PATIENTS AND METHODS. We reviewed patients with SCC of the penis from five different urological centres. The

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1 2008 The Authors; Journal compilation 2008 BJU International Original Article LYMPH-NODE METASTASES IN INTERMEDIATE-RISK SQUAMOUS CELL CARCINOMA OF THE PENIS NAUMANN et al. BJUI BJU INTERNATIONAL Lymph-node metastases in intermediate-risk squamous cell carcinoma of the penis Carsten M. Naumann, Ibrahim Alkatout*, Amr Al-Najar, Joanna Beate Korda, Axel Hegele, Christian Bolenz, Heiko Ziegler, Günter Klöppel*, Klaus-Peter Juenemann and Christof van der Horst Departments of Urology and Paediatric Urology and *Pathology, University Hospital Schleswig Holstein, Campus Kiel, Department of Urology, University Hospital Cologne, University Hospital Giessen and Marburg GmbH, University Hospital Mannheim, and Hospital of Ruppin, Germany Accepted for publication 8 February 2008 C.M.N. and I.A. contributed equally to this manuscript OBJECTIVE To evaluate the metastatic risk of pt1 G2 squamous cell carcinoma (SCC) of the penis. PATIENTS AND METHODS We retrospectively reviewed 20 patients with pt1 G2 penile SCC and determined their groin status at first presentation, their nodal status after inguinal lymph node dissection and their follow-up for at least 18 months. RESULTS Four of the 20 patients had a clinically positive groin; three of these were found to have lymph node metastases. Among the 16 patients with a clinically negative groin, one of five who had surgical lymph node staging had lymph node metastases. During surveillance six of 11 patients developed lymph node metastases. There was lymphovascular invasion in three of 10 patients with lymph node metastases. CONCLUSIONS As the metastatic risk of pt1 G2 penile SCC was 50% in this series of patients, and 44% in those with an initially negative groin, surgical staging of inguinal lymph nodes is recommended in patients with pt1 G2 penile SCC. KEYWORDS penile carcinoma, intermediate risk, lymph node metastases, surveillance INTRODUCTION The presence, extent and adequate therapy of inguinal lymph node metastases (LNMs) in patients with penile squamous cell carcinoma (SCC) are all crucial determinants of the survival rate [1 3]. Patients with penile SCC benefit from early removal of occult LNM, but LN dissection (LND) as a standard procedure in all patients leads to a significant number of unnecessary surgical interventions, accompanied by severe morbidity rates [4,5]. The European Association of Urology (EAU) is the only urological association that has defined risk groups for the development of lymphatic spread, to counterbalance the survival benefit and morbidity of early LN removal. According to the EAU guidelines (the only available guidelines published), pt1 G2 penile carcinomas with impalpable inguinal LNs at presentation represent the intermediate-risk group, with an estimated metastatic risk between that of low-risk (<16.5%) and high-risk tumours (>68%) [1]. The precise risk for the development of LNMs in patients with pt1 G2 penile SCC and clinically negative groins (cn0) is so far unknown. The reason might be that pt1 G2 penile SCCs are usually combined with noninvasive papillary tumours, in situ carcinomas and/or different tumour grades [2,6]. There are only a few studies describing the metastatic potential of pt1 G2 carcinoma [7 9]. Recently published abstracts discussing the incidence of LNMs in a few patients with pt1 G2 SCC of the penis show an overall metastatic risk of 55 66%, and suggest that the metastatic potential of this tumour might have been underestimated in earlier reports [10,11]. The aim of the present study was to determine the metastatic potential of pt1 G2 SCC of the penis in patients whose disease and follow-up was well documented, and whose histopathology of the primary tumour was re-assessed. PATIENTS AND METHODS We reviewed patients with SCC of the penis from five different urological centres. The criteria for inclusion were: initial treatment of the primary tumour in one of the study centres; T1 stage and G2 differentiation; known groin status at first presentation (established by clinical examination and/or CT/ultrasonography); and free surgical margins during primary treatment with no local recurrence during the follow-up. All tumour specimens were re-assessed by two pathologists (I.A. and G.K.) using the current TNM and WHO classifications [12,13]. According to the TNM guidelines, a pt1 SCC of the penis is defined as a tumour invading the subepithelial connective tissue without invading the corpora cavernosa, corpora spongiosa (pt2), the urethra or the prostate (pt3) or other adjacent structures (pt4). G2 SCC show moderate epithelial dysplasia extending into the middle third of the epithelium with cytologically atypical cells (increased nuclear pleomorphism and mitotic activity) [12 14]. In addition, the number of mitoses per 10 high-power fields ( 400) was determined, and the depth of invasion and tumour thickness were measured from the 1102 JOURNAL COMPILATION 2008 BJU INTERNATIONAL 102, doi: /j x x

2 L YMPH-NODE METASTASES IN INTERMEDIATE-RISK SQUAMOUS CELL CARCINOMA OF THE PENIS TABLE 1 The clinical course of 20 patients with pt1 G2 SCC of the penis; clinical groin status had no significant effect on pathological nodal status (P = 0.582, two-sided Fisher s exact test) Clinical groin status (n) Therapeutic approach (n) Nodal status cn+ (4) ILND 3 pn + (2 N1, 1 N3), 1 pn0 cn0 (16) Surgical LN staging 1 pn + (pn1), 4 pn0 ILND (4) DSNB (1) Surveillance 6 pn + (1 N1, 3 N2, 2 N3) (11) 5 cn0 intact basement membrane at the edge of the primary tumour to the deepest tumour cell. Tumour thickness was measured from the top of the tumour to the deepest tumour cell. The nodal status was based on an uneventful clinical follow-up for 18 months, inguinal (I)LND or dynamic sentinel node biopsy (DSNB). In case of prophylactic ILND, the applied techniques were either a modified ILND according to Catalona [15] or a radical ILND, depending mainly on the surgeon s preference and the guidelines of the participating institution. The criteria for selecting the therapeutic approach in the cn0 group depended on the preferred treatment policy within the participating departments and on the patients preference. If there were two or more pathologically confirmed LNM, LND was followed by pelvic LND. The effect of the clinical groin status on pathological LNMs was tested by Fisher s exact test. Further analyses of the effects of histopathological features on the metastatic risk were used in the cn0 group only, as groin dissection is strongly recommended for persisting enlarged LNs. The follow-up was initiated at the date of primary surgery with or without ILND, depending on the therapeutic approach. Because there were relatively few patients and many pathological features, the statistical power of the study was limited. Therefore, only the growth pattern, lymphatic or venous invasion (Fisher s exact test), depth of invasion and tumour size (Mann Whitney test) were tested for their effect on the development of lymphatic spread. For disease-free survival (DFS), the event was nodal recurrence; in the absence of an event, censoring took place at the last follow-up visit. DFS was analysed using the Kaplan- Meier method and rates were analysed for significance using the log-rank test. Overall survival was not considered as there were few events. Significance was defined at P < In Germany, institutional review board approval was not needed for this retrospective clinical study, but each patient provided signed informed consent before surgery, including a statement about the anonymous use of clinical data for scientific purposes. RESULTS Between 1996 and 2005, 20 of 88 patients with SCC of the penis met the inclusion criteria of the study (mean age 65 years, range 39 84); the mean (range) follow-up was 31.4 (11 83) months. Patients had partial penile amputation, circumcision or local excision. There was no local recurrence during the follow-up. At initial presentation, four patients had clinically positive ILNs (cn+) and 16 had a negative groin (cn0). The clinical course and therapeutic approach in these patients are shown in Table 1. After antibiotic therapy for 3 6 weeks, all patients in the cn+ group had a radical ILND for persistently enlarged LN; three of four patients in this group had LNMs (Table 1). In the cn0 group of 16 patients, five had surgical LN staging of both groins (prophylactic ILND in four and DSNB in one), either during surgery of the primary tumour or within 2 6 weeks after initial surgery. The mean (range) number of dissected LN was 19.5 (11 25) per patient for both groins. The patient who had DNSB had an uneventful follow-up of 26 months. One of five patients in this group staged by surgical dissection had an isolated LNM, while six of 11 in the surveillance group developed LNMs. The metastatic risk was 50% (10 of 20 patients) for all patients, and seven of 16 in the cn0 group. The clinical groin status had no significant effect on the pathological nodal status (P = 0.582, two-sided Fisher s exact test; Table 1). There was no nodal relapse in the surgically staged LN group, in which the mean (range) DFS (defined as the time from primary treatment to nodal relapse) was 36.8 (18 83) months. However, the mean DFS in the surveillance group was 19.6 (4 62) months. The mean time that elapsed in the six patients who developed LNM during surveillance was 6.5 (4 11) months. The difference in the DFS in the two groups (i.e. those with and those with no surgical staging of LN) was not significant, although there was a clear trend to a prolonged DFS in the surgically staged group (P = 0.055, log-rank test). As there was no recurrence or death in the patients who had surgical LN staging, overall survival was equal to DFS (36.8, months). In the surveillance group, one patient died from toxicity of the neoadjuvant chemotherapy (methotrexate, cisplatin and bleomycin). Two further patients died because of progressive metastatic disease despite extensive surgical treatment and subsequent adjuvant chemotherapy. Overall survival was not statistically analysed as there were too few events (three deaths) and different adjuvant regimens in patients with more than one positive LN within this multi-institutional approach. In the surgically staged group two patients developed mild wound dehiscence, which required no further surgical therapy. One lymphocele was treated by a single puncture. However, the morbidity in patients who had therapeutic ILND due to metastases was severe. Two patients had complex wound healing failure requiring multiple surgical interventions and subsequent vacuumassisted wound closure. Two other patients had radiotherapy for lymphorrhoea and recurrent lymphoceles. Table 2 shows the histopathological features of patients with and with no LNMs in the cn0 group. Figure 1 shows histopathological slides of patients with and with no LNMs in the cn0 group. JOURNAL COMPILATION 2008 BJU INTERNATIONAL 1103

3 NAUMANN ET AL. TABLE 2 Histopathological features of tumours with and without confirmed LNMs according to the WHO classification [13] in the cn0 group. As most patients with penile SCC usually develop LNM within 18 months [1], those with no events during surveillance over this period were considered to be free of lymphatic spread. LVI, growth pattern, depth of invasion and tumour size in both groups were analysed; there was a significant difference only for depth of invasion (P = 0.011, Mann Whitney test). Remarkably, four of seven patients with confirmed metastases had no LVI Variable cn0/pn0 pn+ No. of patients 9 7 LVI Lymphatic 3 Venous 2 Growth pattern Vertical 3 3 Superficial spreading 6 4 Multicentric 1* Histological type Usual 8 6 Papillary, not otherwise specified Warty (condylomatous) 1 Verrucous Basaloid 1 Sarcomatoid Adenosquamous Mean (range): Depth of invasion, mm 2.9 (0.8 6) 5.4 (2.5 10) Tumour size, cm 2.3 ( ) 2.8 ( ) FIG. 1. a, pt1g2 penile SCC with no LNM during the clinical course, showing superficial spreading, moderately differentiated SCC invading subepithelial tissue: b, pt1g2 penile SCC which developed LNM (both haematoxylin and eosin, 5). a b *Superficial spreading. At the initial histopathological examination, one tumour showed lymphatic invasion. Two other tumours were only found to have lymphatic invasion after examination of additional serial sections. All three patients developed LNMs. Both tumours with venous invasion also showed lymphatic invasion. In the cn0 group, four of seven patients with confirmed metastases had no lymphovascular invasion (LVI). Four of 13 patients with clinically negative LNs and absence of LVI were confirmed to have LN involvement. Among the pathological features that were statistically analysed, only the depth of invasion was a risk factor for nodal involvement (P = 0.011, Mann Whitney test), whereas lymphatic or venous invasion, growth pattern and tumour size had no significant effect on nodal involvement. DISCUSSION SCC of the penis spreads mainly through the lymphatic vessels to inguinal and subsequently to pelvic LNs. The survival of the patient depends on the presence and extent of LNMs and their adequate therapy [1,16]. However, the therapeutic approach, particularly if for clinically node-negative groins, is a matter of controversy, due to the high morbidity of ILND of 24 87% [1 3]. The significant survival benefit of up to 49% resulting from early prophylactic ILND for the 29% of these patients with clinically occult metastases [1,3 5] must be contrasted with the risks and substantial morbidity of unnecessary ILND in the 71% of patients in whom there is no metastatic disease [2]. Single-centre studies, although sometimes with only small groups of patient, have shown novel diagnostic approaches like DSNB, lymphotropic nanoparticle MRI and 18 F- fluorodeoxyglucose positron emission tomography/ct to be useful in this diagnostic dilemma. Unfortunately, the predictive value of these techniques for metastatic LN involvement in low- or intermediate-risk carcinoma has yet to be established [17 19]. In earlier retrospective and prospective series with four pt1 G2 tumours each, Solsona et al. [8,9] reported a 25% incidence of lymphatic spread. Further studies assessing the incidence of LNM in pt1 G2 SCC of the penis suggested that the metastatic potential of this tumour might have been underestimated in previous reports. Series with fewer than 10 patients have shown the overall metastatic risk to be 50 66% [7,10,11]. Although pt1 G2 SCC of the penis with clinically impalpable ILNs represents the intermediate-risk group, according to the guidelines of the EAU, the incidence of metastatic disease in this risk group is not mentioned [1]. This might be because pt1 G2 penile SCCs are usually pooled with noninvasive tumours and/or well or poorly differentiated tumours [2,20,21]. In the present study we focused exclusively on the metastatic potential of pt1 G2 SCC of the penis; the overall metastatic risk was 50%. Provided that the clinical groin status is negative, the estimated probability of occult metastatic disease was 44%. These results confirm the findings of Leijte et al. [22], who 1104 JOURNAL COMPILATION 2008 BJU INTERNATIONAL

4 L YMPH-NODE METASTASES IN INTERMEDIATE-RISK SQUAMOUS CELL CARCINOMA OF THE PENIS detected lymphatic spread in four of nine patients with intermediate-risk penile carcinoma using DSNB. The evidence of LN involvement was about three times greater in the surveillance group than in the surgically dissected group, possibly because a standard histological examination of grossly negative LNs occasionally fails to detect lymphatic spread. Ornellas et al. [23] reported a series of 350 surgically treated patients with penile carcinoma; in the group with clinical stage N0 tumours, 39% (nine of 23) of the surgically staged patients had confirmed inguinal metastases, but 94% (16 of 17) of patients who had initial surveillance developed LNMs. However, in the series of Ficarra et al. [24] the incidence of LNMs was comparable in the surgically staged and the surveillance group (20% vs 21%). Sampling errors and understaging by conventional methods for examining non-sentinel LNs remain an unsolved problem in LN staging. To our knowledge no step-sectioning technique, with or without immunohistochemistry, has been applied so far to non-sentinel nodes in penile cancer. Therefore, it remains to be established to what extent histological examination of grossly negative LNs contributes to nodal understaging in penile cancer. The few available data on the metastatic risk of T1 penile SCC that are not pooled with non-invasive tumours are contradictory. Slaton et al. [20] reported no LN involvement in 15 T1 carcinomas, whereas Theodorescu et al. [21] found a 58% risk of metastatic disease in 24 patients with T1 carcinoma, irrespective of the tumour grade. The few patients and pooled data, that make no allowances for different tumour grades with their respective metastatic risks, might be responsible for these diverse clinical findings. In 2005 Ficarra et al. [6] retrospectively analysed the data from 175 patients with penile SCC and established a nomogram predicting LN involvement, using the same patients as in 2006 [24]. In the subgroup of patients with T1G2 penile SCC and negative clinical groins, only four of 17 were reported to have LN involvement [6]. According to that nomogram, intermediately differentiated and superficially spreading tumours have a greater risk of metastasis than poorly differentiated and vertically growing tumours. These results are in contradiction to those of other studies, and were recently critically discussed by Leijte and Horenblas [25]. LVI is thought to be a helpful criterion in deciding for or against ILND [1,6,20]. In the present series, the histopathological evaluation showed LVI in only three patients, all of whom developed metastases. By contrast, LVI was absent in seven of 10 patients who had metastatic disease. In the study by Malhotra et al. [11] LVI was absent in all pt1g2 penile carcinomas; four of six patients developed positive nodes. Moreover, in a series of 40 patients with histopathologically confirmed metastases, 33 primary tumours (83%) had no LVI [5]. These findings suggest that the absence of LVI might not be a reliable indicator of the absence of occult LNMs, while lymphatic spread must be assumed when LVI is confirmed. These data and our findings suggest that molecular diagnostic markers predicting LNM are needed. E-cadherin immunostaining might be a candidate, but further studies are necessary [26]. The present results are retrospective and were collected from relatively few patients, but to our knowledge this study includes the most patients with pt1g2 penile SCC. It is obvious that these limitations lead to a restricted statistical power, which could only be overcome by assessing more patients in a multicentre approach. Nevertheless, the clinical course of these patients showed that they clearly benefited from surgical LN staging, although the comparison of DFS in the two groups was not quite statistically significant. As long as reliable predictive markers and novel imaging techniques are unavailable, and studies with more patients have not confirmed a substantially lower metastatic potential, surgical staging of the groin is to be recommended, as in this study half of all patients with pt1 G2 penile SCC and 44% of those with clinically node-negative groins developed inguinal LNM. DSNB might be an alternative to ILND [17], but one should be aware of possible false-negative rates and the issue of quality control in this rare disease. In conclusion, from our experience, surgical LN staging is to be recommended in pt1 G2 SCC of the penis, even in the face of clinically negative groins and the absence of LVI. A surveillance strategy no longer seems to be justified in these tumours, as the early removal of occult metastases improves survival. ACKNOWLEDGEMENTS We thank Mrs Ulrike Schulz for her statistical advice and Mrs Almut Kalz for assistance in preparing this manuscript. Research Funding by the Medical Faculty of Christian Albrecht University (CAU), Kiel. CONFLICT OF INTEREST None declared. REFERENCES 1 Solsona E, Algaba F, Horenblas S, Pizzocaro G, Windahl T. Guidelines on Penile Cancer. European Association of Urology. Available at: guidelines/22891_penile_cancer.pdf. Accessed March Sanchez-Ortiz RF, Curtis A, Pettaway CA. The role of lymphadenectomy in penile cancer. Urol Oncol 2004; 22: Pandey D, Mahajan V, Kannan R. Prognostic factors in node-positive carcinoma of the penis. J Surg Oncol 2006; 93: McDougal WS. Carcinoma of the penis: improved survival by early regional lymphadenectomy based on the histological grade and of invasion of the primary lesion. J Urol 1995; 154: Kroon BK, Horenblas S, Lont AP, Tanis PJ, Gallee MPW, Nieweg OE. Patients with penile carcinoma benefit from immediate resection of clinically occult lymph node metastases. J Urol 2005; 173: Ficarra V, Zattoni F, Cunico SC et al. Lymphatic and vascular embolizations are independent predictive variables of inguinal lymph node involvement in patients with squamous cell carcinoma of the penis: Gruppo Uro-Oncologico del Nord Est (Northeast Uro-Oncological Group) Penile Cancer data base data. Cancer 2005; 103: Naumann CM, Filippow N, Seif C et al. JOURNAL COMPILATION 2008 BJU INTERNATIONAL 1105

5 NAUMANN ET AL. Penile carcinoma (pt1g2): surveillance or inguinal lymph node dissection? Onkologie 2005; 28: Solsona E, Iborra I, Ricos JV et al. Corpus cavernosum invasion and tumor grade in the prediction of lymph node condition in penile carcinoma. Eur Urol 1992; 22: Solsona E, Iborra I, Rubio J, Casanova JL, Ricos JV, Calabuig C. Prospective validation of the association of local tumor stage and grade as predictive factor for occult lymph node micrometastasis in patients with penile carcinoma and clinically negative inguinal lymph nodes. J Urol 2001; 165: Protzel C, Knodel JE, Zimmermann U, Klebingat KJ, Giebel J, Woenckhaus C. Strong expression of proliferation marker KI67 predict lymph node metastasis in patients with penile cancer. J Urol 2004; 171 (Suppl.): Malhotra SM, Rouse RV, Azzi R, Reese JH. Expectant management in patients with T1 moderately differentiated penile cancer: is observation truly appropriate? J Urol 2006; 175 (Suppl.): Sobin LH, Wittekind Ch. TNM Classification of Malignant Tumors, 6th edn. New York: Wiley-Liss, Cubilla AL, Dillner J, Schellhammer PF et al. Tumours of the penis. In Eble J, Sauter G, Epstein JI, Sesterhenn IA eds, World Health Organization Classification of Tumours. Pathology and Genetics of Tumours of the Urinary System and Male Genital Organs. Lyon: International Agency for Research on Cancer (IARC) Press, 2004: Broders AC. Squamous cell epithelioma of the skin. Ann Surg 1921; 73: Catalona WJ. Modified inguinal lymphadenectomy for carcinoma of the penis with preservation of saphenous veins: technique and preliminary results. J Urol 1988; 140: Culkin JC, Beer TM. Advanced penile carcinoma. J Urol 2003; 170: Kroon BK, Horenblas S, Meinhardt W et al. Dynamic sentinel node biopsy in penile carcinoma. Evaluation of 10 years experience. Eur Urol 2005; 47: Tabatabaei S, Harisinghani M, McDougal WS. Regional lymph node staging using lymphotropic nanoparticle enhanced magnetic resonance imaging with ferumoxtran-10 in patients with penile cancer. J Urol 2005; 174: Scher B, Seitz M, Reiser M et al. 18F-FDG PET/CT for staging of penile cancer. J Nucl Med 2005; 46: Slaton JW, Morgenstern N, Levy DA et al. Tumor stage, vascular invasion and percentage of poorly differentiated cancer: independent prognosticators for inguinal lymph node metastasis in penile squamous cancer. J Urol 2001; 165: Theodorescu D, Russo P, Zhang ZF, Morash C, Fair WR. Outcomes of initial surveillance of invasive squamous cell carcinoma of the penis and negative nodes. J Urol 1996; 155: Leijte JAP, Kroon BK, Valdes Olmos RA, Nieweg OE, Horenblas S. Reliability and safety of current dynamic sentinel node biopsy for penile carcinoma. Eur Urol 2007; 52: Ornellas AA, Seixas AL, Marota A, Wisnescky A, Campos F, de Moraes JR. Surgical treatment of invasive squamous cell carcinoma of the penis: retrospective analysis of 350 cases. J Urol 1994; 151: Ficarra V, Zattoni F, Artibani W et al. Penile Cancer Project Members. Nomogram predictive of pathological inguinal lymph node involvement in patients with squamous cell carcinoma of the penis. J Urol 2006; 175: Leijte JAP, Horenblas S. Rebuttal from Authors re. Eric Wespes. The management of regional lymph nodes in patients with penile carcinoma and reliability of sentinel node biopsy. Eur Urol.; 52: 15 6 and re: Vincenzo Ficarra and Antonio Galfano. Should the dynamic sentinel node biopsy (DSNB) be considered the gold standard in the evaluation of lymph node status in patients with penile carcinoma? Eur Urol 2007, 52: Eur Urol 2007; 52: Campos RS, Lopes A, Guimaraes GC, Carvalho AL, Soares FA. E-cadherin, MMP-2, and MMP-9 as prognostic markers in penile cancer: analysis of 125 patients. Urology 2006; 67: Correspondence: Carsten Maik Naumann, Department of Urology and Paediatric Urology, University Hospital Schleswig Holstein, Campus Kiel, Arnold Heller Str. 7, Kiel, Germany. c.naumann@urology.uni-kiel.de Abbreviations: SCC, squamous cell carcinoma; (I)(LN)(M)(D), (inguinal) lymph node (metastasis) (dissection); DSNB, dynamic sentinel node biopsy; EAU, European Association of Urology; DFS, disease-free survival; LVI, lymphovascular invasion JOURNAL COMPILATION 2008 BJU INTERNATIONAL