Soft tissue tumours of the penis. The 30-year Istituto Nazionale Tumori di Milano experience.

Objective: Small series and individual cases of penile soft tissue tumours are reported in the literature: these are rare tumours that represent less than 5% of all penile tumours. Methods: Penile soft tissue tumours were collected from the archive of the Department of Pathology at the Istituto Nazionale dei Tumori of Milan between January 1990 and October 2021. All available medical records were retrieved and reviewed to obtain clinical information. Results: Our series refers to the 30-year experience of highlighting the heterogeneity in the presentation and microscopic features of these rare sarcomas. 18 penile soft tissue tumours are described, 4 benign and 14 malignant. The mean age at diagnosis was 58.2 years (range 24-96 years) and 53.6 years among malignancies (range 24-89). The most frequent histotype was Kaposi's sarcoma (nr = 4) and very unusual histotypes were observed, namely low-grade fibromyxoid sarcoma, synovial sarcoma, proximal type epithelioid sarcoma and the first reported case of dedifferentiated liposarcoma of the penis. Conclusions: Among sarcomas of the genitourinary tract, tumours of the soft tissues of the penis are the rarest. Penile sarcomas can present at a young age. Kaposi's sarcoma in HIV-negative patients has a favorable outcome, while deep sarcomas have an aggressive behavior and poor prognosis.

External validation of the computerized analysis of TRUS of the prostate with the ANNA/C-TRUS system: a potential role of artificial intelligence for improving prostate cancer detection.

PURPOSE: Prostate cancer (PCa) imaging has been revolutionized by the introduction of multi-parametric Magnetic Resonance Imaging (mpMRI). Transrectal ultrasound (TRUS) has always been considered a low-performance modality. To overcome this, a computerized artificial neural network analysis (ANNA/C-TRUS) of the TRUS based on an artificial intelligence (AI) analysis has been proposed. Our aim was to evaluate the diagnostic performance of the ANNA/C-TRUS system and its ability to improve conventional TRUS in PCa diagnosis. METHODS: We retrospectively analyzed data from 64 patients with PCa and scheduled for radical prostatectomy who underwent TRUS followed by ANNA/C-TRUS analysis before the procedure. The results of ANNA/C-TRUS analysis with whole mount sections from final pathology. RESULTS: On a per-sectors analysis, sensitivity, specificity, negative predictive value (NPV), positive predictive value (PPV) and accuracy were 62%, 81%, 80%, 64% and 78% respectively. The values for the detection of clinically significant prostate cancer were 69%, 77%, 88%, 50% and 75%. The diagnostic values for high grade tumours were 70%, 74%, 91%, 41% and 74%, respectively. Cancer volume (≤ 0.5 or greater) did not influence the diagnostic performance of the ANNA/C-TRUS system. CONCLUSIONS: ANNA/C-TRUS represents a promising diagnostic tool and application of AI for PCa diagnosis. It improves the ability of conventional TRUS to diagnose prostate cancer, preserving its simplicity and availability. Since it is an AI system, it does not hold the inter-observer variability nor a learning curve. Multicenter biopsy-based studies with the inclusion of an adequate number of patients are needed to confirm these results.

Minimally invasive retroperitoneal lymph node dissection for men with testis cancer: a retrospective cohort study of safety and feasibility.

PURPOSE: To describe the perioperative safety, functional and immediate post-operative oncological outcomes of minimally invasive RPLND (miRPLND) for testis cancer. METHODS: We performed a retrospective multi-centre cohort study on testis cancer patients treated with miRPLND from 16 institutions in eight countries. We measured clinician-reported outcomes stratified by indication. We performed logistic regression to identify predictors for maintained postoperative ejaculatory function. RESULTS: Data for 457 men undergoing miRPLND were studied. miRPLND comprised laparoscopic (n = 56) or robotic (n = 401) miRPLND. Indications included pre-chemotherapy in 305 and post-chemotherapy in 152 men. The median retroperitoneal mass size was 32 mm and operative time 270 min. Intraoperative complications occurred in 20 (4%) and postoperative complications in 26 (6%). In multivariable regression, nerve sparing, and template resection improved ejaculatory function significantly (template vs bilateral resection [odds ratio (OR) 19.4, 95% confidence interval (CI) 6.5-75.6], nerve sparing vs non-nerve sparing [OR 5.9, 95% CI 2.3-16.1]). In 91 men treated with primary RPLND, nerve sparing and template resection, normal postoperative ejaculation was reported in 96%. During a median follow-up of 33 months, relapse was detected in 39 (9%) of which one with port site (< 1%), one with peritoneal recurrence and 10 (2%) with retroperitoneum recurrences. CONCLUSION: The low proportion of complications or peritoneal recurrences and high proportion of men with normal postoperative ejaculatory function supports further miRPLND studies.

A prospective prostate cancer screening programme for men with pathogenic variants in mismatch repair genes (IMPACT): initial results from an international prospective study.

BACKGROUND: Lynch syndrome is a rare familial cancer syndrome caused by pathogenic variants in the mismatch repair genes MLH1, MSH2, MSH6, or PMS2, that cause predisposition to various cancers, predominantly colorectal and endometrial cancer. Data are emerging that pathogenic variants in mismatch repair genes increase the risk of early-onset aggressive prostate cancer. The IMPACT study is prospectively assessing prostate-specific antigen (PSA) screening in men with germline mismatch repair pathogenic variants. Here, we report the usefulness of PSA screening, prostate cancer incidence, and tumour characteristics after the first screening round in men with and without these germline pathogenic variants. METHODS: The IMPACT study is an international, prospective study. Men aged 40-69 years without a previous prostate cancer diagnosis and with a known germline pathogenic variant in the MLH1, MSH2, or MSH6 gene, and age-matched male controls who tested negative for a familial pathogenic variant in these genes were recruited from 34 genetic and urology clinics in eight countries, and underwent a baseline PSA screening. Men who had a PSA level higher than 3·0 ng/mL were offered a transrectal, ultrasound-guided, prostate biopsy and a histopathological analysis was done. All participants are undergoing a minimum of 5 years' annual screening. The primary endpoint was to determine the incidence, stage, and pathology of screening-detected prostate cancer in carriers of pathogenic variants compared with non-carrier controls. We used Fisher's exact test to compare the number of cases, cancer incidence, and positive predictive values of the PSA cutoff and biopsy between carriers and non-carriers and the differences between disease types (ie, cancer vs no cancer, clinically significant cancer vs no cancer). We assessed screening outcomes and tumour characteristics by pathogenic variant status. Here we present results from the first round of PSA screening in the IMPACT study. This study is registered with ClinicalTrials.gov, NCT00261456, and is now closed to accrual. FINDINGS: Between Sept 28, 2012, and March 1, 2020, 828 men were recruited (644 carriers of mismatch repair pathogenic variants [204 carriers of MLH1, 305 carriers of MSH2, and 135 carriers of MSH6] and 184 non-carrier controls [65 non-carriers of MLH1, 76 non-carriers of MSH2, and 43 non-carriers of MSH6]), and in order to boost the sample size for the non-carrier control groups, we randomly selected 134 non-carriers from the BRCA1 and BRCA2 cohort of the IMPACT study, who were included in all three non-carrier cohorts. Men were predominantly of European ancestry (899 [93%] of 953 with available data), with a mean age of 52·8 years (SD 8·3). Within the first screening round, 56 (6%) men had a PSA concentration of more than 3·0 ng/mL and 35 (4%) biopsies were done. The overall incidence of prostate cancer was 1·9% (18 of 962; 95% CI 1·1-2·9). The incidence among MSH2 carriers was 4·3% (13 of 305; 95% CI 2·3-7·2), MSH2 non-carrier controls was 0·5% (one of 210; 0·0-2·6), MSH6 carriers was 3·0% (four of 135; 0·8-7·4), and none were detected among the MLH1 carriers, MLH1 non-carrier controls, and MSH6 non-carrier controls. Prostate cancer incidence, using a PSA threshold of higher than 3·0 ng/mL, was higher in MSH2 carriers than in MSH2 non-carrier controls (4·3% vs 0·5%; p=0·011) and MSH6 carriers than MSH6 non-carrier controls (3·0% vs 0%; p=0·034). The overall positive predictive value of biopsy using a PSA threshold of 3·0 ng/mL was 51·4% (95% CI 34·0-68·6), and the overall positive predictive value of a PSA threshold of 3·0 ng/mL was 32·1% (20·3-46·0). INTERPRETATION: After the first screening round, carriers of MSH2 and MSH6 pathogenic variants had a higher incidence of prostate cancer compared with age-matched non-carrier controls. These findings support the use of targeted PSA screening in these men to identify those with clinically significant prostate cancer. Further annual screening rounds will need to confirm these findings. FUNDING: Cancer Research UK, The Ronald and Rita McAulay Foundation, the National Institute for Health Research support to Biomedical Research Centres (The Institute of Cancer Research and Royal Marsden NHS Foundation Trust; Oxford; Manchester and the Cambridge Clinical Research Centre), Mr and Mrs Jack Baker, the Cancer Council of Tasmania, Cancer Australia, Prostate Cancer Foundation of Australia, Cancer Council of Victoria, Cancer Council of South Australia, the Victorian Cancer Agency, Cancer Australia, Prostate Cancer Foundation of Australia, Asociación Española Contra el Cáncer (AECC), the Instituto de Salud Carlos III, Fondo Europeo de Desarrollo Regional (FEDER), the Institut Català de la Salut, Autonomous Government of Catalonia, Fundação para a Ciência e a Tecnologia, National Institutes of Health National Cancer Institute, Swedish Cancer Society, General Hospital in Malmö Foundation for Combating Cancer.

Clinical Outcomes in Clinical N0 Squamous Cell Carcinoma of the Penis According to Nodal Management: Early, Delayed or Selective (following Dynamic Sentinel Node Biopsy) Inguinal Lymph-Node Dissection.

PURPOSE: We evaluated the oncologic efficacy of early inguinal lymph-node dissection, observation or dynamic sentinel node biopsy followed by delayed or selective inguinal lymph-node dissection in cN0 patients with penile squamous cell carcinoma. MATERIALS AND METHODS: Between 1980 and 2017 (inclusive), 296 evaluable consecutive cN0 penile squamous cell carcinoma patients underwent early inguinal lymph-node dissection (16), observation (114) or dynamic sentinel node biopsy (166). Median followup was 50 months. Tumor stage, grade, lympho-vascular invasion and age were considered. Kaplan-Meier plots illustrated 5-year inguinal relapse-free and cancer specific survival rates. Multivariable Cox regression models tested the treatment effect. Analyses were repeated after inverse probability of treatment weighting adjustment. RESULTS: The 5-year inguinal relapse-free survival and cancer specific survival rates following early, observation and dynamic sentinel node biopsy inguinal lymph-node dissection were 100%, 87%, 89%, and 84%, 81%, 85%, respectively. The 5-year crude inguinal relapse-free survival and cancer specific survival rates were 90% and 93% in low-risk patients undergoing observation. Clavien grade 3 complications were 0.6 vs 12.5% in the dynamic sentinel node biopsy and early inguinal lymph-node dissection group, respectively. After inverse probability after treatment weighting adjustment, 5-year inguinal relapse and cancer specific survival were 90% vs 73% and 90% vs 77% following dynamic sentinel node biopsy and observation, respectively. At multivariable Cox regression model, patients undergoing dynamic sentinel node biopsy had significantly lower inguinal relapse (HR 0.4, 95% CI 0.2-0.85, p 0.02) and cancer specific mortality (HR 0.29, 95% CI 0.11-0.77; p=0.01) compared to those under observation. The low number of patients undergoing early inguinal lymph-node dissection made a reliable comparison with this group impractical. CONCLUSIONS: Selective inguinal lymph-node dissection following dynamic sentinel node biopsy significantly improved inguinal relapse and cancer specific mortality when compared with observation, providing evidence of efficacy of dynamic sentinel node biopsy in clinical stage N0 squamous cell carcinoma of the penis.

How to implement the requirements of a quality assurance system for prostate cancer.

PURPOSE: In 2003, the German Cancer Society (Deutsche Krebsgesellschaft, DKG) launched a certification program aimed at improving the quality of cancer care. The purpose of this article is to describe the experience of the Prostate Cancer Unit (PCU) at Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, in the process towards DKG certification. METHODS: In 2018, PCU decided to apply for certification by adopting DKG catalogue of requirements (CoR) and quality indicators. A multiprofessional working group was established with the aim of acting the necessary steps to meet DKG standards. RESULTS: Our organizational setting (procedures, personnel) and activities were accurately analyzed, thus outlining strengths and weaknesses, and modified to comply with DKG CoR and indicators. As examples, (1) a quality management plan was developed; (2) measures were taken to strengthen the surgical expertise; (3) cases evaluated in weekly tumor boards were expanded to include surgical cases with pathological risk factors, metastatic, relapsed and castration-resistant patients; (4) a survey was added to the patient-dedicated initiatives already scheduled; (5) the TuDoc software became the tool to register all new cases of prostate cancer patients referred to PCU. CONCLUSIONS: The process of certification requires many efforts but represents a unique opportunity of improving quality of care of prostate cancer patients, making it comparable on an international scale.

Laparoscopic Retroperitoneal Lymph Node Dissection for Clinical Stage I Nonseminomatous Germ Cell Tumors of the Testis: Safety and Efficacy Analyses at a High Volume Center.

PURPOSE: The prognosis of stage I nonseminomatous germ cell tumor of the testis is favorable. Early and late side effects of treatment may affect quality of life and survival. We determined the tolerability, safety and efficacy of laparoscopic retroperitoneal lymph node dissection in patients with stage I nonseminomatous germ cell tumor of the testis at a high volume center. MATERIALS AND METHODS: Unilateral laparoscopic retroperitoneal lymph node dissection was prospectively recorded in 225 patients from 2000 to 2014. Since 2007, patients have been treated at a multidisciplinary clinic and were proposed surgery as an alternative to surveillance or adjuvant chemotherapy. The indication for adjuvant chemotherapy changed during the study period. Descriptive statistics and regression analyses were used to evaluate the domains of safety and oncologic outcomes. RESULTS: A total of 221 patients were evaluable. Median operative time was 200 minutes. Conversion to open surgery was done in 20 cases (9%). A median of 14 nodes (IQR 11-20) was retrieved. Grade greater than 2 complications in 8 cases (3.6%) increased as the number of retrieved nodes increased. Antegrade ejaculation was maintained in 98.6% of patients. Nodal metastases were found in 29 patients (13%), of whom 7 underwent adjuvant chemotherapy. There were 14 recurrences (6.3%), including 8 of 192 (4.2%) associated with no nodal metastases and 6 of 22 (27.3%) associated with nodal metastases in patients not undergoing adjuvant chemotherapy. At regression analyses lymph node ratio was the only significant factor predictive of recurrence and of the administration of any chemotherapy (each p <0.001). Operative time, the number of retrieved nodes and conversions improved with time. CONCLUSIONS: In the context of a high volume center laparoscopic retroperitoneal lymph node dissection was safe and its oncologic efficacy was comparable to that of open surgery. Select patients with stage I nonseminomatous germ cell tumor could be offered laparoscopic retroperitoneal lymph node dissection as an alternative to other options.

First-line therapy with dacomitinib, an orally available pan-HER tyrosine kinase inhibitor, for locally advanced or metastatic penile squamous cell carcinoma: results of an open-label, single-arm, single-centre, phase 2 study.

OBJECTIVE: To harness the frontline therapy in advanced penile squamous cell carcinoma (PSCC), for which chemotherapy exerts moderate activity but poor efficacy. Dacomitinib is an irreversible, pan-epidermal growth factor receptor (HER) inhibitor. PATIENTS AND METHODS: In a phase 2 study (NCT01728233), patients received dacomitinib 45 mg/day, orally, continuously. Inclusion criteria were SCC histology, clinical stage N2-3 or M1 (Tumour-Node-Metastasis classification system 2009), and no prior chemotherapy administration. The primary endpoint was the objective response rate (ORR, according to the Response Evaluation Criteria in Solid Tumors, version 1.1). Stopping rules based on the Bayesian posterior probability (PP) to demonstrate that the ORR exceeded 20% were set. RESULTS: From June 2013 to October 2016, 28 patients were treated. Eight (28.6%) had visceral metastases, 14 (50%) had pelvic and 17 (60.7%) clinically involved bilateral lymph nodes. One complete and eight partial responses were obtained (ORR 32.1%, 80% credibility interval 21.0-43.0%). The median (interquartile range [IQR]) follow-up duration was 19.8 (6.3-25.7) months; 12-month progression-free survival was 26.2% (95% confidence interval [CI] 13.2-51.9); 12-month overall survival (OS) was 54.9% (95% CI 36.4-82.8). The median (IQR) OS of locally advanced patients was 20 (11.1-not reached) months. The Bayesian PP of exceeding the 20% ORR target was 92.3%. Grade 3 adverse events (skin rash) were seen in three patients (10.7%). Tissue samples from 25 patients were analysed. Only two patients had high-risk human papillomavirus-positive tumours. Epidermal growth factor receptor (EGFR) amplification was found in four patients (equally responders and non-responders) and it was confirmed in all post-dacomitinib samples. Telomerase reverse transcriptase (TERT) mutations were found in responders only (60%), and phosphatidylinositol 3-kinase/mammalian target of rapamycin (PI3K/mTOR) pathway gene mutations were found in 42.9% of responders vs 8.3% of non-responders. CONCLUSION: Dacomitinib was active and well tolerated in patients with advanced PSCC and may represent an option when combined chemotherapy cannot be administered. Mutations in downstream effectors of EGFR signalling in relation to dacomitinib activity deserve further studies.

Treatment and Clinical Outcomes of Patients with Teratoma with Somatic-Type Malignant Transformation: An International Collaboration.

PURPOSE: We assessed prognostic factors, treatments and outcomes in patients with teratoma with malignant transformation, a rare occurrence among germ cell tumors. MATERIALS AND METHODS: Data on patients diagnosed with teratoma with malignant transformation between June 1981 and August 2014 were collected across 5 referral centers. Chemotherapy was dichotomized as based on germ cell tumor or teratoma with malignant transformation. Cox analyses were done to evaluate prognostic factors of overall survival, the primary end point. Each factor was evaluated in a univariable model. Forward stepwise selection was used to construct an optimal model. RESULTS: Among 320 patients the tumor primary site was gonadal in 287 (89.7%), retroperitoneal in 17 (5.3%) and mediastinal in 16 (5%). Teratoma with malignant transformation and germ cell tumor were diagnosed concurrently in 130 patients (40.6%). A total of 49 patients (16.8%) initially presented with clinical stage I. The remaining patients were at good (123 or 42.3%), intermediate (42 or 14.4%) and poor (77 or 26.5%) risk for metastasis according to IGCCCG (International Germ Cell Cancer Collaborative Group). First line chemotherapy was given for germ cell tumor in 159 patients (49.7%), chemotherapy for teratoma with malignant transformation was performed in 14 (4.4%) and only surgery was done in 147 (45.9%). Median followup was 25.1 months (IQR 5.4-63.8). Five-year overall survival was 83.4% (95% CI 61.3 to 93.5) in patients with clinical stage I and it was also worse than expected in those with metastasis. On multivariable analyses nonprimitive neuroectodermal tumor histology (overall p = 0.004), gonadal primary tumor (p = 0.005) and fewer prior chemotherapy regimens (p <0.001) were independent predictors of better overall survival. Chemotherapy was not independently prognostic. CONCLUSIONS: Less heavily pretreated teratoma with malignant transformation with a gonadal primary tumor and nonprimitive neuroectodermal tumor histology appears to be associated with longer overall survival. Generally, teratoma with malignant transformation had a worse prognosis than germ cell tumor. Uncertainties persist regarding optimal chemotherapy.

An open-label, single-arm, phase 2 study of the Aurora kinase A inhibitor alisertib in patients with advanced urothelial cancer.

BACKGROUND: Progress in developing effective salvage therapies for UC is warranted. Alisertib is an orally available, selective inhibitor of the aurora kinase A. METHODS: A single-group, phase 2 trial was conducted with alisertib 50 mg orally BID for 7 days, with 14d rest until disease progression (PD) (NCT02109328). The primary endpoint (EP) was RECIST 1.1 objective response-rate (ORR, H0 ≤ 5%, H1 ≥ 20%, α = 10% and ß = 20%). Eligibility included failure of at least one platinum-based regimen. RESULTS: From 10/2014 to 04/2015, 22 patients were enrolled (20 evaluable for response), 8 (36.4%) in second-line and 14 (63.6 %) beyond the second-line. Eight (36.4%) had an ECOG-performance status 1-2. Two partial responses (PR, ORR: 9.1%), 7 stable disease (SD) and 11 PD were obtained. Median follow-up was 8.3 months (IQR: 7-10.3), 6-month progression-free survival (PFS) was 13.6% (95%CI: 4.8-39.0). Two SD are still receiving treatment after 11.5 and 6.3 months. Median overall survival (OS) was not reached (6-month OS: 59.1%, 95%CI: 41.7-83.7). Hb < 10 g/dl was significantly associated with shorter PFS and OS multivariably (p = 0.031 and p = 0.033). Tissue of the case with 11.5 month SD harbored a missense mutation of mTOR (E1813D), the nonsense mutation Q527STOP of TSC1, HER3 and TAF1L missense mutations. Grade 3-4 adverse events (AE) were: 40.9% mucositis, 36.4% fatigue, 18.2% neutropenia (13.6% febrile neutropenia). There were 2 treatment-related deaths. CONCLUSIONS: The study did not meet the primary EP, yet sustained disease control was obtained in about 14% of patients. The incidence of AE and the issue of patient selection are two major concerns.

Extent of pelvic lymph node dissection in penile cancer may impact survival.

INTRODUCTION: Current guidelines on management of penile carcinoma (PC) recommend ipsilateral pelvic lymph node dissection (PLND) in patients with inguinal lymph node metastasis (LNM) who meet specific criteria. The aim of this article was to assess outcomes in patients treated with bilateral PLND in the presence of unilateral metastatic pelvic nodes. METHODS: After IRB approval, four international centers contributed to this study. Men with PC and unilateral inguinal LNM and pelvic node metastases were retrospectively analyzed. Estimates of overall survival (OS) and cancer-specific survival were provided by the Kaplan-Meier method. Comparisons between subgroups were made using the log-rank test, and Cox regression analysis was used to adjust comparisons for covariates of interest. RESULTS: From 1978 to 2012, fifty-one men with unilateral inguinal LNM and positive pelvic nodes on PLND were identified. Thirty-eight (75 %) had ipsilateral and 13 (25 %) had bilateral PLND. Except the extent of the PLND, patients were comparable with respect to disease and therapeutic interventions. The Kaplan-Meier estimated median OS was significantly longer in the bilateral PLND patients (21.7 vs. 13.1, p = 0.051). On Cox regression analysis, bilateral PLND [HR 0.25, (95 % CI 0.10-0.64)], multiple pelvic node involvement [HR 2.12 (95 % CI 1.02-4.43)], neoadjuvant chemotherapy [HR 0.01, (95 % CI 0.02-0.44)] and adjuvant therapies [HR 0.16, (95 % CI 0.06-0.45)] (compared to no additional therapy) were independent predictors of OS. CONCLUSIONS: Men with PC and pelvic node metastases may benefit from a bilateral PLND. This hypothesis requires further confirmation.

The role of surgery in metastatic squamous cell carcinoma of the penis.

PURPOSE OF REVIEW: Prognosis of penile squamous cell cancer (PeSCC) depends on the involvement of the groin(s) as first step. We introduce the current available evidences that should rule the use of surgery in the management of PeSCC. RECENT FINDINGS: Prophylactic inguinal node dissection in patients with no palpable nodes associates with immediate and long-term side-effects in up to 70% of patients. Recent findings support selective intervention based on early identification of dynamic sentinel node biopsy (DSNB) with false negative rate of 4-12%. Adequate node retrieval and extending surgery to the pelvis have been addressed as important key factors as staging and therapeutic factors in patients with nodal metastases. Pelvic dissections could be spared only in patients with small (< 3 cm), limited (< 3 nodes) and no extranodal extension. Bilateral pelvic dissection should be recommended in case of involvement of bilateral nodes of at least four. Cisplatin-based neo-adjuvant chemotherapy has a moderate activity, whereas adjuvant chemotherapy associates with prolonged survival in a proportion of patients. SUMMARY: In case of nodal metastases, surgery still represents the most effective treatment. Preventive surgery could be driven by DSNB, which needs an accurate multistep pathway. Extent of surgery is of paramount importance, and inguinal only and unilateral dissections should be reserved to selected patients with the most favorable features. Definitive conclusions concerning perioperative chemotherapy cannot be drawn.

Establishing Criteria for Bilateral Pelvic Lymph Node Dissection in the Management of Penile Cancer: Lessons Learned from an International Multicenter Collaboration.

PURPOSE: Penile carcinoma with bilateral pelvic lymph node metastasis is a relatively rare condition with poor outcomes. There are little data available on optimal strategies for staging and treating this group of patients. We assessed factors predicting bilateral pelvic lymph node metastasis in patients with penile cancer and confirmed inguinal lymph node metastasis. MATERIALS AND METHODS: Multi-institutional data from a total of 4 centers in Europe, the People's Republic of China and the United States were retrospectively analyzed. Patients with penile carcinoma and inguinal lymph node metastasis who underwent bilateral pelvic lymphadenectomy were included in analysis. The Kaplan-Meier and log rank tests were used to express overall survival. Logistic regression was used for multivariate analysis of factors predicting bilateral pelvic lymph node metastasis. Cox regression was done in the multivariable analysis of overall survival. RESULTS: We identified 140 patients with penile carcinoma who had confirmed pelvic lymph node metastasis. Of the patients 83 had bilateral inguinal lymph node metastasis and 64 underwent bilateral pelvic lymphadenectomy. Bilateral pelvic lymph node metastasis was observed in 16 patients (25%). The ROC of the total number of inguinal lymph node metastases and the detection of bilateral pelvic lymph node metastasis had an AUC of 0.76 (p = 0.002) with 95% sensitivity for the cutoff point of 4 inguinal nodes. On logistic regression analysis the detection of 4 or more positive inguinal nodes was the only independent predictor of bilateral pelvic lymph node metastasis (OR 14.0, CI 1.71-115). On Cox regression analysis 4 or more inguinal lymph node metastases, adjuvant chemotherapy, inguinal extraprostatic extension and bilateral procedures were associated with overall survival. CONCLUSIONS: Patients with bilateral inguinal lymph node metastasis who are treated with unilateral pelvic lymphadenectomy should be considered for bilateral pelvic lymphadenectomy in the presence of 4 or more metastatic inguinal nodes.

Relationship between lymph node ratio and cancer-specific survival in a contemporary series of patients with penile cancer and lymph node metastases.

OBJECTIVE: To evaluate the association between lymph node ratio (LNR) and cancer-specific survival (CSS) in a population of patients with penile cancer and lymph node metastases (LNM). PATIENTS AND METHODS: We evaluated 81 patients with pathologically determined LNM who were surgically treated at our institution between 2000 and 2012. We considered LNR both as a continuously coded and as a categorically coded variable. The minimum-P-value approach was used to determine the most significant LNR threshold. The Kaplan-Meier method was used to determine CSS rates, and univariable and multivariable Cox regression models were fitted to test the predictors of CSS. RESULTS: The median (interquartile range [IQR]) numbers of positive and removed lymph nodes were 2 (1-4) and 22 (13-30), respectively. The median (IQR) LNR was 10.3 (6.3-16.6)% and the most significant LNR threshold was 22%. The median (IQR) follow-up was 26 (16-62) months. Overall, the 5-year CSS rate was 50.5%. After stratification according to LNR, 5-year CSS rates were 65.2% vs 9.6% in patients with LNR < 22% vs LNR ≥ 22%, respectively (P < 0.001). In multivariable Cox regression models, after adjusting for several established prognostic factors, LNR was as independent predictor of CSS (P≤0.012). Finally, LNR significantly improved the accuracy of multivariable Cox regression models by 4.9-10.5%. CONCLUSIONS: Although further investigations are needed to evaluate the relationship between tumour burden and treatment intensity, LNR may represent a powerful predictor of CSS in patients with penile cancer and pathologically determined LNM.

The relationship between characteristics of inguinal lymph nodes and pelvic lymph node involvement in penile squamous cell carcinoma: a single institution experience.

PURPOSE: We determined predictors of pelvic lymph node metastases in patients with penile cancer. MATERIALS AND METHODS: We retrieved a total of 188 node positive inguinal groins from 142 patients treated for penile cancer. Logistic regression models were fitted to test for predictors of pelvic lymph node metastases. The minimum p value method was used to determine the most significant cutoff values of each predictor. RESULTS: Pelvic lymph node metastases were observed in 45 cases (31.7%). The 5-year cancer specific survival rate was 71.0% vs 33.2% in patients with inguinal vs pelvic lymph node metastases. The most significant cutoff values were 3 inguinal lymph node metastases and a metastasis diameter of 30 mm. According to univariable logistic regression models the number of inguinal metastases (OR 1.92, p <0.001), the diameter of the metastases (OR 1.03, p = 0.001) and extranodal extension (OR 8.01, p <0.001) were significant predictors of pelvic lymph node metastases. These variables were also independent predictors of metastases in multivariable logistic regression models (p ≤ 0.012). Patients with 3 or more inguinal lymph node metastases and those with a metastasis diameter of 30 mm or greater were at 4.77 and 2.53-fold higher risk, respectively, of harboring pelvic lymph node metastases (p ≤ 0.006). The proportion of metastases increased significantly from 0% in cases with no risk factors to 57.1% when all 3 risk factors were observed (p <0.001). CONCLUSIONS: The number and diameter of inguinal lymph node metastases as well as extranodal extension are significantly associated with pelvic lymph node metastases. These variables should be considered to determine the need for pelvic lymph node dissection. Patients with no risk factors may be spared this dissection.

Surveillance or Dynamic Sentinel Lymph-Node Biopsy in Low-Risk Clinically N0 Penile Squamous Cell Carcinoma: Single-Institution Real World Data.

INTRODUCTION: Surveillance is the standard management in low-risk cN0 penile squamous cell carcinoma (peSCC) patients. However, no previous analysis focused on early and long-term outcomes of these patients. We report on main oncological outcomes of a large series of low-risk cN0 peSCC patients. PATIENTS AND METHODS: Between 1980 and 2017 included, 93 evaluable consecutive low-risk (ie, pT1a G1 cN0M0) peSCC patients underwent primary tumor surgery and either observation (74) or dynamic sentinel node biopsy (DSNB) (19) following a clinical diagnosis of T1 in 66 (71%), T2 in 15 (16.1%) and Tx in 12 (12.9%) patients, respectively. The statistical significance of differences in medians and proportions was tested with the Kruskal-Wallis and chi-square tests. Kaplan-Meier plots illustrated 5-year inguinal relapse (IR)-free survival rates. RESULTS: Median age was 60 years (IQR: 50-69 years). Median follow-up was 92 months (IQR 54-133 months). Surveillance was more frequently adopted in clinical (c)T1 than in cT2 tumors (79.7% vs. 36.8%). None of 19 patients who had DSNB had nodal metastasis. Overall, 7 (7.5%) out of 93 pT1aG1cN0 peSCC patients had IR after a median interval of 9 months. Of note, 1 patient only relapsed after 12 months of surveillance. After stratification according to IR, relapses occurred more frequently in younger patients (59 vs. 64 years, P < .001). The 5-year IR-free survival rates for the entire cohort was 92% (95% Confidence interval [CI] 87-98%). CONCLUSIONS: Observation is a safe and effective management for low-risk peSCC patients. Younger patients may be offered a mini-invasive staging as an alternative.