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Purpose: Inguinal lymph node dissection within 3 months of primary tumor resection in penile cancer has been associated with longer recurrence-free and cancer-specific survival. However, the optimal timing and effect of lymphadenectomy performed concurrently at the time of primary lesion management on oncologic outcomes in clinically lymph node positive penile squamous cell carcinoma remains unknown. Materials and Methods: An international, multicenter cohort of 966 penile cancer cases was queried for penile squamous cell carcinoma management after the year 2000, clinically lymph node positive status, and performance of penile surgery and inguinal lymph node dissection. Cohorts were stratified as concomitant if inguinal lymph node dissection and penile surgery occurred on the same date or staged when inguinal lymph node dissection was performed after penile resection. Rates and patterns of penile squamous cell carcinoma recurrence were reported. Distant recurrence-free, cancer-specific, and overall survival were estimated using Kaplan-Meier analyses and groups compared with log-rank testing. Results: Of 253 contemporary men with clinically lymph node positive penile squamous cell carcinoma, 96 (38%) underwent concomitant inguinal lymph node dissection and 157 (62%) had inguinal lymph node dissection performed in a staged manner. Penile cancer was most likely to recur distantly (19%) followed by in the groin (14%) or pelvis (5%). There were no differences in distant recurrence-free, cancer-specific, or overall survival between management strategies. Multivariable analysis adjusting for stage, treatment center, and perioperative chemoradiation also demonstrated no recurrence-free, cancer-specific, or overall survival benefit between management strategies. Conclusions: Inguinal lymph node dissection performed concurrently with excision of the penile tumor for clinically node positive penile squamous cell carcinoma is not associated with differences in recurrence-free, cancer-specific, or overall survival compared to staged lymph node dissection. [ABSTRACT FROM AUTHOR]

Objective: To present the long‐term adjuvant radiotherapy outcomes of patients with pN3 squamous cell carcinoma of the penis (SCCp) treated at two UK centres. Patients and Methods: We conducted a retrospective audit of all pN3 SCCp patients, deemed suitable for adjuvant therapy by a specialist multidisciplinary team at St George's and Leeds Hospitals, who received adjuvant radiotherapy. Primary outcomes were recurrence‐free survival (RFS), cancer‐specific survival (CSS) and overall survival (OS). Secondary outcomes were time to adjuvant treatment, frequency of in‐field recurrence, site and side of recurrence, and dose and schedule of radiotherapy. Results: A total of 146 patients were included: 121 completed radiotherapy, 4 did not complete radiotherapy and 21 did not start it. The median (interquartile range [IQR]) age was 59 (54–70)years. The 5‐year RFS was 51%, CSS was 51% and OS was 44%. Adjuvant radiotherapy was started at a median (IQR) of 75 (48–106) days. A dose of 45 Gy in 20 fractions was most commonly used. Of the 125 patients who started adjuvant treatment, 55 relapsed. Of these relapses, 30 occurred in an inguinal or pelvic nodal station and 26 of the 30 were in a radiation field. Relapses in 18 of the 55 cases were in visceral sites only and seven were in both nodal (non‐irradiated sites) and visceral sites. Doses of <50 Gy were used more commonly before 2013 and higher doses (>50 Gy) were more commonly used after 2013. Conclusions: Application of a standard radiotherapy protocol within a centralized supra‐network setting has achieved survival outcomes that would appear better than those previously documented for either radiotherapy or chemotherapy in a cohort with solely pN3 disease. The addition of adjuvant chemotherapy may improve these outcomes further. These data suggest that adjuvant radiotherapy has a role to play in the management of men with pN3 SCCp. [ABSTRACT FROM AUTHOR]

Objectives: To identify predictive pathological factors for local recurrence (LR) and to study the impact of LR on survival in patients treated with glansectomy for penile squamous cell carcinoma (pSCC). Patients and Methods: We retrospectively studied patients treated with glansectomy at international, high‐volume reference centres. We analysed histopathological predictors of LR, stratified patients into risk groups based on the number of risk factors present, and studied the impact of LR on survival outcomes using Kaplan–Meier survival analysis and stepwise Cox proportional hazards regression models. Subsequently, we performed sensitivity analyses excluding margin‐positive cases, pT3 disease, and cN+ disease, or all of these factors. Results: Across nine institutions, 897 patients were included, of whom 94 experienced LR. On multivariable analysis, presence of high‐grade disease and pT3 stage were independent predictors of LR. LR‐free survival rates significantly differed according to the number of risk factors present, with a hazard ratio (HR) of 1.90 (95% confidence interval [CI] 1.17–3.07; P = 0.01) for the intermediate‐risk group (one risk factor) and 6.11 (95% CI 3.47–10.77; P < 0.001) for the high‐risk group (two risk factors), using the low‐risk group (no risk factors) as reference. Patients who experienced LR had significantly worse overall survival (OS; HR 2.89, 95% CI 2.02–4.14; P < 0.001) and cancer‐specific survival (CSS; HR 5.64, 95% CI 3.45–9.22; P < 0.001). LR (HR 3.82, 95% CI 2.14–6.8; P < 0.001), lymphovascular invasion and cN status were significant predictors of decreased CSS. LR remained a strong predictor of both OS and CSS in all sensitivity analyses. Conclusions: Pathological T3 stage and presence of high‐grade disease were independent histopathological predictors of LR after glansectomy for primary pSCC, which allowed risk stratification into three groups with significantly different risk of developing LR. Additionally, LR is related to poor OS and CSS, indicating that LR is a manifestation of underlying aggressive disease and clearly challenging the dogma of using organ‐sparing surgery whenever possible since survival is unaffected by higher LR rates. [ABSTRACT FROM AUTHOR]

Objectives: To identify predictors of poor overall survival (OS) amongst patients with penile squamous cell carcinoma (pSCC) with clinical inguinal lymphadenopathy (cN+), in order to define the best candidates for neoadjuvant chemotherapy (NAC). Patients and Methods: Using an international, multicentre database of 924 patients with pSCC, we identified 334 men who harboured cN+ with available clinical and follow‐up data. Lymph node involvement was defined either by the presence of palpable inguinal node disease or by preoperative computed tomography (CT) assessment. Fluorine‐18 fluorodeoxyglucose positron‐emission tomography (18F‐FDG‐PET)/CT scan was performed based on clinical judgment of the treating physician. Regression‐tree analysis generated a risk stratification tool for prediction of 24‐month overall mortality (OM). Kaplan–Meier explored the OS benefit related to the use of NAC according to the regression‐tree‐stratified subgroups. Results: Overall, 120 (35.9%), 152 (45.5%), and 62 (18.6%) patients harboured cN1, cN2, and cN3 disease. 18F‐FDG‐PET/CT was performed in 48 (14.4%) patients, and 16 (4.8%) had inguinal and pelvic nodal PET detection. The median OS was 107 months, with a 24‐month OS of 66%. At regression‐tree analysis (area under the curve = 70%), patients with cN3 and cN2 with PET/CT‐detected inguinal and pelvic nodal activity had a higher risk of 24‐month OM (>50%). NAC was associated with improved 24‐month OS rates (54% vs 33%) only in this subgroup of patients (P = 0.002), which was also confirmed after multivariable adjustment (hazard ratio 0.28, 95% confidence interval 0.13–0.62; P = 0.002). Conclusion: Patients with pSCC with cN3 or cN2 and inguinal and pelvic 18F‐FDG‐PET/CT scan detected disease had higher 24‐month OM rates according to our regression‐tree model. NAC was associated with improved OS only in these subgroups of patients. Our novel decision model may help to stratify cN+ patients, and identify those who most likely will benefit from NAC prior to radical surgical resection. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the prognostic impact of lymph node yield (LNY) on survival outcomes for penile squamous cell carcinoma (SCC). Patients and methods: In all, 532 patients who underwent inguinal LN dissection (ILND) across tertiary referral centres from Europe, China, Brazil and North America were retrospectively evaluated. From this cohort, 198 patients received pelvic LND (PLND).We identified threshold values for ILND and PLND using receiver operating characteristic curves. We tested prognostic value of LNY for recurrence‐free survival (RFS), disease‐specific survival (DSS), and overall survival (OS) using the Kaplan–Meir method and Cox proportional hazard regression models. Results: The median (interquartile [IQR]) age was 59 (49–68) years and the median (IQR) follow‐up after ILND was 28 (12–68.2) months. Overall, 85% of the patients had bilateral dissections. The median (IQR) number of inguinal LNs removed was 15 (10–22). Of those receiving PLND, The median (IQR) number of LNs was 13 (8–19). A LNY of ≥15 was used for dichotomisation of ILND patients, and a LNY of ≥9 was used in the PLND cohort. Patients with a LNY ≥15 had significantly better 5‐year OS vs patients with a LNY <15 (70.1% vs 58.7%). On multivariable analyses, a LNY ≥15 was a predictor of OS (hazard ratio [HR] 0.68, P = 0.029). For cN0 patients, a LNY ≥15 was an independent predictor of RFS (HR 0.52, P = 0.043) and OS (HR 0.53, P = 0.021). In the PLND cohort, a LNY ≥9 was a predictor of RFS (HR 0.53, P = 0.032). Conclusions: Using one of the largest LND datasets to date, we found LNY to be a significant predictor of outcomes after lymphatic staging for penile SCC. Prospective validation is warranted. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the significance of close surgical margins in organ‐sparing surgery (OSS) in the treatment of penile squamous cell carcinoma (pSCC) and clinicopathological factors that may influence local recurrence. Patients and Methods: At our tertiary referral centre, between March 2001 and September 2012, 332 patients treated with OSS for pSCC had clear surgical margins. As the focus was the impact of close clear margins on local recurrence, patients with positive margins were excluded for the purpose of this study. Our overall positive margin rate for OSS in penile cancer is 7.6% (42 patients). Analysis was carried out on an on‐going prospective database, including prospective accurate pathological recording of surgical margins. Patients underwent OSS after multidisciplinary team (MDT) discussion. Local recurrence was the primary outcome measured and Fisher's exact test and time‐to‐recurrence curves were used in the analysis. All local recurrences were scrutinised by the MDT and were categorised into: true recurrences or metachronous new occurrences (i.e. tumours arising from a background of penile intraepithelial neoplasia and forming on an epithelial surface not related to the site of initial resection). A multivariate analysis was also conducted to elucidate other factors influencing local recurrence. Results: In all, 64% of the patients had a <5 mm clear deep surgical margin, with 16% clear by <1 mm. Overall, 4% of patients had a true local recurrence, with a median time to recurrence of 6 months. In all, 53% were due to embolic spread, with residual occult local disease accounting for 47%. There was a statistically significant relationship between cavernosal involvement (P = 0.014) and lymphovascular invasion (LVI; P = 0.001) and local recurrence. Although multivariate analysis revealed that the extent of clear margin was not a predictor of disease (P = 0.405), we found an increased risk of local recurrence in the clear margin cohort of <1 mm compared to those of >1 mm (P < 0.001). Those patients considered to have metachronous tumours were scrutinised by our MDT, and eight patients (2.4%) were found to have new occurrences. Our overall proportion of patients therefore needing further treatment for either new occurrences or recurrent disease after OSS stands at 6.4%. Conclusions: Overall the presence of local recurrent disease in OSS in our experience is low (4%). We report an embolic mechanism of local recurrence, strongly suggested by the presence of cavernosal involvement and LVI. We conclude that a deep clear margin of >1 mm has a very low risk of local recurrence in penile OSS. [ABSTRACT FROM AUTHOR]

Introduction Nodal involvement is the most important prognostic factor in patients with squamous cell carcinoma of the penis (SCCp). However, optimal staging of regional lymph node remains controversial. Methods The literature was reviewed to examine current management of regional lymph nodes in SCCp patients with clinically nonpalpable inguinal lymph nodes (cN0). Results Radiological staging and selective risk-profile nomograms are unreliable in the detection of occult micrometastases in cN0 patients. Prophylactic inguinal lymph node dissection (ILND) is associated with significant morbidity and a high rate of postoperative complications. Dynamic sentinel lymph node biopsy (DSNB) is a reliable minimally invasive surgical staging technique for cN0 patients. Ipsilateral ILND is indicated only in inguinal basins with positive DSNB. Conclusions DSNB has excellent performance characteristics in staging cN0 patients, with high sensitivity and a low morbidity rate. [ABSTRACT FROM AUTHOR]

Objective To develop a novel postoperative prognostic tool, which attempts to integrate both pathological tumour stage and histopathological factors, for prediction of cancer-specific mortality ( CSM) of squamous cell carcinoma of the penis ( SCCP). Patients and Methods Patients with SCCP treated with inguinal lymph node dissection ( ILND) or sentinel LN biopsy at a single institution were used for nomogram development and internal validation ( n = 434), while a second cohort was used for external validation ( n = 338). Multivariable Cox proportional hazards were used to examine the prognostic ability of patient age, a modified tumour staging that distinguishes between spongiosum and cavernosum body ingrowth tumours, a modified LN staging that integrates information on presence/absence of LN metastasis, extent of inguinal LN metastases, pelvic LN involvement, and extranodal involvement, and tumour grade. Model performance was quantified using measures of discrimination and calibration. Results Overall, 36% of patients had positive LN metastases ( n = 156). In univariable analyses, the modified tumour and LN staging systems were statistically significantly associated with CSM, and remained in the final model with a discrimination of 89% within internal validation, and 95% within external validation. Calibration was nearly perfect. Conclusions The newly developed model integrates important prognostic factors, which existing models do not consider. Its performance was highly accurate using measures of discrimination and calibration. [ABSTRACT FROM AUTHOR]

OBJECTIVE To examine the tissue expression of DNA topoisomerase I (Topo I) and IIα (Topo II), to pursue the possibility of future chemotherapy regimens for squamous cell carcinoma of the penis (SCCP), as high expression of Topo I might indicate sensitivity to the camptothecins, whereas high Topo II might indicate sensitivity to etoposide. PATIENTS AND METHODS In all, 73 patients with SCCP were reviewed and then tissue samples microarrayed. These were then stained with immunohistochemistry for Topo I, Topo II and Ki-67. Tumour stage, grade and type were available. RESULTS Topo II showed a strong positive correlation with the proliferation index as measured by Ki-67 ( P < 0.001) but no correlation with Topo I. There were also strong correlations between tumour grade and Ki-67, and Topo II expression (both P < 0.001). Tumour type was also strongly correlated with Topo II and Ki-67 expression, with the highest expression in basaloid carcinomas and the lowest in verrucous carcinomas. However, Topo I expression was not correlated with any other tumour variable. CONCLUSION The expression of Topo I is grade- and type-independent, and chemotherapy using the camptothecins is unlikely to be effective. The strong positivity of Topo II in high-grade and basaloid SCCPs suggests that treatment with etoposide or other Topo II ‘poisons’ might be a better target for future clinical trials. [ABSTRACT FROM AUTHOR]

OBJECTIVE To determine the presence or absence of micrometastases in lymph node dissection specimens of men with squamous cell carcinoma (SCC) of the penis using immunohistochemistry, and to correlate the results with clinical outcome. PATIENTS AND METHODS In all, 13 men (mean age 55.8 years) with penile SCC, treated at St George’s hospital between 2001 and 2005, were selected. All had prophylactic lymph node dissections; (12 bilateral and one unilateral). All lymph nodes were negative on standard haematoxylin and eosin (H&E) staining. Each block was stained for cytokeratins MNF 116 and LP34. In all, 217 lymph nodes were examined (mean 16.7 per patient). The median (range) follow-up was 23 (10–52) months. RESULTS The mean tumour size and depth of invasion were 30.2 mm and 15.9 mm, respectively. There were eight T2 and four T3 tumours. Four tumours showed lymphovascular invasion. Information on tumour size and pathological grade was not available in one case. None of the patients have to date developed a local recurrence. A single lymph node was found to contain a micrometastasis, which was identified retrospectively on the original H&E slide. This measured 0.24 mm in maximum dimension. This patient had a T2G2 tumour with no vascular invasion; he has not progressed clinically in 10 months of follow-up. CONCLUSIONS Anticytokeratin immunohistochemistry on H&E-negative inguinal dissection specimens in men with SCC of the penis can detect micrometastases that might be overlooked on routine stains. Their prognostic and therapeutic significance needs further study. [ABSTRACT FROM AUTHOR]

Patients with advanced penile squamous cell cancer have a poor prognosis and can benefit from early palliative care consultation. We built a model to identify those patients most likely to benefit. Patients with penile squamous cell cancer undergoing inguinal lymph node dissection were identified from the National Cancer Database (NCDB) and a multi-institutional international dataset (INT). A multivariable Cox proportional hazards model for overall survival (OS) was developed using the NCDB and applied to the INT dataset. Parameters were used to make receiver operating characteristic (ROC) curves. ROC-related criteria were optimized to identify a predictive probability cut point and dichotomize patients from INT into risk groups for limited OS of <6 and <12 months. NCDB had 860 deaths; 105 (5%) at 6 months and 296 (15%) at 12 months. INT had 257 deaths; 56 (8%) at 6 months and 124 (18%) at 12 months. Limited OS was associated with older age, greater T and N stage, and fewer lymph nodes removed. Optimized ROC criteria using the OS <6 months curve best dichotomized INT patients into high-risk group with median OS of 24 months (95% CI 18-34) and low-risk group with median OS of 174 months (95% CI 120-NE). We developed a simple model that could be used as a screening tool for early palliative care referral. [ABSTRACT FROM AUTHOR]

Context Management of men with penile squamous cell carcinoma (PSCC) who have high-risk features following radical inguinal lymphadenectomy (ILND) remains controversial. European Association of Urology guidelines state that adjuvant inguinal radiotherapy (AIRT) is “not generally recommended”. Despite this, many centres continue to offer AIRT to a subset of men. Objective To undertake a systematic review of the evidence on AIRT in node-positive men with PSCC. Evidence acquisition A systematic review was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, with no language or date restriction. Inclusion criteria were men with PSCC, pathologically staged inguinal node positive after ILND. The intervention included ILND with AIRT compared with ILND alone. Primary outcomes were relapse-free survival and toxicity. Risk of bias assessment was undertaken. Evidence synthesis A total of 913 abstracts were identified and screened independently by two reviewers. Seven studies were eligible for inclusion: six full-text manuscripts and one conference abstract. All were retrospective series and at a high risk of bias. The selected studies included 1605 men. Indications for AIRT varied but were typically involvement of two or more inguinal nodes or extranodal extension. Regional recurrence rate following AIRT was reported at 10–91.7%. Only one study reported on toxicity. Two studies compared recurrence and survival between men who received and who did not receive AIRT, with no significant difference ( p > 0.05). Conclusions The evidence indicates that men treated with AIRT do not gain benefit with respect to relapse or survival. Uncertainty remains due to the retrospective nature and high risks of bias across the evidence. Given the lack of evidence supporting AIRT, it cannot be recommended for routine practice. Patient summary Men with penile cancer who have involvement of the inguinal lymph nodes are at a high risk of cancer recurrence and death. We reviewed the literature to see if radiation treatment after removal of the nodes provided benefit. We did not find any good-quality evidence supporting this treatment, and hence it cannot be recommended. [ABSTRACT FROM AUTHOR]

Abstract: Background: Dynamic sentinel node biopsy (DSNB) in combination with ultrasound scan (USS) has been the technique of choice at our centre since 2004 for the assessment of nonpalpable inguinal lymph nodes (cN0) in patients with squamous cell carcinoma of the penis (SCCp). Sensitivity and false-negative rates may vary depending on whether results are reported per patient or per node basin, and with or without USS. Objective: To determine the long-term outcome of patients undergoing DSNB and USS-guided fine-needle aspiration cytology (FNAC) in our cohort of newly diagnosed cN0 SCCp patients, as well as to analyse any variation in sensitivity of the procedure. Design, setting, and participants: A series of consecutive patients with newly diagnosed SCCp, over a 6-yr period (2004–2010), were analysed prospectively with a minimum follow-up period of 21 mo. All patients had definitive histology of ≥T1G2 and nonpalpable nodes in one or both inguinal basins. Patients with persistent or untreated local disease were excluded from the study. Intervention: All eligible patients had DSNB and USS with or without FNAC of cN0 groins. Outcome measurements and statistical analysis: The primary end point was no nodal disease recurrence on follow-up. The secondary end point was complications after DSNB. Sensitivity of the procedure was calculated per node basin, per patient, with DSNB alone, and with USS with DSNB combined. Results and limitations: Five hundred inguinal basins in 264 patients underwent USS with or without FNAC and DSNB. Seventy-three positive inguinal basins (14.6%) in 59 patients (22.3%) were identified. Four inguinal basins in four patients were confirmed false negative at 5, 8, 12, and 18 mo. Two inguinal basins had positive USS and FNAC and negative DSNB results. Sensitivity of DSNB with USS, with and without FNAC, per inguinal basin was 95% and per patient was 94%. Sensitivity of DSNB alone per inguinal basin and per patient was 92% and 91%, respectively. The DSNB morbidity rate was 7.6%. Conclusions: DSNB in combination with USS has excellent performance characteristics to stage patients with cN0 SCCp, with a 5% false-negative rate per node basin and a 6% false-negative rate per patient. [Copyright &y& Elsevier]

Abstract: Background: The risk of lymph node (LN) metastasis in G2T1 penile cancer has been previously reported as 0–50% and is classified as “intermediate” in the European Association of Urology (EAU) guidelines. The management of impalpable regional nodes in this cohort of patients remains contentious and varies among treatment centres depending on tumour factors and local resources. Objectives: To establish the risk of LN metastasis in G2T1 disease. Design, settings, and participants: We interrogated the databases of two referral centres for penile cancer. Measurements: Out of 902 patients, 117 (13%) patients were identified with G2T1 cancers. Those with palpable inguinal nodes (cN1) underwent early inguinal LN dissection (iLND). Those with clinically node negative (cN0) inguinal basins were either observed or surgically staged with iLND or by dynamic sentinel LN biopsy (DSLNB). Median follow-up was 44 mo, with minimum follow-up of 6 mo. Results and limitations: Fifteen of 117 (13%) patients with G2T1 cancer had LN metastasis at initial staging or during follow-up. Six of 12 (50%) cN1 patients had histologically proven LN metastasis on iLND. One hundred five patients were cN0 at presentation. Ten cN0 patients had prophylactic iLND, none of which yielded LN metastasis; 5 of 64 (8%) cN0 patients who had DSLNB had tumour-positive LNs, and 4 of 31 (13%) cN0 patients who were observed developed LN metastasis during follow-up. In cN0 patients, the risk of LN metastasis at initial staging or during surveillance was 9%. Conclusions: We consider that in cN0 patients with G2T1 penile cancer, the risk of developing metastases during surveillance warrants surgical and potentially curative staging. However, the morbidity of prophylactic bilateral iLND is too great to justify a detection rate of 9%. Less morbid alternatives such as DSLNB are advisable in G2T1 disease. [Copyright &y& Elsevier]

Objectives: To identify incidence and risk factors for upstaging from cN1 to pN2/N3 at inguinal lymphadenectomy (ILND) for penile cancer (pSCC). Our secondary objective is to assess survival outcomes and associations for cN1 patients undergoing ILND.Subjects/patients and Methods: Patients with pT≥1cN1cM0 pSCC who underwent bilateral ILND and had complete data were identified in a multi-institutional international cohort from 8 referral centers in 7 countries diagnosed from 1980 to 2017. Upstaging was defined as pN2/N3 at ILND. Multivariable logistic regression analysis was used to determine associations with upstaging, and Cox multivariable logistic regression analysis to determine associations with overall survival (OS).Results: Of 144 patients were included in the final study population. 84 patients (58%) were upstaged from cN1 to pN2/N3, and 25 (17%) were down staged to pN0. Upstaging was associated with pT3/T4 (OR 4.1, 95%CI 1.5-11.7, P < 0.01) and pTX (OR 7.1, 95CI 1.6-51.1, P = 0.02). Age, smoking status, HPV status, and LVI were not associated with upstaging. Age (HR 1.03/y, 95%CI 1.01-1.06, P < 0.01) and upstaging (HR 2.8, 95%CI 1.3-5.9, P < 0.01) were associated with worse OS. Upstaged patients had a 5-year OS of 49%, compared with 86% for patients who were not upstaged.Conclusion: The majority of cN1 pSCC patients harbor a higher-risk disease state than their clinical staging suggests, especially those with higher pT stages. More intensive pre-operative workup may be warranted for these patients to identify upstaging prior to ILND and potentially qualify them for neoadjuvant chemotherapy or clinical trials. [ABSTRACT FROM AUTHOR]

Objectives: To improve the prognostic allocation of patients with penile squamous-cell carcinoma (PSCC) receiving regional lymph node dissection (LND).Patients and Methods: An international, multicenter, retrospective study was performed on patients with PSCC who received regional LND, with or without perioperative therapy, from 1980 to 2017. We first used a random forest (RF) method with missing data imputation. Additionally, data were modeled using Cox proportional hazard regression, and a Cox model was also fit including prespecified variables. Based on the latter model, a nomogram for estimating 12-month and 24-month overall survival (OS) was developed.Results: There were 743 patients who received LND at 7 referral centers from Europe, the USA, Brazil, and China. Of these patients, 689 were analyzed: 86 (12.5%) received neoadjuvant chemotherapy (NAC); 171 (24.8%) received adjuvant chemotherapy (AC), and 74 (10.7%) received adjuvant radiotherapy. The variables significantly associated with OS were age (P < 0.001), the pathologically involved/total removed LN ratio (P < 0.001), pN stage (overall P < 0.001), and NAC (P = 0.013). NAC and AC were ineffective in N1-2 patients (clinical and pathological, respectively), whereas they provided OS improvements in N3 patients. Finally, we developed a nomogram predicting 12- and 24-month OS based on prespecified variables (c-index: 0.75). The study is limited by its retrospective nature.Conclusions: We propose a tool that can be offered as an aid to physicians to enhance decision-making, clinical research, and patient counseling whenever LND is needed for PSCC. Administration of NAC and AC should be restricted to clinical and pathological N3 patients, respectively. [ABSTRACT FROM AUTHOR]