Niels M. Graafland

Two-Center Evaluation of Dynamic Sentinel Node Biopsy for Squamous Cell Carcinoma of the Penis

PURPOSE Sentinel node biopsy is used to evaluate the nodal status of patients with clinically node-negative penile carcinoma. Its use is not widespread, and the majority of patients with clinically node-negative disease undergo an elective inguinal lymph node dissection. Reservations about the use of sentinel node biopsy include the fact that most current results come from one institution and the supposedly long learning curve associated with the procedure. The purpose of this study was to address these issues by analyzing results from two centers and by evaluating the learning curve. PATIENTS AND METHODS All patients undergoing sentinel node biopsy for penile carcinoma at two centers were included. The sentinel node identification rate, false-negative rate, and morbidity of the procedure were calculated. RESULTS from the first 30 procedures were assessed for a potential learning curve. Results A total of 323 patients with penile squamous cell carcinoma, which included 611 clinically node-negative groins, were scheduled for sentinel node biopsy. A sentinel node was found in 572 of the 592 groins (97%) that proceeded to sentinel node biopsy. In 79 groins, a sentinel node was positive for tumor. Six inguinal node recurrences occurred after a negative sentinel node procedure, all within 15 months after sentinel node biopsy. The combined false-negative rate was 7%. Complications occurred in 4.7% of explored groins. None of the false-negative procedures occurred in the initial 30 procedures. CONCLUSION Sentinel node biopsy is a suitable procedure to stage clinically node-negative penile cancer, and it has a low complication rate. No learning curve was demonstrated in this study.

Scanning with 18F-FDG-PET/CT for Detection of Pelvic Nodal Involvement in Inguinal Node-Positive Penile Carcinoma

BACKGROUND Penile carcinoma patients with inguinal lymph node involvement (LNI) have an increased risk for pelvic nodal involvement with or without distant metastases. OBJECTIVE To evaluate the diagnostic accuracy of fluorine-18 fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) with computed tomography (CT; 18F-FDG PET/CT) scanning in determining further metastatic spread in patients with tumour-positive inguinal nodes. DESIGN, SETTING, AND PARTICIPANTS Eighteen patients with penile squamous cell carcinoma with unilateral or bilateral cytologically tumour-positive inguinal disease underwent whole-body 18F-FDG-PET/CT scanning for tumour staging. MEASUREMENTS Images were blindly assessed by two nuclear medicine physicians. All scans were evaluated for pelvic nodal involvement per basin and for distant metastases. Histopathology (when available), radiologic imaging, and clinical follow-up (with a minimum of 1 yr) served as a reference standard. The diagnostic value of PET/CT scanning for predicting pelvic nodal involvement was evaluated using standard statistical methods. RESULTS AND LIMITATIONS The reference was available in 28 of the 36 pelvic basins. Of the 11 tumour-positive pelvic basins, 10 were correctly predicted by PET/CT scan, as were all 17 tumour-negative pelvic basins. PET/CT scan showed a sensitivity of 91%, a specificity of 100%, a diagnostic accuracy of 96%, a positive predictive value of 100%, and a negative predictive value of 94% in detecting pelvic nodal involvement. Additionally, PET/CT scans showed distant metastases in five patients. In four patients, the presence of distant metastases could be confirmed, while in one patient, no radiologic confirmation was found for that particular lesion. A potential limitation is that the diagnostic accuracy of PET/CT scanning was calculated on 28 pelvic basins only. Furthermore, no comparison was made with conventional CT scans, as not all patients had undergone contrast-enhanced CT scans. CONCLUSIONS PET/CT scanning appears promising for detecting pelvic lymph node metastases with great accuracy, and it identifies distant metastases in penile carcinoma patients with inguinal LNI. In our practice, PET/CT scanning has become part of routine staging in such patients.

Prognostic Factors for Occult Inguinal Lymph Node Involvement in Penile Carcinoma and Assessment of the High-Risk EAU Subgroup: A Two-Institution Analysis of 342 Clinically Node-Negative Patients

BACKGROUND The European Association of Urology (EAU) guidelines advise an elective bilateral lymphadenectomy in clinically node-negative (cN0) patients with high-risk penile carcinoma (≥pT2, G3, or lymphovascular invasion [LVI]). OBJECTIVE Our aim was to assess prognostic factors for occult metastasis and to determine whether current EAU guidelines accurately stratify patients at high risk. DESIGN, SETTING, AND PARTICIPANTS Data of 342 cN0 patients with histologically proven invasive penile squamous cell carcinoma who had undergone the current dynamic sentinel node biopsy (DSNB) protocol were analysed. A complete ipsilateral inguinal lymphadenectomy was only done if the sentinel node was tumour positive. MEASUREMENTS The presence of occult metastasis was established by preoperative ultrasound and tumour-positive fine-needle aspiration cytology, tumour-positive sentinel nodes, and groin metastases during follow-up after a negative DSNB procedure. Median follow-up was 31 mo. RESULTS AND LIMITATIONS Sixty-eight of 342 patients (20%) and 87 of 684 groins (13%) had occult nodal involvement including 6 patients (2%) with a groin metastasis after negative DSNB. Corpus spongiosum invasion, corpus cavernosum invasion, histologic grade, and LVI were each significant prognosticators for occult metastasis on univariate analysis. On multivariate analysis, grade (odds ratio [OR]: 3.3 for intermediate and 4.9 for poor, respectively) and LVI (OR: 2.2) remained predictive factors. In total, 245 patients (72%) were classified high risk according to EAU guidelines. Among them, the incidence of occult metastasis was 23% (57 of 245). A potential limitation of this study is the lack of external review. CONCLUSIONS Histologic grade and LVI are independent prognostic factors for occult metastasis in penile carcinoma. Although both predictors are incorporated into the current EAU guidelines, the stratification of patients needing a lymph node dissection is inaccurate. Approximately 77% of high-risk patients (188 of 245) would have had a negative bilateral inguinal lymphadenectomy. For the time being, DSNB is considered a more suitable staging method than EAU risk stratification for an accurate determination of patients who require lymph node dissection.

Prognostic Significance of Extranodal Extension in Patients With Pathological Node Positive Penile Carcinoma

PURPOSE We assessed the prognostic significance of extranodal extension, defined as tumor extension through the lymph node capsule into the perinodal fibrous-adipose tissue, as well as several other risk factors in node positive penile cancer cases. MATERIALS AND METHODS We analyzed prospectively collected data on a consecutive series of 156 chemotherapy naïve patients with proven lymph node involvement who underwent therapeutic regional lymphadenectomy. Postoperative external radiotherapy was indicated when histopathological analysis revealed more tumor than 1 intranodal metastasis. We estimated cancer specific survival using the Kaplan-Meier method. Multivariate analysis was done according to the Cox proportional hazards model of factors statistically significant on univariate analysis. RESULTS Adjuvant radiotherapy was done in 70 patients (45%). Median followup was 57.8 months. Overall 5-year cancer specific survival was 61%. Men with extranodal extension had significantly decreased 5-year cancer specific survival compared with men without it (42% vs 80%). Other prognostic variables on univariate analysis were bilateral metastatic involvement vs unilateral, 3 or greater unilateral metastatic inguinal nodes vs 2 or fewer, inguinal lymphadenectomy positive margin status vs negative status and pelvic lymph node involvement. Pathological T stage or differentiation grade were not significant predictors of outcome. On multivariate analysis extranodal extension and pelvic lymph node involvement remained associated with decreased cancer specific survival (HR 2.37 and 2.20, respectively). CONCLUSIONS Metastatic inguinal lymph node extranodal extension and pelvic lymph node involvement are independent predictive parameters of cancer specific survival in patients with pathologically node positive penile carcinoma despite surgery with postoperative radiotherapy.

Contemporary management of regional nodes in penile cancer-improvement of survival?

PURPOSE The management of regional nodes of penile squamous cell carcinoma has changed with time due to improved knowledge about diagnosis and treatment. To determine whether changes in the treatment of regional nodes have improved survival, we compared contemporary 5-year cancer specific survival of patients with squamous cell carcinoma of the penis with that of patients in previous cohorts. MATERIALS AND METHODS In an observational cohort study of 1,000 patients treated during 56 years 944 were eligible for analysis. Tumors were staged according to the 2009 TNM classification, and patients were divided into 4 cohorts of 1956 to 1987, 1988 to 1993, 1994 to 2000 and 2001 to 2012, reflecting changes in clinical practice regarding regional nodes. Kaplan-Meier survival curves with the log rank test and Cox proportional hazards modeling were used to examine trends in 5-year cancer specific survival. RESULTS The 5-year cancer specific survival of patients with cN0 disease treated between 2001 and 2012 was 92% compared to 89% (1994 to 2000), 78% (1988 to 1993) and 85% (1956 to 1987). The 5-year cancer specific survival improved significantly since 1994, the year dynamic sentinel node biopsy was introduced, at 91% (1994 to 2012) vs 82% (1956 to 1993) (p = 0.021). This conclusion still holds after adjustment for pathological T stage and grade of differentiation (HR 2.46, p = 0.01). Extranodal extension, number of tumor positive nodes and pelvic involvement in node positive (pN+) cases were associated with worse 5-year cancer specific survival. CONCLUSIONS Despite less surgery being performed on regional nodes, 5-year cancer specific survival has improved in patients with cN0 disease. The number of tumor positive nodes, extranodal extension and pelvic involvement were highly associated with worse cancer specific survival in patients with pN+ disease. In this group other treatment strategies are needed as no improvement was observed.

Early Wound Complications After Inguinal Lymphadenectomy in Penile Cancer: A Historical Cohort Study and Risk-factor Analysis

BACKGROUND Complication rates after inguinal lymph node dissection (ILND) are high. Risk factors for early wound complications after ILND in patients with penile carcinoma have not yet been studied. OBJECTIVES To assess the frequency of early wound complications in a contemporary series and to identify clinical risk factors for early wound complications after ILND for penile carcinoma. DESIGN, SETTING, AND PARTICIPANTS We evaluated 237 ILNDs in 163 patients with penile cancer treated between 2003 and 2012 at the Netherlands Cancer Institute. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS We assessed the occurrence of wound infection, skin-flap problems, and seroma formation and graded complications using the modified Clavien system. Univariable and multivariable penalised mixed effects logistic regression was used to identify clinical risk factors for occurrence of any complication (grade ≥ 1) and of moderate to severe complications (grade ≥ 2). RESULTS AND LIMITATIONS One complication or more occurred in 58% of the procedures, and 10% of those complications were severe. Wound infection occurred in 43%, seroma formation occurred in 24%, and skin-flap problems occurred in 16%. Palpable disease was the only factor associated with grade ≥ 1 complications in the univariable analysis (odds ratio [OR]: 0.43; p=0.02). In the multivariable model, after penalisation, no statistically significant risk factors remained. Univariable associations for grade ≥ 2 complications were present for body mass index (BMI; OR of 1.66 for a 5.8-point change in BMI; p=0.05) and sartorius muscle transposition (OR: 2.64; p=0.04). In the reduced multivariable model, the OR for sartorius muscle transposition was 2.12 (p=0.06) and for BMI was 1.76 (p=0.03). In addition, bilateral dissection approached significance in the multivariable model (OR: 2.17; p=0.06). This study is limited by its observational nature. CONCLUSIONS Wound complication rates after ILND are high in this cohort. BMI, sartorius muscle transposition, and bilateral dissection were the factors most strongly associated with the occurrence of grade ≥ 2 wound complications.

Prospective evaluation of hybrid 18F-fluorodeoxyglucose positron emission tomography/computed tomography in staging clinically node-negative patients with penile carcinoma.

To prospectively evaluate the performance of 18F‐fluorodeoxyglucose positron emission tomography/computed tomography (18F‐FDG PET/CT) to detect occult metastasis in patients with clinically node‐negative (cN0) penile carcinoma, as there is little information on the use of 18F‐FDG‐PET/CT in penile carcinoma.

Incidence trends and survival of penile squamous cell carcinoma in the Netherlands

We examined trends in the incidence and mortality, and described the survival of patients with penile squamous cell carcinoma in the Netherlands between 1989 and 2006. On the basis of nationwide population‐based data, 3‐year moving average European age‐standardized incidence and 10‐year relative survival estimates were calculated. Penile squamous cell carcinomas were categorized according to stage grouping based on the TNM classification. In the 17‐year study period, 2000 primary penile cancers were diagnosed in the Netherlands of which 1883 (94%) were squamous cell carcinomas. Median age at diagnosis was 68 years. The majority of patients (57%) were diagnosed with localized tumors (Stage 0 or I). The percentage of missing disease characteristics increased with increasing age. The 3‐year moving average incidence rate of patients with penile squamous cell carcinoma increased significantly from 1.4 per 100,000 person‐years in 1989 to 1.5 in 2006 with an estimated annual percentage of change of 1.3%. Ten‐year relative survival of patients according to the different stage groups was 93% for Stage 0, 89% for Stage I, 81% for Stage II, the 9‐year survival was 50% for patients with Stage III disease and a 2‐year survival of 21% for patients was found for Stage IV disease. Our study shows that the incidence rate of penile squamous cell carcinoma in the Netherlands has increased slightly, especially the incidence of carcinomas in situ. Patients with Stage III and IV tumors have poor survival.

Inguinal Recurrence Following Therapeutic Lymphadenectomy for Node Positive Penile Carcinoma: Outcome and Implications for Management

PURPOSE We investigated the treatment results and outcomes of patients with pathological node positive penile carcinoma who experienced an inguinal recurrence after therapeutic lymphadenectomy, and determined the clinicopathological features predictive of such recurrences. MATERIALS AND METHODS Data of 161 patients with pN+ penile carcinoma were analyzed. Ipsilateral postoperative radiotherapy was given if histopathology revealed 2 or more metastases and/or extranodal extension. Medium observed followup was 60 months. The 5-year incidence of inguinal recurrence was estimated using a competing risk analysis considering death a competing risk. RESULTS An inguinal recurrence developed in 26 patients following lymphadenectomy after a median of 5.3 months. The overall estimated 5-year inguinal recurrence rate was 16%. Of the 26 patients with inguinal recurrence ipsilateral adjuvant radiotherapy was indicated in 22 but given in 11. The other 11 patients had recurrence in the groin before the start of adjuvant radiotherapy. Median survival after inguinal recurrence was 4.5 months. Only 2 of 26 patients (8%) underwent successful salvage after inguinal recurrence. Pronounced differences in estimated recurrence rates were found among several clinicopathological variables indicating extensive penile cancer. Patients with 3 or more unilateral metastatic inguinal nodes and/or extranodal extension and/or pelvic nodal involvement defined a subgroup with high risk pN+ penile cancer. CONCLUSIONS Most inguinal recurrence following therapeutic lymphadenectomy in pN+ penile carcinoma occurs within a short time. Patients experiencing such a recurrence have a poor outcome with limited salvage options. Patients with 3 or more unilateral metastatic inguinal nodes and/or extranodal extension and/or pelvic nodal involvement represent a high risk group that may benefit from multimodality treatment.

Nodal Staging in Penile Carcinoma by Dynamic Sentinel Node Biopsy After Previous Therapeutic Primary Tumour Resection

BACKGROUND Dynamic sentinel node biopsy (DSNB) is used to evaluate the nodal status of patients with penile carcinoma and clinically node-negative groins. This minimally invasive procedure is usually done at the same time as the treatment of the primary tumour. OBJECTIVE Our aim was to evaluate results of so-called postresection DSNB, that is, DSNB after previous resection of the penile tumour. DESIGN, SETTING, AND PARTICIPANTS All 40 patients who had undergone DSNB after previous penile carcinoma resection with histopathologically tumour-negative margins between February 2003 and July 2009 were analysed. Twenty patients (50%) had known unilateral nodal involvement, and DSNB was used to stage the clinically normal contralateral groin. Hence the study concerned 60 groins without palpable nodes. The median time between primary tumour resection and DSNB was 2.8 mo. The technique of postresection DSNB was similar to the standard procedure. MEASUREMENTS The sentinel node visualisation rate, identification rate, histopathologic results, and outcome during follow-up were investigated. RESULTS AND LIMITATIONS A sentinel node was visualised on the lymphoscintigrams of 56 of the 60 eligible groins (93%). A sentinel node was identified intraoperatively in all these 56 groins. A median of two sentinel nodes were removed. Histopathologic analysis revealed involvement of seven groins (12%) in seven patients (18%). The median size of these metastases was 6mm. Additional dissemination was found in one completed ipsilateral inguinal node dissection specimen. No recurrences developed in the groins from which one or more tumour-free sentinel nodes had been taken during a median follow-up of 28 mo after the primary tumour resection. A potential limitation of this study is the short follow-up and relatively small cohort number. CONCLUSIONS Postresection DSNB is a suitable procedure to stage clinically node-negative penile carcinoma after previous therapeutic primary tumour resection. The results seem similar to the favourable experience with DSNB in patients with their tumour still present.