed. Fluorescence visualisation was correlated to histopathology. Based on tumour and healthy tissue regions of interest, mean fluorescence intensity was calculated for each individual patient. RESULTS: Significant differences between tumour and healthy mean fluorescence intensity were found with tumour-to-background ratios of a median (IQR) of 1.51 (0.99) and a mean (SD) of 1.51 (0.32) in the excision specimen and tissue slices, respectively. One patient showed a high relative fluorescence intensity with a signal-to-background ratio of 1.79, corresponding to a tumour-positive margin on fresh frozen sectioning. CONCLUSION: In this Phase I study we showed that cetuximab-800CW seems suitable to discriminate PSCC from background tissue. The tracer was well tolerated, and no false positive spots were seen.

Diagnostically Challenging Multifocal Penile Epithelioid Hemangioma Successfully Treated With Doxorubicin Hydrochloride.

ABSTRACT: Epithelioid hemangioma (EH), also known as angiolymphoid hyperplasia with eosinophilia, is an unusual vascular proliferation that tends to manifest in the head and neck region. Its occurrence on the penis is rare, with only scarce reported cases in the literature. The histopathological examination of this condition poses a challenge because it shares similarities with other entities, such as epithelioid hemangioendothelioma, epithelioid angiosarcoma, cutaneous epithelioid angiomatous nodule, or Kaposi sarcoma (KS). The infrequency of EH in penile locations underscores the need for accurate diagnostic differentiation and tailored treatment strategies for this atypical presentation. This case report highlights a rare instance of multifocal penile EH. The patient's lesions exhibited distinctive histopathologic features, with extensive eosinophilic infiltration, presence of necrosis, and infiltration to subcutaneous fat. The patient was treated with doxorubicin, a chemotherapy drug, with a very good response. This successful therapeutic outcome underscores the potential efficacy of doxorubicin in the management of multifocal penile EH. The comprehensive analysis of this case contributes to our understanding of the clinical presentation, histopathologic features, and treatment modalities for this rare penile tumor, providing valuable insights for future clinical considerations.

New Therapeutic Horizons for Advanced or Metastatic Penile Cancer.

Penile cancer is a rare malignancy with a poor prognosis. Studies with single-agent immune checkpoint inhibitors (ICIs) have demonstrated efficacy, but response rates are low. Studies combining ICIs with both chemotherapy and targeted therapy are ongoing. Up to 50% of penile cancer cases are associated with human papillomavirus (HPV). HPV-targeting therapies, such as HPV-targeting vaccines and T-cell receptor therapies, are an area of active investigation. Penile cancer cells also express cell surface antigens that may be targeted by the emerging class of antibody-drug conjugates.

Clinical Profile and Outcomes of Carcinoma Penis Patients Receiving Systemic Therapy at an Indian tertiary care Center: A Retrospective Observational Study.

BACKGROUND: Penile cancer is a rare malignancy with scant data on the impact of systemic therapy on outcomes. METHODS: Retrospective observational study of patients with a histological diagnosis of carcinoma penis treated with systemic therapy at the Tata Memorial Centre (Mumbai, India) between August 2010 and February 2018. Primary objective was overall survival (OS); secondary objectives included assessment of clinical characteristics, treatment approaches, and toxicity profiles. RESULTS: We included 91 patients with penile carcinoma who received systemic therapy at our center. Intent of therapy was curative in 71 patients (78%), and palliative in 20 (22%). Median age was 57 years (interquartile range [IQR], 50-65.5) for curatively treated patients and 58.5 years (IQR, 44-65.2) for those with advanced disease. Common presenting symptoms were lumps (70%), and pain (57%). Neoadjuvant chemotherapy (NACT) with paclitaxel + platinum was administered to 19 patients (20.9%), of which 7 (37%) attained complete or partial response. Six patients (31.5%) underwent R0 surgery post-NACT. All 71 patients underwent primary surgery; 47 (66.2%) undergoing partial penectomy. Of the 20 patients treated with palliative first-line chemotherapy, 4(20%) attained a partial response. Median OS of patients treated in curative and palliative settings was 33.8 months (95% CI, 17.2-not recorded) and 11.4 months (95% CI, 9.53-23.3), respectively. CONCLUSIONS: Patients with penile cancer treated with systemic therapy have poor outcomes. Little over a third of the patients respond to neoadjuvant chemotherapy and those with advanced disease have poor survival despite systemic therapy, emphasizing the need for early detection and optimum management of primary and nodal disease.

Trajectories of squamous cell carcinoma antigen and outcomes of patients with advanced penile cancer after chemotherapy based on paclitaxel, ifosfamid, and cisplatin regimen.

INTRODUCTION: Penile cancer (PC) is a lethal malignancy with no effective prognostic biomarker. We aim to investigate associations between trajectories of squamous cell carcinoma antigen (SCC-A) and patient outcomes after chemotherapy based on paclitaxel, ifosfamid, and cisplatin (TIP) regimen. METHODS: Consecutive AJCC staging III/IV PC patients who received TIP chemotherapy and repeated SCC-A measurements in 2014-2022 were analyzed. Latent class growth mixed (LCGM) models were employed to characterize patients' serum SCC-A trajectories. Patient survival, and clinical and pathological tumor responses were compared. Inverse probability treatment weighting was used to adjust confounding factors. RESULTS: Eighty patients were included. LCGM models identified two distinct trajectories of SCC-A: low-stable (40%; n = 32) and high-decline (60%; n = 48). Overall survival (HR [95% CI]: 3.60 [1.23-10.53], p = 0.019), progression-free survival (HR [95% CI]: 11.33 [3.19-40.3], p < 0.001), objective response rate (37.5% vs. 62.5% p = 0.028), disease control rate (60.4% vs. 96.9% p < 0.00), and pathological complete response rate (21.2% vs. 51.9%, p = 0.014) were significantly worse in the high-decline arm. CONCLUSION: PC patients' SCC-A change rate was associated with tumor response and patient survival after TIP chemotherapy. SCC-A might assist tumor monitoring after systemic therapies.

Insights into the management of penile squamous cell carcinoma: from conventional approaches to emerging novel therapies.

INTRODUCTION: Penile squamous cell carcinoma (PSCC), a rare genitourinary cancer, is associated with poor outcomes due to limited treatment effectiveness, especially in advanced stages. AREAS COVERED: While chemotherapy and/or surgery remain the standard of care, emerging therapies like immunotherapy, targeted therapy, and human papillomavirus (HPV) directed therapies show promise. Key to advancing treatment is understanding the immune microenvironment to gain insights into tumor resistance mechanisms and potential therapeutic targets. The scarcity of data on PSCC is a major obstacle in advancing research for this rare cancer. EXPERT OPINION: Future research should prioritize collaborative efforts across various research centers and countries. Enhancing data sharing and pooling resources can lead to a more comprehensive understanding of PSCC, ultimately supporting the development of precision medicine strategies tailored to this specific cancer type. This collaborative approach is essential for making significant strides in PSCC treatment and care.

Neoadjuvant platinum-based chemotherapy and lymphadenectomy for penile cancer: an international, multi-institutional, real-world study.

INTRODUCTION: This study investigated the efficacy and safety of neoadjuvant chemotherapy for locally advance penile squamous cell carcinoma for which current evidence is lacking. METHODS: Included patients had locally advanced penile squamous cell carcinoma with clinical lymph node metastasis treated with at least 1 dose of neoadjuvant chemotherapy prior to planned consolidative lymphadenectomy. Objective response rates were assessed using Response Evaluation Criteria in Solid Tumors v1.1. The primary and secondary outcomes were overall survival and progression-free survival, estimated by the Kaplan-Meier method. Treatment-related adverse events were graded per the Common Terminology Criteria for Adverse Events v5.0. RESULTS: A total of 209 patients received neoadjuvant chemotherapy for locally advanced and clinically node-positive penile squamous cell carcinoma. The study population consisted of 7% of patients with stage II disease, 48% with stage III, and 45% with stage IV. Grade 2 treatment-related adverse events occurred in 35 (17%) patients, and no treatment-related mortality was observed. Of the patients, 201 (97%) completed planned consolidative lymphadenectomy. During follow-up, 106 (52.7%) patients expired, with a median overall survival of 37.0 months (95% confidence interval [CI] = 23.8 to 50.1 months) and median progression-free survival of 26.0 months (95% CI = 11.7 to 40.2 months). Objective response rate was 57.2%, with 87 (43.2%) having partial response and 28 (13.9%) having a complete response. Patients with objective response to neoadjuvant chemotherapy had a longer median overall survival (73.0 vs 17.0 months, P < .01) compared with those who did not. The lymph node pathologic complete response rate was 24.8% in the cohort. CONCLUSION: Neoadjuvant chemotherapy with lymphadenectomy for locally advanced penile squamous cell carcinoma is well tolerated and active to reduce the disease burden and improve long-term survival outcomes.

Erythroplasia of Queyrat treated with topical 5-fluorouracil

Abstract We report a 33-year-old male patient diagnosed with erythroplasia of Queyrat. The patient had an erythematous and eroded lesion affecting more than 50% of the glans associated with bleeding and local pain. Despite previous indication of penectomy, he was successfully treated with topical 5-fluorouracil.

Neoplasias genitales intraepiteliales: a propósito de dos pacientes inmunosuprimidos / Penile intraepithelial neoplasia: two case report

Las neoplasias genitales intraepiteliales constituyen lesiones que afectan a todo el espesor de la epidermis e incluyen entidades específicas, como la eritroplasia de Queyrat, la enfermedad de Bowen y papulosis bowenoide. Actualmente se describe aumento de la frecuencia de neoplasias intraepiteliales, pero la real incidencia de los carcinomas in situ genitales es desconocida. Se describen factores predisponentes, tanto para las neoplasias in situ como para los carcinomas invasores, dentro de los que se encuentran los pacientes no circuncidados, deficiente higiene genital, balanitis recurrente, liquen escleroso, fimosis, inmunosupresión, infección por virus papiloma humano, etc. Existen distintas terapias descritas para estas lesiones; sin embargo, aún no hay consenso en su manejo. Las opciones de tratamiento dependen de la localización, de la extensión de la enfermedad, costo de la terapia, etc. En general se ha descrito recidiva de las lesiones, con todos los tratamientos mencionados; no obstante, la cirugía micrográfica de Mohs es considerada por algunos autores la terapia de elección en estos casos. En este artículo se presentan dos casos de neoplasias genitales intraepiteliales tratadas con Imiquimod 5 por ciento y 5-Fluoracilo con buenos resultados.

The intraepithelial neoplasias of genitals are lesions that affect all the thickness of the epidermis and include specific carcinomas such as erythroplasia of Queyrat, Bowen’s disease and bowenoid papulosis. Presently, there is an increase in the frequency of intraepithelial neoplasias, but the real incidence of in situ genital carcinoma is unknown. Many predisposing factors are described for both in situ and invasive carcinomas, for example, the lack of circumcision, poor genital hygiene, recurrent balanitis, penile lichen sclerosus, phimosis, immune suppression, HPV infections, etc. Different therapies are described for these illnesses, but there is no uniform guideline assessment. Treatment depends on location, extension of the illness, cost of the therapy, etc. In general, recurrence of carcinomas has been described with all treatments, although Mohs micrographic surgery is considered by some authors as the therapy of choice in these cases. We present two cases of intraepithelial neoplasias of genitals that were treated with Imiquimod 5 percent and 5-Fluoracilo with positive results.

Linfadenectomia inguinal radical versus modificada no tratamento do câncer de pênis / Radical linphadenectomy versus modified in the treatment of the penis carcinoma

Foram comparadas a morbidade e a mortalidade da linfadenectomia radical e modificada no tratamento do carcinoma de pênis; correlacionar o tamanho inicial da lesão e o produto da linfadenectomia (linfonodos com invasão tumoral) com o prognóstico da doença. Entre 1995 e 2000, 34 portadores de câncer de pênis, matriculados no Hospital de Câncer do Pernambuco, foram submetidos à linfadenectomia. As seguintes variáveis foram analisadas: idade, raça, estadiamento, incidência de fimose, tipo histológico, tamanho do tumor, tratamento cirúrgico e média de linfonodos ressecados. O diagnóstico de câncer nestes pacientes foi realizado através de anamnese, exame físico e biópsia. A linfadenectomia bilateral realizada, após tratamento com antibioticoterapia por 4 semanas foi feita de maneira aleatória: 10 pacientes foram submetidos à linfadenectomia radical (7 deles no Estágio II 70% e 3 no Estágio III 30%) e 24, à linfadenectomia modificada (11 deles no Estágio II 45,8% e 13 no Estágio III 54,2%). A idade dos pacientes variou de 33 a 85 anos com média de 54.1 ± 13.0 anos. Seguimento de 7 a 286 semanas, média 146,5 mediana 135,5 (p=0,0023) Na linfadenectomia radical foram ressecados, em média, quatro linfonodos com menos de 5cm e 6 com mais de 5cm e na linfadenectomia modificada 15 linfonodos com menos de 5cm e 9 com mais de 5cm. O percentual de positividade para neoplasia nos linfonodos ressecados foi de 44% nos pacientes com estágio II e de 62% nos pacientes com estágio III. As complicações apresentadas em relação às técnicas cirúrgicas empreendidas foram semelhantes (linfedema e necrose das bordas. Os índices de progressão da doença foram maiores, tanto quanto maior foi o número de linfonodos acometidos

Neoadjuvant chemotherapy interferon for epidermoid penile cancer: a case report

Antecedentes. El carcinoma avanzado de pene es un tumor con un pronóstico malo con el tratamiento estándar por lo que la quimioterapia neoadyuvante se ha estado evaluando para mejorar la preservación del órgano y la supervivencia. Caso clínico. Paciente de 56 años visto en el Instituto Nacional de Cancerología en noviembre de 1993 siendo diagnosticado de cáncer de pene T3 N3 MO. El tratamiento consistió en cisplatino 100 mg/m2 cada 21 días por cinco ciclos alternados con metotrexato intravenoso a dosis de 250 mg/m2 más rescate con leucovorín oral a dosis de 10 mg/m2 cada ocho horas por seis dosis. El metotrexato y leucovorín se administraron cada 15 días en siete ocasiones. Además recibió interferón-alfa 4.5 x 10 6 U por vía subcutánea cada tercer día durante las 12 semanas del tratamiento. Resultados. El tratamiento fue bien tolerado alcanzando una respuesta clínica del 70 por ciento en el tumor primario y completa en los ganglios inguinales. Fue sometido a penectomía radical en abril de 1994 y actualmente está libre de enfermedad a los 61 meses de seguimiento. Conclusiones. Esta modalidad de quimioinmunoterapia parece ser muy activa en el cáncer de pene y debería evaluarse en un número mayor de pacientes con el fin de preservar el órgano e incrementar la supervivencia

Cáncer de Pene. Tratamiento en el INOR / Penis cancer. Treatment at the National Institute of Oncology and Radiobiology

Se informan los resultados de tratamientos no quirurgicos realizados en 19 pacientes portadores de cáncer de pene. El tratamiento consistió básicamente en radiaciones, quimioterapia o ambas. Hubo respuesta completa en 18 enfermos y cinco presentaron recaída: 3 al año, 1 a los 5 años y 1 en 3 meses. Un solo paciente con recaída local no fue susceptible al tratamiento y falleció por enfermedad incrontrolable. Se recomiendan estas alternativas al tratamiento quirúrgico (amputación del pene con linfadenectomía inguinal bilateral) como método de control de la enfermedad y conservación del órgano

Câncer de pênis, incidência e avaliação das diversas formas de tratamento: estudo retrospectivo com 455 pacientes no Instituto Nacional de Câncer

O estudo visou dar contribuição para ajudar na resolução das diversas controvérsias que existem na abordagem terapêutica do câncer de pênis. Os prontuários de 455 pacientes portadores de carcinoma de pênis, matriculados no Instituto Nacional de Câncer entre 1960 e 1987, foram examinados. Houve uma preponderância de pacientes da raça branca(68 por cento)provenientes principalmente da região sudeste do país.A idade média dos pacientes foi de 56 anos e 93,7(por cento)deles apresentavam fimose. O carcinoma epidermóide invasivo foi o tipo histológico mais encontrado (91 por cento) seguido do carcinoma verrucoso (7,5 por cento)e do carcinoma "in situ" (1,5 por cento). Nos 31 pacientes com carcinoma epidérmóide invasivo submetidos a biópsia de linfonodos inguinais, a falha de detecção de metástase foi de 67 (por cento). O percentual de incidência de necrose de retalho, após a linfadectomia, foi de 5 (por cento) nas 85 abordagens nas quais a incisão de Gibson foi utilizada. Metástase inguinais estavam presentes em 39 (por cento) dos 23 pacientes portadores de carcinoma epidermóide invasivo estadiados como NO, em 49 (por cento) dos 92 pacientes estadiados como N1 e N2 e 100 (por cento) dos 18 estadiados como N3. Os testes estatísticos revelaram melhor prognóstico, quanto a sobrevivência em cinco anos, para os pacientes submetidos a linfadectomia concomitante a cirurgia peniana quando comparados aos submetidos a linfadectomia tardia (p 0,001). Pacientes com linfadectomia aprecoce negativa tiveram melhor prognóstico do que aqueles com linfadectomia precoce positiva (p 0,001). Estes últimos apresentaram melhor prognóstico quando comparados com aqueles com linfadectomia tardia positiva (p=0,0103). Pacientes portadores de carcinoma bem e moderadamente diferenciados apresentaram percentual de sobrevida em cinco anos mais alto do que os portadores de carcinoma pouco diferenciado (p0,001 e p=0,003). Todos os óbitos por doença metástica ocorreram em 24 meses nos pacientes submetidos à linfadectomia e até cinco anos após a cirurgia peniana simples. O debridamento cirúrgico aliado a técnicas de reconstrução promoveu, a curto prazo, melhoria nas condições de vida dos pacientes com doença lo-regional avançada. A radioterapia exclusiva aplicada em 13 pacientes com lesões penianas falhou por não controlar a doença em 76% dos casos. A radioterapia terapêutica foi efetiva em um entre 16 pacientes tratados. Duas remissões totais e sete parciais ocorreram com a quimioterapia sistêmica porém não houve correlação entre resposta clínica objetiva e sobrevida, obtendo-se melhores resultados nos pacientes portadores de carcinoma epidermóide bem diferenciado. A cirurgia peniana simples foi efetiva no tratamento dos pacientes com carcinoma verrucoso. O tratamento quimioterápico sistêmico permitiu cirurgias mais limitadas em quatro dos seis pacientes portadores de carcinoma verrucoso. A cirurgia peniana simples, a radioterapia exclusiva e a quimioterapia tópica com 5- fluorouracil foram efetivas no tratamento dos cinco pacientes portadores de carcinoma "in situ", porém o melhor resultado estético foi obtido com a quimioterapia tópica.

This study aims towards contributing for the resolution of several controversies that exist in the therapeutic approach to penile cancer. During the period 1960-1987, 455 patients with penile carcinoma, referred to Instituto Nacional de Câncer, were investigated. There was a majority of white patients (68%) derived mainly from the Southeast of the country. The mean age of the patients was of 56 years and 93.7% of them presented phimosis. The invasive squamous cell carcinoma was the most frequently found (91%) followed by the verrucous carcinoma (7.5%) and by the carcinoma "in situ" (1.5%). Of the 31 patients with invasive squamous cell carcinoma submitted to the biopsy of inguinal lymphnodes the failure in detecting metastases was of 67%. The percentual of incidence of flap necrosis after lymphadenectomy was of 5% in the 85 approaches in which the Gibson incision was used. Inguinal metastases were present in 39% of the 23 patients with invasive squamous cell carcinoma staged as N0, in 49% of the 92 patients staged as N1 and 100% of the 18 staged as N3. The statistics revealed a better prognosis, as related to a five year survival, to the patients submitted to lymphadenectomy concomitantly to penile surgery when compared to those submitted to late lymphadenectomy (p<0,00l). Patients with precocious negative lymphadenectomy had better prognosis than those with precocious positive lymphadenectomy (p<0.001). These last ones presented a better prognosis when compared to those with late positive lymphadenectomy (p=0.0103). Patients with well and moderately differentiated carcinoma presented a higher survival percentual in five years than those with poorly differentiated carcinoma (p<0.001 and p=0.003). All deaths due to metastatic disease occurred within 24 months in the patients submitted to lymphadenectomy and up to five years after simple penile surgery. The surgical debulking linked to reconstructive techniques allowed, at short term, an improval in the conditions of life of the patients with local-regional disease. The exclusive radiotherapy applied to 13 patients with penile lesions failed in not controlling the disease in 76% of the cases. The therapeutic radiotherapy was effective in one among 16 patients treated. Two total and seven partial remissons occurred with systemic chemotherapy but there was no correlation between the objetive clinical reponse and survival, better results being obtained in the patients with well differentiated squamous cell carcinoma. The simple penile surgery was effective in the treatment of patients with verrucous carcinoma. The systemic chemotherapic treatment allowed more limited surgeries in four out of six patients with verrucous carcinoma. The simple penile surgery, the exclusive radiotherapy, and the topical chemotherapy with 5-fluorouracil were effective in the treatment of five patients with carcinoma “in situ”, but the best aesthetic result was obtained with topical chemotherapy.