EUROPEAN UROLOGY 63 (2013)

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1 EUROPEAN UROLOGY 63 (2013) available at journal homepage: Platinum Priority Penile Cancer Editorial by Nicola Nicolai on pp of this issue Dynamic Sentinel Lymph Node Biopsy in Patients with Invasive Squamous Cell Carcinoma of the Penis: A Prospective Study of the Long-Term Outcome of 500 Inguinal Basins Assessed at a Single Institution Wayne Lam a, Hussain M. Alnajjar a, Susannah La-Touche a, Matthew Perry a, Davendra Sharma a, Cathy Corbishley b, James Pilcher c, Sue Heenan c, Nick Watkin a, * a Department of Urology, St. George s Hospital, London, UK; b Department of Cellular Pathology, St. George s Hospital, London, UK; c Department of Radiology, St. George s Hospital, London, UK Article info Article history: Accepted October 18, 2012 Published online ahead of print on October 27, 2012 Keywords: Penile cancer Sentinel lymph node Squamous cell carcinoma False negative Sensitivity 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 USSguided 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 ( ), 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. # 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Corresponding author. Penile Cancer Centre, Department of Urology, St. George s Hospital, Tooting, London SW17 0QT, UK. address: nick.watkin@stgeorges.nhs.uk (N. Watkin) /$ see back matter # 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved.

2 658 EUROPEAN UROLOGY 63 (2013) Introduction Nodal involvement is the single most important prognostic factor in patients with squamous cell carcinoma of the penis (SCCp) [1]. Patients without nodal involvement have been reported to have excellent long-term survival. In our centre, we have recently shown a 5-yr cancer-specific survival of 98.4% in patients with N0 disease. However, this rate diminishes considerably if nodal metastases are present [2]. A number of studies have shown that approximately 20% of SCCp patients with clinically nonpalpable inguinal nodes harbour occult metastasis [3]. Historically, there was a debate on whether these patients should be kept under surveillance or undergo prophylactic bilateral inguinal lymph node dissection (ilnd). For patients with a high risk of micrometastasis (T1G3), the recommended assessment of inguinal basins is ilnd [1]. However, our previous study showed that strict adherence to European Association of Urology (EAU) guidelines would have led to negative bilateral ilnd in 77% of the high-risk patients [4]. Therefore, a large number of patients do not need to undergo such surgery, which is associated with a substantial morbidity rate of 30 50% [5 7] and a mortality rate of 2% [5]. To reduce morbidity associated with nodal staging in SCCp, dynamic sentinel node biopsy (DSNB) has been developed as a minimally invasive technique to stage inguinal status. Cabanas first described the sentinel lymph node biopsy concept for penile cancer in 1977 [8]. However, this method was found to be unreliable. The false-negative rate of sentinel lymph node biopsy was unacceptably high, and the technique was difficult to reproduce [9,10]. However, the concept was later adopted for nodal assessment in melanoma and breast cancer. The use of sentinel lymph node biopsy in penile cancer was revisited and further developed by Horenblas et al. in 1994 [11,12]. The use of preoperative ultrasound scan (USS) with or without fine-needle aspiration cytology (FNAC) aids the detection of lymph nodes that are infiltrated extensively by tumour deposits that cause complete blockage of lymphatic drainage [3]. As a result, USS of inguinal basins and cytologic examination of suspicious inguinal lymph nodes have been added as a routine part of the nodal assessment procedure with DSNB to improve sensitivity and decrease false-negative rates. The revised technique of DSNB has a significantly reduced morbidity rate of 5.7 8% reported in our unit, as well as other units [3,13]. With increasing evidence of the reliability of DSNB, the EAU guidelines have been modified. The 2004 EAU guidelines [14] recommended ilnd in patients with T1G3 SCCp and cn0 disease. This recommendation has been revised in the current 2009 EAU guidelines, which recommend the use of DSNB in patients with intermediate- and high-risk disease who are clinically inguinal node negative [1]. However, sensitivity and false-negative rates of DSNB may vary depending on whether results are reported per patient (clinical sensitivity) or per node basin (technical sensitivity) and with or without USS. This study is to report the long-term outcome in our cohort of newly diagnosed cn0 SCCp patients who underwent DSNB and USS nodal assessment, as well as to investigate whether there is any variation in the sensitivity and false-negative rates when calculated per node basin, per patient, with DSNB alone, and with USS and DSNB combined. 2. Patients and methods 2.1. Patient selection Since 2004, the combination of DSNB and preoperative USS has been the technique of choice at our penile cancer centre. Approvals from the ethics committee and the new and novel procedure committee were obtained. All patients referred to the supraregional penile cancer centre were enrolled in an ongoing prospective study from October 2004, with analysis of the first 500 inguinal basins completed in October Inclusion criteria were all patients with newly diagnosed SCCp, with either bilateral or unilateral cn0 inguinal basins and histologically confirmed stage T1 and G2 disease (ie, intermediate- or high-risk disease according to the EAU guidelines). Patients with evidence of clinically node-positive disease were excluded from the study. We defined false-negative DSNB as the development of regional nodal recurrence after a negative DSNB, without evidence of a new primary tumour or SCCp recurrence that predated nodal recurrence. Patients with persistent or untreated local disease were therefore excluded from the study. Ipsilateral completion ilnd was performed in patients with positive metastatic nodal disease identified on DSNB and/or USS FNAC. Further pelvic nodal surgery and adjuvant therapy were considered, determined by the number of positive nodes and the presence of extranodal disease in the ilnd specimen Dynamic sentinel node and ultrasound nodal assessment method and technique Full details of the technique have been described in a previous study [15] and are summarised in Figure 1. Standardised USS criteria for FNAC are summarised in Table Follow-up In patients with negative USS and DSNB, clinical examination of inguinal basins was performed at regular intervals under our standardised surveillance program. This program consisted of three-monthly followup in the first year postoperatively, four-monthly follow-up in the second year, and six-monthly follow-up thereafter. In patients with challenging physical examination because of body habitus or groin Table 1 Ultrasound scan criteria to identify suspicious inguinal lymph nodes for fine-needle aspiration cytology Increased size Abnormal shape Rounded, with a short-long axis ratio <2 Eccentric cortical hypertrophy Absence of an echogenic hilum Hypoechogenicity of the node compared with adjacent muscle Lymph node necrosis Abnormal vascularity using power Doppler Fine-needle aspiration cytology was performed if one or more of the outlined criteria were detected with ultrasound scan.

3 [(Fig._1)TD$FIG] EUROPEAN UROLOGY 63 (2013) SCCp with definitive histology of T1 or G2 and no clinically palpable inguinal nodes (cn0). Ultrasound assessment of cn0 inguinal basins by uroradiologists prior to DSNB. FNAC is performed if abnormal nodes are detected according to our standardized USS criteria (Table 1). Positive On the same day, injection of ml of technetium Tc 99m nanocolloid (Nanocoll, Amersham Health, Milan, Italy) around the base of the penis 4 h prior to surgery. Dynamic lymphoscintigram obtained with a dual-headed gamma-camera (Siemens ECAM Signature Series, Berkshire, UK), demonstrating drainage of the radioactive tracer to the inguinal basins. Real-time imaging allowed depth gauging, and surface marking of the locations of the detected inguinal sentinel nodes was done with permanent ink. Injection of 1 ml of patent blue dye (Martindale Pharmaceuticals, Essex, UK) intradermally after anaesthesia, circumferentially into the proximal penile shaft shortly before surgery. Standardised nodal biopsy surgery by a dedicated surgical team. Nodes were harvested through small inguinal incisions, guided by staining of patent blue dye and/or gamma probe (Neoprobe, Johnson and Johnson Medical, West Lothian, UK). Intraoperative palpation of the exposed wound prior to closure to identify extra suspicious lymph nodes not shown on lymphoscintigraphy. Residual radioactive count after lymph node excision was recorded. Entire excised lymph node was paraffin embedded and sectioned at 2-mm intervals. Immunohistochemistry was performed on all blocks containing lymph nodes by a combination of three immunohistochemical markers, covering both high- and low-molecular-weight cytokeratins (either with CK5/6, MNF116 and Cam5.2; or CK5, AE1/3 and CK8/18). Maximum diameter, position of tumour deposits, and presence or absence of extranodal spread were noted. Negative Follow-up with interval clinical examinations with or without USS. Positive Ipsilateral ilnd within 4 wk of DSNB Fig. 1 Technique and protocols for dynamic sentinel node biopsy (DSNB). SCCp = squamous cell carcinoma of the penis; FNAC = fine-needle aspiration cytology; USS = ultrasound scan; ilnd = inguinal lymph node dissection. anatomic deformity, regular USS would also be undertaken for surveillance of nodal recurrence Data analysis All data were collected prospectively in a database. Sensitivity and falsenegative rates were calculated per patient, per inguinal basin, per DSNB alone, and per DSNB with USS. We defined false-negative rate as the rate of occurrence of negative DSNB in patients who were found to have inguinal nodal metastasis during follow-up. Primary tumour and sentinel lymph node histology of patients with false-negative DSNB USS was reviewed. Patients with nodes harvested that did not have any tracer uptake and patients with nodes that were detected by USS FNAC, but not by DSNB, were also identified. Morbidities associated with DSNB were recorded and classified according to the Clavien-Dindo classification of surgical complications [16]. 3. Results 3.1. Demographics, tumour and lymph node characteristics A total of 542 patients with male genital malignancy were referred to our institution between October 2004 and October 2010; of these patients, 267 men with histology of T1 or G2 were eligible for inclusion. Three patients who developed nodal recurrence after negative DSNB were excluded. In these patients, local SCCp recurrence was identified at the same time as inguinal nodal recurrence. The remaining 264 patients included in our study had a mean age of 66.5 yr. The grading and staging of primary tumours in this cohort are summarised in Table 2. Of the 264 patients, 28 (11%) underwent unilateral DSNB and USS on the clinically unaffected (cn0) groin only a total of

4 660 EUROPEAN UROLOGY 63 (2013) Table 2 Summary of grading and staging of primary squamous cell carcinoma of the penis and percentage of positive dynamic sentinel node biopsies for each group of patients Stage G1, no. (% with positive DSNB) G2, no. (% with positive DSNB) G3, no. (% with positive DSNB) T1 Excluded from study 67 (10.4) 43 (25.6) T2 11 (0) 36 (13.9) 68 (38.2) T3 0 9 (11.1) 30 (30) T DSNB = dynamic sentinel node biopsy. Staging according to the 2002 TNM classification. 500 cn0 inguinal basins that had both DSNB and USS assessment of nodal status included in this study. The median length of follow-up was 57 mo (range: 21 94). Of the 264 patients, 120 patients (45%) did not have the primary penile tumour resected at the same time as DSNB, mostly because of difficulty in confirming the primary penile tumour stage and grade. Eleven patients (2.2%) had only unilateral tracer uptake during lymphoscintigraphy, which gives a visualisation rate of 95.8% per patient and 97.8% per inguinal basin. All 11 patients were offered ipsilateral prophylactic ilnd. One patient opted for active surveillance and remained diseasefree at 65 mo. Of the 10 patients who had ilnd, 1 patient (10%) was found to have metastatic nodal disease. In total, 1021 lymph nodes were biopsied. Eighty-seven nodes (8.5%) were found to contain metastasis. Lymph node blue dye status was recorded in 996 of the excised lymph nodes (98%). Of these 996 lymph nodes, 686 (69%) were both radioactive and stained blue by patent-blue dye; 309 lymph nodes (31%) were only radioactive. One excised sentinel node was only blue but not radioactive, and it did not contain any metastatic disease on subsequent histologic analysis Ultrasound scan, fine-needle aspiration cytology, and dynamic sentinel node biopsy sensitivities Seventy-three inguinal basins (14.6%) in 59 patients (22.3%) were found to contain metastasis using a combination of USS, FNAC, and DSNB. Fourteen patients (5.3%) were found to have bilateral positive lymph nodes. Two inguinal basins (2.7%) were found to have positive USS FNAC but negative DSNB findings. No further metastases were identified in either patient, and they remained disease-free at 32 and 69 mo after lymph node dissection. Twenty-five inguinal basins (5%) had unilateral positive USS FNAC findings, and only one inguinal basin (0.2%) had bilateral positive USS FNAC findings. Sensitivity of USS FNAC alone per inguinal basin was therefore 65%. Sensitivity of the DSNB and USS FNAC combination technique 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. These findings are summarised in Table False-negative dynamic sentinel node biopsy False-negative DSNB was identified unilaterally in four patients (patient study numbers 65, 76, 178, and 250). All four patients had DSNB after or at the same time as primary tumour excision surgery with curative intention. All primary tumours were T2G3 SCCp with an endophytic growth pattern. Of the study population, 35 of 264 patients (13.3%) had similar histologic characteristics, and 16 of 35 patients (45.7%) were found to have positive DSNB. All resected tumours had negative margins histologically, with no occult metastatic changes identified in the excised sentinel lymph nodes. All inguinal nodal recurrences were detected by clinical examination and confirmed with USS FNAC on follow-up. No primary tumour recurrences were identified clinically or radiologically. Nodal recurrence was detected at 5, 8, 12, and 18 mo after DSNB. The disease characteristics of the four patients with false-negative DSNB are summarised in Table Morbidity Twenty patients (7.6%) were identified as having postoperative complications. Nine patients had inguinal lymphoceles, in whom two occurred bilaterally. These patients were either treated with a course of antibiotics and clinical surveillance or the lymphoceles were drained under ultrasound guidance (Clavien-Dindo surgical complication classification grade 2 3a). Five patients had inguinal wound infection and were treated with antibiotics (grade 2). Three patients developed a hematoma postoperatively and were treated with compression dressings (grade 1). Two patients developed penoscrotal lymphedema and were treated Table 3 Sensitivity of ultrasound scan, with or without fine-needle aspiration cytology, of dynamic sentinel node biopsy alone and of a combination of dynamic sentinel node biopsy with ultrasound scan and fine-needle aspiration cytology, calculated per inguinal basin and per patient USS FNAC, % (patients, no.) DSNB, % (patients, no.) DSNB with USS FNAC, % (patients, no.) Per inguinal basin (technical sensitivity) 65 (26/40) 92 (71/77) 95 (73/77) Per patient (clinical sensitivity) 64 (25/39) 91 (57/63) 94 (59/63) USS = ultrasound scan; FNAC = fine-needle aspiration cytology; DSNB = dynamic sentinel node biopsy.

5 EUROPEAN UROLOGY 63 (2013) Table 4 Summary of disease characteristics of patients with false-negative dynamic sentinel node biopsy Status (time after recurrence, mo) Time to recurrence, mo. Inguinal radiation count after excision of SLN (>100 meq) Excised blue SLNs, no. Excised radioactive SLNs, no. SLNs excised in FN basin, no. Surgical margin Method of surgical treatment of primary tumour LVI SCCp subtype Age, yr Grade Stage Primary tumour growth pattern FN DSNB patient study number Clear No 8 Died (14) Endophytic Yes Basaloid Glansectomy with Clear No 5 Died (8) Endophytic Yes Usual Glansectomy with Clear No 12 No recurrence (10) Endophytic No Usual Glansectomy with Clear No 18 No recurrence (3) Endophytic No Usual Glansectomy with FN = false negative; DSNB = dynamic sentinel node biopsy; LVI = lymphovascular invasion; SCCp = squamous cell carcinoma of the penis; SLN = sentinel lymph node; SSG = split-skin graft. Staging according to the 2009 TNM classification. conservatively (grade1). One patient required a return to the operating theatre for a bleeding wound (grade 3b). The morbidities associated with our cohort of DSNB patients are summarised in Table Discussion This study provides the largest amount of single-institution outcome data on DSNB to date. The study is a prospective cohort analysis, using a standardised DSNB and USS technique implemented in a homogenous population at a supraregional penile cancer centre. There are several weaknesses that we recognise in our methodology. First, we acknowledge that patients with untreated or persistent primary disease were excluded from our study. In these patients, it is not possible to determine if nodal recurrences were caused by new metastasis from the primary tumour or were because of initial false-negative DSNB. Therefore, our false-negative rate of 5% could be an underestimation. Second, although our standard practice is to obtain lymphoscintigrams 4 h prior to nodal biopsy surgery, we were unable to offer this tool to 5% of our patients because of technical and/or logistical reasons. This group of patients all had their inguinal lymphoscintigraphy markings obtained 12 h prior to DSNB, and none of the patients were found to be false negative on follow-up. Third, FNAC results ideally should be obtained before DSNB, and if FNAC is found to be positive for occult nodal metastasis, an immediate ilnd should be offered to the patient and DSNB could be spared. Unfortunately, this scenario is logistically challenging in our unit, because the vast majority of patients are referred from distant peripheral hospitals. However, as DSNB is spared on only the positive FNAC side of inguinal basins, only 5.2% of inguinal basins would have avoided the DSNB procedure, and only one patient with bilateral positive USS FNAC findings would have avoided DSNB completely. We acknowledge that 134 patients from this study cohort also participated in our previous joint study with the Netherlands Cancer Institute (NCI) group [17]. However, this current study represents the long-term outcome of DSNB for a large cohort of patients treated in a single penile cancer centre. Two systematic reviews are available to date in evaluating the performance of DSNB in penile cancer. Neto et al. published a systematic review and cumulative analysis of 11 studies to evaluate the use of DSNB for nodal staging in patients with SCCp [18]. A total of 519 patients were included in their analysis. However, the majority of patients included were from one joint study performed by our unit with the NCI group [17]. Other studies included in this systematic review had small study populations, and not all included USS as part of the nodal assessment procedure. The median follow-up period was only 28.4 mo. The study showed that DSNB has a pooled sensitivity of 77.1%. Sadeghi et al. published a systematic review and metaanalysis on the accuracy of DSNB [19]. They used 19 studies

6 662 EUROPEAN UROLOGY 63 (2013) Table 5 Summary of complications from dynamic sentinel node biopsy Complication Patients, no. (%) Treatment Clavien-Dindo classification, grade Lymphocele 9 (3.4) Antibiotics with or without ultrasound-guided drainage 2 3a Wound infection 5 (1.9) Antibiotics 2 Haematoma 3 (1.1) Compression dressing 1 Penoscrotal lymphedema 2 (0.8) Conservative 1 Wound bleeding 1 (0.4) Surgical exploration and haemostasis 3b in their sensitivity analysis. Again, many studies included had a small sample size, and not all the studies used USS as part of nodal assessment. The authors also included studies that recruited clinically node-positive patients for DSNB. Their study showed a pooled sensitivity of 88%. The sensitivity of DSNB is considerably higher in our study. This finding is probably because of the procedure s being performed at a high-volume specialist penile cancer centre, in which a high repetitiveness of DSNB is carried out by a team of dedicated surgeons, nuclear radiologists, and histopathologists, in contrast with other centres included in the two systematic reviews. We also routinely continue to search for radioactive nodes until the background count is <100 meq. Therefore, some of the nodes harvested could be secondary nodes. Neto et al. further assessed morbidity associated with DSNB [18]. The complication rate is considerably higher in the lymph node dissection group compared with the DSNB group (27.4% and 3.6%). Our study shows that morbidity associated with nodal assessment in patients with SCCp is significantly reduced with DSNB, at 7.6%, compared with ilnd. This figure is still higher than the 3.6% reported by Neto et al. [18] and the 5.7% reported by the NCI group [3]. There has been inconsistency in reporting the sensitivity of DSNB in the previous literature. Sensitivity when reported per inguinal basin assesses the technical sensitivity of the procedure, while sensitivity of DSNB when reported per patient provides assessment of clinical sensitivity. However, our study demonstrates that the sensitivity of DSNB per inguinal basin and the sensitivity of DSNB per patient do not differ significantly, with figures of 95% and 94%, respectively. With regard to the four false-negative DSNB patients, one patient (patient 250 in Table 4) did not adhere to our standard follow-up program. Recurrence detection in this patient was therefore potentially delayed until 18 mo after his initial DSNB surgery, at which time he presented with unilateral palpable inguinal nodes. In all four patients, no cause of false-negative DSNB could be identified from retrospective review of lymphoscintigrams, post-dsnb background radiation counts, or characteristics of excised sentinel lymph nodes. None of these patients had undergone previous inguinal surgery. One patient had a positive DSNB in his contralateral inguinal basin. However, these patients share the same histologic characteristics of T2G3 disease with an endophytic growth pattern. Further investigations are required to identify the reason. All four patients subsequently underwent radical ilnd. Two patients died of disease progression at 8 and 14 mo after recurrence. The remaining two patients have no evidence of local or metastatic disease 6 and 32 mo after recurrence. Both patients were treated with completion ilnd, adjuvant inguinal radiotherapy, and ipsilateral pelvic lymph node dissection. There was no evidence of pelvic nodal metastasis on histology analysis. 5. Conclusions The use of DSNB in combination with USS has excellent performance characteristics to stage patients with cn0 SCCp, with only a 5% false-negative rate. The addition of USS improves performance by 3% compared with DSNB alone. There is no significant difference in performance of the combined technique if performance is reported per node basin or per patient. The morbidity rate of 7.6% in DSNB appears to be superior to that of ilnd. DSNB is therefore a justified procedure to identify occult metastasis in patients with T1G2 cn0 SCCp. Although no learning curve has been observed, logically, DSNB is best done in a high-volume centre. Author contributions: Nick Watkin had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Lam, Corbishley, Pilcher, Heenan, Perry, Sharma, Watkin. Acquisition of data: Lam, Alnajjar, La-Touche. Analysis and interpretation of data: Lam, Watkin. Drafting of the manuscript: Lam, Watkin. Critical revision of the manuscript for important intellectual content: Lam, Watkin. Statistical analysis: Lam, Watkin. Obtaining funding: None. Administrative, technical, or material support: None. Supervision: Watkin. Other (specify): None. Financial disclosures: Nick Watkin certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: None. Funding/Support and role of the sponsor: None. References [1] Pizzocaro G, Algaba F, Horenblas S, et al. 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