Intermediate-differentiated invasive (pT1 G2) penile cancer—oncological outcome and follow-up

Urologic Oncology: Seminars and Original Investigations 29 (2011) 782–787

Original article

Intermediate-differentiated invasive (pT1 G2) penile cancer— oncological outcome and follow-up Boris Schlenker, M.D.a,*, Derya Tilki, M.D.a, Christian Gratzke, M.D.a, Michael Seitz, M.D.a, Oliver Reich, M.D.a, Peter Schneede, M.D.b, Christian G. Stief, M.D.a, Edwin Hungerhuber, M.D.c a

Department of Urology, University Hospital Grosshadern, Ludwig-Maximilians University, Munich, Germany b Department of Urology, Hospital Memmingen, Memmingen, Germany c Department of Urology, Hospital Muehldorf, Muehldorf, Germany Received 23 July 2009; received in revised form 23 August 2009; accepted 25 August 2009

Abstract Objectives and aims: Due to the low prevalence of penile cancer, little evidence exists on the metastatic potential and the ideal treatment strategies in intermediate-differentiated invasive (pT1 G2) penile cancer. The current study aimed to analyze the oncologic outcome of patients with penile carcinoma with long-term follow-up in a single-center study. Patients and methods: In this retrospective study, 38 patients with histologically proven T1 G2 squamous cell carcinoma of the penis were included. Only the ‘classic’ subtype was analyzed. Treatment of the primary tumor was Nd:YAG laser-therapy, excision, or partial amputation. Follow-up was performed according to EAU guidelines (2004). Results: Mean follow-up was 78.1 months (range: 9 –285 months). Local recurrence was seen in 12 patients (31.6%), but was not correlated with disease related death (P ⫽ 0.7944). Rate of local recurrence was not dependent on treatment modality (P ⫽ 0.3481); 13 patients died, accounting for a disease related survival rate of 81.6% during observation period. Positive lymph nodes were seen in 28.9% of patients and were significantly correlated with disease related death (P ⫽ 0.00004). Clinically enlarged inguinal lymph nodes were not correlated with histologically confirmed positive lymph nodes (P ⫽ 0.5785). Conclusions: For patients with T1 G2 penile cancer, organ preserving therapy appears to be a suitable treatment option. In our series, nearly one third of patients developed inguinal lymph node metastases, which highlights the potential benefit of surgical staging. Larger prospective multicenter studies are needed to define the best treatment strategy for intermediate-differentiated invasive penile cancer. © 2011 Elsevier Inc. All rights reserved. Keywords: Penile cancer; Squamous cell carcinoma; Intermediate-differentiated; Laser-therapy; Lymph node metastases

1. Introduction Penile cancer is a very rare tumor entity in Western countries. The incidence in Europe and the United States ranges between 0.3 and 1.8 per 100,000 men [1]. The treatment of the local tumor is often associated with loss of sexual function and therefore with a significant decline in quality of life [2]. The only available guideline for penile cancer published by the European Association of Urology (EAU) recommends organ preserving therapy for early stages (Tis, T1 G1, and T1 G2) [3]. Particularly in T1 G2 penile cancer, there are controversial reports about its metastatic potential. While some authors re* Corresponding author. Tel.: ⫹49-89-7095-0; fax: ⫹49-89-7095-8890. E-mail address: [email protected] (B. Schlenker). 1078-1439/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.urolonc.2009.08.022

port as little as 0% lymph node metastases after 5 years, recent studies have found positive lymph nodes in 50% of patients [4,5]. In the last 2 years, large retrospective studies designed to evaluate the natural history and treatment options of penile cancer have been published [6,7]. However, no information exists about local recurrence rates and its impact on metastatic spread for T1 G2 tumors. Therefore, the current study aimed to analyze local recurrence and lymphatic spread in patients with T1 G2 tumors. 2. Patients and methods The study was approved by the local ethics committee. Patients with invasive intermediate-differentiated penile cancer presenting in our center were included in this retro-

B. Schlenker et al. / Urologic Oncology: Seminars and Original Investigations 29 (2011) 782–787

spective study (n ⫽ 38). Inclusion criteria were a histologically proven T1 G2 tumor (according to the 2002 TNM classification system [8]) followed by partial amputation (n ⫽ 11), tumor excision (n ⫽ 5), or laser therapy (n ⫽ 22), and a closely documented follow-up. In general organ preserving laser therapy was recommended for younger sexually active patients and smaller tumors. Especially older or sexually not active patients tended to prefer partial amputation due to a lower recurrence rate. The TNM classification system defines a T1 penile carcinoma as a tumor that ‘invades subepithelial connective tissue’ but not corpus spongiosum or cavernosum or other structures like urethra or prostate [8]. A G2 differentiation describes an ‘intermediate’ differentiated tumor, which means that it is neither ‘well differentiated’ (G1) nor ‘poorly differentiated’ or ‘anaplastic’ (G3) [8]. In order to have consistent and, therefore, better comparable results we only included the ‘classic’ subtype of penile squamous cell carcinoma (SCC) [3,8]. Exclusion criteria for the study were nonsurgical therapy (e.g., percutaneous radiation or brachy-therapy) or patient declining further therapy or diagnosis. Additionally, patients were excluded if the initial biopsy of the tumor showed a T1 G2 tumor and the immediate following surgical therapy (e.g., partial amputation) revealed a different tumor stage or differentiation. All histopathologic subtypes other than ‘classic’ (e.g., verrucous or basaloid) were excluded. Local recurrence was defined as a recurrence of the disease later than 3 months after primary treatment. Earlier recurrences were defined as persistent disease and patients were excluded from the study (n ⫽ 3) [7]. Laser therapy was performed using a Nd:YAG-Laser (␭ ⫽ 1064 nm, continuous wave mode, 25– 40 watt, intermittent cooling by water) as described before [9]. Primary laser-therapy always was combined with radical circumcision if the patient was non-circumcised. The oncologic follow-up was documented during the visits in the outpatient clinic of our center or by telephone interviews of the local urologists. The follow-up recommendations were adapted from the EAU guidelines and included 2 monthly visits during the first 2 years, 3 monthly visits in the third year, and 6 monthly visits from year 4 on [3]. Three patients were excluded as they died within 3 month after diagnosis due to cardiovascular events. In addition, lymph node status, time to local recurrence, number of recurrences, and cause of death were assessed. The lymph nodes were classified as negative at the time of first diagnosis of penile cancer if the histopathologic finding of the radical inguinal lymph node dissection [10] was negative. If no inguinal lymph node dissection was performed, the status of the nodes was only defined as negative, if an initial and at least 2 consecutive CT scans during follow-up showed no signs for lymphatic spread. If no CT scan was performed, the status of the inguinal lymph nodes was considered to be negative if in the clinical follow-up (ultrasound plus physical examination) for at least 24

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months no signs for lymphatic spread were monitored. Within this time, inguinal metastases should become clinically apparent [5]. In case of more than 2 positive inguinal lymph nodes, a pelvic lymph node dissection was performed if the patient was fit for treatment. In lymph node positive patients, an adjuvant chemotherapy and/or percutaneous radiation therapy (ipsilateral groin and pelvis) was added. All statistics were calculated using STATISTICA 8 (StatSoft Inc., Tulsa, OK), significance was defined for P ⬍ 0.05. ␹2 Test was used to calculate correlation between clinical lymph node status and pathological lymph node status, the different local therapy options and recurrence rate, impact of recurrence on cancer related survival, and correlation between positive lymph nodes and disease related death.

3. Results Between 1982 and 2008, 38 out of 231 treated patients met the inclusion criteria. Mean age at time of diagnosis was 61.0 years (range: 25–93 years). The mean follow-up was 78.1 months (range: 9 –285 months). During follow-up, 13 patients died, 7 of them due to penile cancer, 3 patients due to other malignant tumors, and the other 3 patients due to cardiovascular events. The disease-related survival rate was 81.6%. Treatment of the primary tumor was performed using Nd:YAG laser-therapy (n ⫽ 22), excision or circumcision (n ⫽ 5), or partial amputation (n ⫽ 11). Local recurrence was seen in 12 patients (overall 31.6%; n ⫽ 9 after lasertherapy; n ⫽ 1 after circumcision; n ⫽ 2 after (partial) amputation), and was monitored 21.2 months after primary treatment on average (range: 4 –234 months). Treatment for local recurrence was partial or total amputation (n ⫽ 6), excision (n ⫽ 2), or repeated laser-therapy (n ⫽ 4). There was no significant correlation between the different local therapy techniques and risk of local recurrence (P ⫽ 0.3481). In the group of patients without local recurrence (n ⫽ 26), 5 patients died due to penile cancer (19.23%). In patients with local recurrence (n ⫽ 12), 2 patients (16.67%) died as a consequence of their underlying disease. There was no significant correlation between the incidence of a local recurrence and death related to penile cancer (P ⫽ 0.7944). At first diagnosis of penile cancer, 13 patients presented with clinical suspicious inguinal lymph nodes, which were either palpable or enlarged in the staging CT scan. A radical inguinal lymph node dissection was performed in 8 patients. Five cN⫹ patients refused surgery. In this patient group, lymphadenectomy confirmed 2 patients with inguinal lymph node metastasis. The other 6 patients were staged pN0 despite clinically suspect inguinal nodes. One patient, however, developed a histologically confirmed inguinal lymph

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node metastasis 7 months after first lymphadenectomy. The remaining 5 patients remained cN0. In the group of patients presenting with clinically nonsuspect inguinal lymph nodes (n ⫽ 25), prophylactic or staging lymphadenectomy was discussed with the patient. Inguinal lymph node dissection was performed in 8 patients. Seven patients were staged pN0, 1 had a positive lymph node. One patient who underwent radical lymphadenectomy developed a histologically confirmed lymph node metastasis 9 months after surgery. Altogether, 6 patients in the cN0 group at first presentation had positive lymph nodes during follow-up. The positive lymph nodes were diagnosed 9.7 months (range: 0 –22) on average after first diagnosis of penile cancer. The positive lymph nodes developed together with a local recurrence in 50% of cases (n ⫽ 3).

The overall rate of positive lymph nodes in our patient group during follow-up was 28.9%. Positive lymph nodes were significantly correlated with disease-related death (P ⫽ 0.00004). There was no correlation between the clinical presentation and examination of inguinal lymph nodes and the histologically confirmed specimen or clinical follow-up, respectively (P ⫽ 0.5785). Table 1 gives an overview of lymph node status at first presentation and during follow-up as well as about local therapy and recurrences.

4. Discussion Due to the low prevalence rate of penile carcinoma, the ideal management of the primary tumor and lymph nodes is

Table 1 Patient characteristics No.

Age at diagnosis [y]

FU [m]

LN status at first presentation (clinical)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38

46 50 67 68 72 54 82 58 60 57 48 78 47 49 47 62 65 33 93 68 73 75 53 56 59 70 25 52 64 64 83 71 68 70 46 62 76 48

182 152 95 83 21 152 17 113 270 160 100 15 15 83 78 80 66 285 28 15 12 64 71 12 244 76 60 58 57 56 55 50 40 42 27 13 12 9

cN⫹ cN0 cN0 cN⫹ cN⫹ cN0 cN0 cN0 cN⫹ cN⫹ cN⫹ cN0 cN0 cN0 cN⫹ cN⫹ cN0 cN⫹ cN0 cN⫹ cN⫹ cN0 cN0 cN⫹ cN0 cN0 cN0 cN0 cN0 cN0 cN0 cN0 cN0 cN0 cN0 cN0 cN0 cN⫹

LN status at first presentation (histologically confirmed) pN0 pN0 pN0 pN0 pN0 pN0 pN0 pN0 pN1 pN0

pN0 pN1 pN1

pN0

pN0

pN0

LN status during FU

Local therapy

Local recurrence

cN0 pN0 pN0 pN0 pN3 pN0 cN0 pN0 pN2 pN0 pN0 pN2 pN1 pN1 pN0 cN0 cN0 pN0 cN0 pN1 pN1 cN0 cN0 pN2 pN3 cN0 cN0 cN0 pN0 cN0 cN0 cN0 pN3 cN0 pN2 cN0 pN0 cN0

Laser therapy Laser therapy Laser therapy Laser therapy (Part.) amputation Laser therapy (Part.) amputation Laser therapy Laser therapy Laser therapy Laser therapy (Part.) amputation Circumcision/excision Laser therapy (Part.) amputation Laser therapy Laser therapy (Part.) amputation (Part.) amputation (Part.) amputation (Part.) amputation Laser therapy Laser therapy (Part.) amputation (Part.) amputation Circumcision/excision Laser therapy Laser therapy Laser therapy Laser therapy Laser therapy Circumcision/excision Circumcision/excision Laser therapy Circumcision/excision Laser therapy (Part.) amputation Laser therapy

Yes No Yes No No No No No Yes No Yes No No Yes No No No Yes No No No Yes No No Yes No No No Yes No No No Yes Yes No Yes No No

Time until local recurrence [m]

Cause of death related to penile cancer

81 4

No No Yes No

177 60 No Yes 41

94 No Yes Yes 53

234

Yes Yes No

16

9 28 9

Yes

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currently under debate. We present results from a large series of patients with T1 G2 penile cancer, focusing on oncological outcome. Local therapy of penile cancer is always a balance of radicality from an oncologic point of view on the one hand and the preservation of sexual function and, thus, quality of life on the other hand. This is especially true for the early stages (Tis–T1) of the disease with well to intermediate differentiated tumors (G1–G2). According to the EAU guidelines on penile cancer, T1 G2 tumors are considered to be of ‘intermediate-risk’ for positive lymph nodes, and an organ-preserving therapy is strongly recommended [3]. However, other studies prove that T1 G2 tumors imply a significant risk for metastatic lymphatic spread. In a small series of 20 patients from 5 different centers, Naumann et al. reported the risk for lymphatic spread to be as high as 50% [11]. These data are similar to a subanalysis of a Dynamic Sentinel Node Biopsy (DSNB) series published by Leijte et al. [5]. In this series, 4 of 9 patients (54%) developed lymph node metastases. In contrast, Hegarty et al. published no positive lymph nodes in the T1 G2 subgroup in a prospective study [4], whereas Solsona reported 25% positive lymph nodes in 2 studies with 4 patients each [12]. In our own series, nearly one-third of patients (28.9%) had positive lymph nodes at first presentation or during follow-up. There might be different explanations for this wide range of positive lymph nodes; first, it could be caused by sampling errors due to the small sample size. Three studies included only 4 patients, one study 9 patients. Furthermore there was no external validation of pathological findings. As penile cancer is a rare tumor entity, interobserver bias between pathologists in different centers does certainly exist. Positive lymph nodes in our series were highly associated with tumor related death. It is well known from larger series analyzing all tumor stages and gradings that positive lymph nodes are involved with worsening of 5-year cancerspecific survival rates. These rates range between 68.9% and 100% for pN0 patients, and drop to 16%– 45% for pN⫹ patients [6,13,14]. In our patients, the disease-specific survival rate was 81.6 % with a mean follow-up of 78.1 months (range: 9 –285 months). Organ preserving surgery even of recurrent SCC seems to be a good and quality-of-life preserving alternative to (partial) amputation [2]. The impact of local recurrence on survival is reported to be weak [15,16]. In our cohort, there was no significant correlation between the event of local recurrence and tumor-associated death. However, patients have to be compliant as well as to be aware of the higher risk of recurrence in organ preserving treatment strategies. Patient self-examination is strongly advisable. In case of local recurrence, the key for successful treatment is early intervention. In addition, patients with penile cancer tend to delay diagnosis and treatment for up to 12 months [17,18]. In our series, there was delay of treatment even in case of local recurrence as patients hesitated to seek treatment.

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Therefore, data about progression of the disease and death related to penile cancer in our series as well as in other published series is often influenced by individual treatment delay and therefore difficult to compare. There were some relatively late local recurrences seen in our series. From our point of view, a local recurrence after more than 5 years (n ⫽ 5) would better be classified as ‘de novo’ cancer. All other local recurrences were seen 4 to 41 months after first treatment, typically within the first 18 months. This observation is in concordance with the follow-up recommendations of the EAU guidelines. The overall recurrence rate in our series was 31.6% with no significant difference for the local treatment options. This is slightly higher than in a subgroup of the biggest published series about the local recurrence rate of 62 patients with T1 G2 penile cancer, which is reported to be 25.8% [7]. In a small series of 20 patients, Naumann et al. reported no local recurrences for T1 G2 penile cancer patients [11]. As there are no detailed data available about recurrence rates for T1 G2 tumors after different local therapy modalities, Table 2 gives an overview of published recurrence rates for penile preserving therapy for all tumor stages. The reported recurrence rates range from 3.1% to 48%. There are some limitations to our study. First, in our center, we primarily focused on organ preserving laser therapy as suggested by the EAU guidelines. Suitable patients for this therapy are selected by preoperative tumor biopsy. After histologic confirmation of the T1 G2 tumor, Nd:YAG laser is used for coagulation. Coagulated tissue is then removed in successive layers similar to the technique described as Mohs micrographic surgery. As a consequence, the removed completely coagulated tissue is not suitable for further diagnosis of histopathologic parameters like lymphatic embolization or vascular and perineural invasion, as suggested in other publications assessing local risk factors

Table 2 Local recurrence rates after organ preserving conventional surgery and laser-therapy Study

Therapy

Number of patients

Pietrzak et al. (2004) [25] Frimberger et al. (2002) [9] Tietjen et al. (1998) [26] McDougal (2005) [27] Windahl et al. (2003) [16] van Bezooijen et al. (2001) [28] Bissada et al. (2003) [29] Meijer et al. (2007) [30]

Conservative surgery

32

3.1%

Laser therapy

29

6.8%

Laser therapy

44

11.4%

7

14.2%

Conservative surgery

Recurrence rate

Laser therapy

67

19%

Laser therapy

19

26%

Conservative surgery

30

30%

Laser therapy

44

48%

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for recurrence and systemic spread. Therefore, comparison with other published series is difficult as, to our knowledge, all available nomograms are based on partial amputation or excision specimens [19,20 –22]. As for Tis to T1 tumor stages, organ preserving techniques are considered to be the standard, it is to be expected that those nomograms have a better predictive value for higher tumor stages (T2–T4) [23]. Another limitation of the organ preserving strategy is the risk of understaging a T2 or T3 tumor in the preoperative biopsy. Biopsies of penile cancer are difficult to interpret, since the deepest point of invasion, histologic grade, and risk factors like vascular invasion are reported to be incorrect in 30%–91% of cases [24]. This leaves the urologic surgeon in therapeutic dilemma either to limit organ-preserving techniques to highly selected patients or to miss a more deeply invading tumor. In our center, we used intraoperative frozen sections to guide laser therapy and to minimize the risk of a positive surgical margin. Nonetheless, it is often difficult to judge clinically or by frozen sections if the deepest invasion point of a tumor on the glans penis is invading subepithelial connective tissue only (T1) or corpus spongiosum (T2). The local recurrence rate for laser therapy in our series is comparable to other published recurrence rates, ranging between 7% and 48% for all tumor stages and gradings [9,25,26]. However, patient selection by pre- or intraoperative biopsy remains demanding for both pathologist and surgeon, and certainly harbors risks to miss more advanced stages or more aggressive gradings. Nevertheless, it seems that the described rapid section guided therapy in a high-volume center offers a good oncologic outcome. Another limitation is the retrospective nature of the study. We did, however, include only patients with a detailed follow-up. As far as we know, this is one of the largest series of patients with T1 G2 penile cancer published so far. Previous studies either included a smaller number of patients or did not concentrate on T1 G2 tumors in detail [7,11,12]. Also, the frequency and impact of local recurrence on survival has not been assessed before.

5. Conclusions Based on the current data, patients with T1 G2 penile cancer should be offered organ preserving local therapy though local recurrence occurs. However, local therapy did not significantly influence disease related survival. On the other hand, nearly one-third of patients presented with inguinal lymph node metastasis at first diagnosis or developed positive lymph nodes during follow-up. Inguinal lymphadenectomy or dynamic sentinel node biopsy, if available, should therefore be offered to all patients to achieve a correct staging and, as consequence, to improve survival. Larger multicenter studies with detailed follow-up for T1 G2 penile cancer and organ preserving surgery are urgently

needed to obtain detailed information about this rare tumor entity.

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