- Email: [email protected]
Organ-sparing Surgery for Penile Cancer: Complications and Outcomes
Oncology Organ-sparing Surgery for Penile Cancer: Complications and Outcomes Jian Li, Yao Zhu, Shi-Lin Zhang, Chao-Fu Wang, Xu-Dong Yao, Bo Dai, and Ding-Wei Ye OBJECTIVE METHODS
RESULTS
CONCLUSION
To evaluate the complications and outcomes of organ-sparing surgery in penile cancer. Thirty-two penile cancer patients had undergone organ-sparing surgery between 2006 and 2010 in Fudan University Shanghai Cancer Center. Applied surgical techniques included radical circumcision and/or wide local excision. Intraoperative frozen section analyses of circumference and deep margins were performed to guarantee complete removal of cancerous tissue. Complications and oncological and functional outcomes were recorded prospectively. Bilateral inguinal lymphadenectomy was routinely performed in patients with invasive penile cancer. Of 32 patients, 8 underwent radical circumcision, 18 were treated with wide local excision, and 6 received wide local excision and circumcision. Postoperatively, only 3 (9.4%) patients had minor complications. With a median follow-up of 26.5 months, local control was achieved in 29 (90.6%) patients, and 3 patients (9.4%) with positive lymph nodes died of disseminated disease. Of 29 patients who completed follow-up surveys of functional outcome, only 1 (4.5%) claimed decreased sexual function and all reported satisfied urination. Organ-sparing surgery, such as radical circumcision and wide local excision is an appropriate treatment option for selected penile cancer patients. It preserves sexual and urination function without significantly increasing the risk of recurrence. UROLOGY 78: 1121–1124, 2011. © 2011 Elsevier Inc.
P
enile cancer is a rare disease in urban Shanghai, accounting for ⬍1% of all male malignancies.1 However, in certain areas where hygiene and health conditions are poor, it is still a substantial health problem, constituting up to 10% of cancers in men.2 For the management of invasive disease, partial or total penectomy with a 2-cm margin has historically been considered the gold standard. With complete extirpation of the penile lesion, radical surgery results in a high local control rate of nearly 90%.3,4 However, these treatments also have a significant negative impact on the patient’s sexual function, quality of life, social interactions, selfimage, and self-esteem.5-7 Several penis-preserving strategies were attempted for penile cancer patients, especially those with early localized disease (ⱕT2).8 Detailed pathologic examinations of the primary disease revealed that microscopic extension of penile cancer was mostly confined within 1 cm of the clinical edge.9-11 For poorly defined boundaries, intraoperative frozen section analyses are helpful to ensure a tumor-free surgical margin.12 These findings provide a rational basis for the Jian Li and Yao Zhu contributed equally to this work. From the Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Department of Urology and Department of Pathology, Fudan University, Shanghai Cancer Center, Shanghai, China Reprint requests: Ding-Wei Ye, M.D., Department of Urology, Fudan University, Shanghai Cancer Center, No. 270 Dong’an Road, Shanghai, 200032, People’s Republic of China. E-mail: [email protected]. Submitted: May 10, 2011, accepted (with revisions): August 1, 2011
© 2011 Elsevier Inc. All Rights Reserved
recommendation of local resection in selected patients. In the literature, radical circumcision, wide local excision, and glansectomy are all feasible procedures for the conservative management of primary disease.13 There were, however, limited studies that comprehensively discussed the complications, oncological and functional outcomes of organ-sparing surgery. To provide more data on this topic, we present our experience of conservative management of primary disease.
MATERIAL AND METHODS Patients and Surgical Procedures Thirty-two Chinese penile cancer patients received organ-sparing surgery in Fudan University Shanghai Cancer Center from March 2006 to May 2010. Clinicopathological records were prospectively collected in the database. In our center, conservative treatment was only recommended to patients who refused extirpative surgery. Risk of recurrence was thoroughly discussed before informed consent was obtained. The types of organ-sparing surgery were radical circumcision and wide local excision, which were described in a review.13 Patients with small and localized lesions in the foreskin were treated with radical circumcision, whereas those with tumor situated at the glans underwent wide local excision. Incisions were made with a clinical tumor-free margin of at least 5 mm. Intraoperative frozen section analyses of circumference and deep margins were performed to guarantee complete removal of cancerous tissue. Suspicious skin changes were also evaluated by pathologic examination to exclude multifocal lesions. After satisfactory he0090-4295/11/$36.00 doi:10.1016/j.urology.2011.08.006
1121
Figure 1. (A) Preoperative appearance of a lesion in the foreskin; (B) radical circumcision; (C) primary closure of the defect; (D) appearance 3 months postoperatively; (E) preoperative appearance of a lesion involving foreskin and glans; (F) wide local excision, cautery was used for hemostasis; (G) defect covered by skin flap; and (H) appearance 3 months postoperatively.
mostasis, surgical defects were closed by primary closure or skin flap.14,15 Representative cases were shown in Figure 1. Postoperatively, antibiotics were used for prophylaxis of infection. No adjuvant therapy before or after the surgery was given in this series. Patients with invasive penile cancer underwent bilateral inguinal lymphadenectomy, which was a routine practice in our center. The study was approved by the institutional review board, and written informed consent was obtained from each patient. Complications within 30 days of surgery were prospectively recorded and graded according to the Clavien classification.16 Intervention-related complications included bleeding, wound dehiscence, skin/flap necrosis, hematoma, abscess, and wound infection.
or wide local excision according to the lesion size, depth of invasion, and patient’s willingness. Local recurrence-free survival was calculated from the date of operation to the date of local recurrence or last follow-up. Sexual function was assessed preoperatively using the simplified International Index of Erectile Function (IIEF-5). Three months after the operation, patients were invited to complete a follow-up questionnaire. Erectile dysfunction (ED) severity was classified into 5 categories based on IIEF-5 scores from none (22-25) through severe (5-7).19 Urination was another functional outcome in this study. Satisfied urination was defined as patients who could urinate as before without stenosis of the urethral meatus.
Statistical Analysis Pathology and Immunohistochemistry Pathologic slides of the primary disease were independently reviewed by 2 pathologists without clinical data. Tumors were staged according to AJCC 2002 staging system.17 Histologic grade was classified according to the percentage of undifferentiated cells: G1, ⬍25%; G2, 25-50%; and G3, ⬎50%. Lymphovascular embolization was defined by the presence of tumor emboli within endothelium-lined spaces bounded by a thin wall. All discrepancies were resolved by joint review of the slides in question. For those patients who had recurrent disease in the penis, the primary and recurrent diseases were submitted for immunostaining. As previously described, two-step EnVision/horseradish peroxidase technique (Dako, Glostrup, Denmark) was used to detect p53, p16INK4a, epithelial growth factor receptor (EGFR), and cyclin D1 protein expression.18
Assessment of Outcomes Follow-up examinations were performed every 3 months in the first 2 years and every 6 months in the following 3 years. Biopsy-confirmed recurrent disease was treated with penectomy 1122
For comparisons of proportions, Fisher’s exact test was used. The level of statistical significance was taken to be P ⬍.05. Statistical analysis was performed using R 2.12.1.20
RESULTS Demographic data of patients and tumors are shown in Table 1. Of 32 cases, 8 underwent radical circumcision, 18 were treated with wide local excision, and 6 received wide local excision and circumcision. Complete removal of the tumor was accomplished in all patients with negative margins on both frozen sections and final permanent sections. Postoperative recovery was uneventful in 29 (90.6%) patients. Of 3 patients with surgical morbidity, 2 had grade I wound dehiscence and 1 had grade II abscess. With a median follow-up of 26.5 months (range 2-61), local control was achieved in 29 (90.6%) patients. All 3 recurrences occurred within 6 months after surgery and were treated with wide local excision (1 patient) or total UROLOGY 78 (5), 2011
Table 1. Demographic data of penile cancer patients and tumors Median age (range) T stage (%) Tis Ta T1 T2 Grade (%)* G1 G2 G3 Lesion location (%) Foreskin Glans Penile shaft No. lymphovascular embolization (%) No. lymph node metastases (%)
45.5
(24-70)
2 5 23 2
(6.3%) (15.6%) (71.9%) (6.3%)
21 3 1
(65.6%) (9.4%) (3.1%)
10 20 2 3 5
(31.3%) (62.5%) (6.3%) (9.4%) (15.6%)
* Grade was reported in 25 T1/T2 disease.
penectomy (2 patients). Except for 1 man who died of disseminated disease shortly after surgery, salvage penile surgery was successful with a minimal follow-up of 12 months. The comparisons of histopathological characteristics between primary and recurrent tumors showed 2 patients had upstaging (from T1 to T2 disease) and 1 case had increased expression of EGFR in recurrent disease. Tumor grade and the expression of other molecular markers were similar in the primary and recurrent tumors. At last visit, 1 patient with local recurrence and 2 patients without local failures had died from penile cancer. All 3 men had pathologically positive lymph nodes at initial lymphadenectomy. Except for 3 patients who had poor performance status because of metastatic disease, follow-up sexual function evaluations were available for 29 cases. Before surgery, 7 (24.1%) patients reported having moderate to severe ED, and 22 (75.9%) reported having none to mild ED. In the latter group, only 1 (4.5%) man claimed to have mildmoderate ED after the operation and the other 21 cases had the same ratings of sexual function as before. All responding patients reported satisfied urination in the postoperative survey. In the same period, 84 patients received partial/total penectomy at our institution. Eleven (13.1%) patients had recorded postoperative morbidity, which included hematoma, abscess, wound infection, and urethra orifice necrosis. After partial/total penectomy, recurrence in the penis was found in 6 patients (7.1%). There was no statistically significant difference in rates of recurrence and morbidity between extirpative surgery and conservative treatment (P ⫽ .71 and 0.75, respectively).
COMMENT For primary disease of penile cancer, partial and total penectomy achieved excellent local control rates and remains the oncological “gold standard.”3,4 In the last decade, because of improvements in treatment techniques and growing attention to functional issues, the UROLOGY 78 (5), 2011
management of primary tumors has started to evolve in favor of conservative surgery. Recently, European guidelines have recommended an organ-sparing approach for early stage penile cancer whenever possible.21 Although several surgical procedures were introduced, there were few studies evaluating the strategy in a scientifically rigorous manner.21 In this study, we prospectively assessed the complications and outcomes of penis-preserving surgery in a series of Chinese patients. Several surgical procedures have been established for achieving the goal of eliminating disease without severe sacrifice of the penis.8 The selection of appropriate techniques depends mainly on the invasive depth, extent, and location of disease. Total glans resurfacing is an effective treatment for carcinoma in situ, especially after failure of topical chemotherapy. The local recurrence rate was 4% in a recent study of 25 patients with carcinoma in situ.22 Noninvasive verrucous carcinoma and small T1/2 disease can be managed with wide local excision. Although local excision is easy to perform, special care should be taken to ensure adequate tumor-free margins. Bissada et al reported a recurrence rate of 7.7% in 26 patients with solitary disease.23 Consistent with their findings, the local recurrence rate after radical circumcision and/or wide local excision was 9.4% in our series. For large or multifocal T1/2 penile tumors limited to the glans, glansectomy and resurfacing were advocated as an alternative to penectomy with similar oncological outcome and satisfactory esthetic results.24,25 With a mean follow-up of 27 months, the recurrence rate after glansectomy was 4% in a cohort of 72 patients.24 The procedure, however, had disadvantages such as reduced glans sensitivity, the spraying of urine when voiding, and the complications of a more technically complex procedure, including graft failure and infection.24 More advanced disease as T2 tumors with corpora cavernosa invasion or T3/4 tumors often requires penectomy and reconstruction to achieve better oncological and functional outcome. Functional outcome is an important measurement of organ-sparing surgery. Unfortunately, no previous study formally assessed sexual function changes with a multidimensional scale. Our results showed that 95.5% of the patients with none to mild ED maintained their sexual function after the operation. By using the IIEF questionnaire, Romero et al evaluated erectile function and satisfaction in 18 Brazilian patients treated with partial penectomy.7 Although all patients reported that they were moderately or very satisfied with sexual function before surgical treatment, only 6 (33.3%) sustained their degree of satisfaction after. The reasons for ED included small size of the penis, an absence of the glans, and surgical complications. To achieve the functional goal of penis-preserving surgery, these reasons should be taken into account. Consistent with previous studies, satisfied urination was reported by all patients. This is the advantage of surgery compared with radiotherapy, which may lead to urethral stenosis and urethral fistula. 1123
Local recurrence was the main concern of organ-sparing strategy. Although salvage surgical intervention is mostly successful for the primary disease, it may subsequently result in higher mortality by nodal or systematic spread.3,26 Lont et al reviewed 157 T1-T2 penile cancer patients treated with various penis-preserving approaches over a nearly 50-year span.3 The 5-year local recurrencefree rates were 63% and 88% for conservation management and partial amputation, respectively. In multivariate analysis, only a microscopically incomplete resected primary tumor was an independent prognostic factor for local recurrence. Because of the improvement of surgical technique and meticulous pathologic examination, the local recurrence rates have decreased to approximately 10% in recent reports.24-27 Brown et al analyzed the histopathological factors for predicting local recurrence after conservative resection in a large cohort.26 They found higher tumor stage (ⱖpT2), lymphovascular invasion, and lymph nodes metastases were independently associated with a greater incidence of local tumor recurrence. Because of a limited number of patients, we were unable to perform robust analysis for possible predictors of local recurrence. Because all recurrence occurred within 6 months and had similar pathologic characteristics to primary disease, the recurrences were most likely a result of residual disease rather than second primary disease. Thus, factors affecting the completeness of surgical excision may be important predictors of local recurrence. Our study is not without limitations. After patients were informed of the risks, benefits, and alternatives to organ-sparing surgery, the number enrolled in this study was limited. With more evidence of safety and efficacy, the procedure may be appropriate treatment options for select penile cancer patients in the future.
CONCLUSION
7. 8.
9.
10.
11.
12.
13.
14.
15.
16.
17. 18.
19.
20.
Organ-sparing surgery, such as radical circumcision and wide local excision, is an appropriate treatment option for selected penile cancer patients. It preserves sexual and urination function without significantly increasing the risk of recurrence.
21.
References
23.
1. Jin F, Devesa SS, Zheng W, et al. Cancer incidence trends in urban Shanghai, 1972-1989. Int J Cancer. 1993;53:764-770. 2. Misra S, Chaturvedi A, Misra NC. Penile carcinoma: a challenge for the developing world. Lancet Oncol. 2004;5:240-247. 3. Lont AP, Gallee MP, Meinhardt W, et al. Penis conserving treatment for T1 and T2 penile carcinoma: clinical implications of a local recurrence. J Urol. 2006;176:575-580; [Discussion:580]. 4. Korets R, Koppie TM, Snyder ME, et al. Partial penectomy for patients with squamous cell carcinoma of the penis: the Memorial Sloan-Kettering experience. Ann Surg Oncol. 2007;14:3614-3619. 5. D’Ancona CA, Botega NJ, De Moraes C, et al. Quality of life after partial penectomy for penile carcinoma. Urology. 1997;50:593-596. 6. Maddineni SB, Lau MM, Sangar VK. Identifying the needs of penile cancer sufferers: a systematic review of the quality of life,
1124
22.
24.
25.
26.
27.
psychosexual and psychosocial literature in penile cancer. BMC Urol. 2009;9:8. Romero FR, Romero KR, Mattos MA, et al. Sexual function after partial penectomy for penile cancer. Urology. 2005;66:1292-1295. Shapiro D, Shasha D, Tareen M, et al. Contemporary management of localized penile cancer. Expert Rev Anticancer Ther. 2011;11:29-36. Hoffman MA, Renshaw AA, Loughlin KR. Squamous cell carcinoma of the penis and microscopic pathologic margins: how much margin is needed for local cure? Cancer. 1999;85:1565-1568. Minhas S, Kayes O, Hegarty P, et al. What surgical resection margins are required to achieve oncological control in men with primary penile cancer? BJU Int. 2005;96:1040-1043. Agrawal A, Pai D, Ananthakrishnan N, et al. The histological extent of the local spread of carcinoma of the penis and its therapeutic implications. BJU Int. 2000;85:299-301. Algaba F, Arce Y, López-Beltrán A, et al. Intraoperative frozen section diagnosis in urological oncology. Eur Urol. 2005;47:129136. Hegarty PK, Shabbir M, Hughes B, et al. Penile preserving surgery and surgical strategies to maximize penile form and function in penile cancer: recommendations from the United Kingdom experience. World J Urol. 2009;27:179-187. Ubrig B, Waldner M, Fallahi M, et al. Preputial flap for primary closure after excision of tumors on the glans penis. Urology. 2001; 58:274-276. Brown CT, Minhas S, Ralph DJ. Conservative surgery for penile cancer: subtotal glans excision without grafting. BJU Int. 2005;96: 911-912. Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg. 2004;240:205-213. Greene FL. AJCC Cancer Staging Manual. New York, NY: Springer; 2002. Zhu Y, Zhou XY, Yao XD, et al. The prognostic significance of p53, Ki-67, epithelial cadherin and matrix metalloproteinase-9 in penile squamous cell carcinoma treated with surgery. BJU Int. 2007;100: 204-208. Rosen RC, Cappelleri JC, Smith MD, et al. Development and evaluation of an abridged, 5-item version of the International Index of Erectile Function (IIEF-5) as a diagnostic tool for erectile dysfunction. Int J Impot Res. 1999;11:319-326. Team RDC. R: A language and environment for statistical computing. Vienna, Austria: R Foundation for Statistical Computing; 2010. Pizzocaro G, Algaba F, Horenblas S, et al. EAU penile cancer guidelines 2009. Eur Urol. 2010;57:1002-1012. Shabbir M, Muneer A, Kalsi J, et al. Glans Resurfacing for the Treatment of carcinoma in situ of the Penis: Surgical Technique and Outcomes. Eur Urol. 2011;59:142-147. Bissada N, Yakout H, Fahmy W, et al. Multi-institutional longterm experience with conservative surgery for invasive penile carcinoma. J Urol. 2003;169:500-502. Smith Y, Hadway P, Biedrzycki O, et al. Reconstructive surgery for invasive squamous carcinoma of the glans penis. Eur Urol. 2007; 52:1179-1185. Morelli G, Pagni R, Mariani C, et al. Glansectomy with splitthickness skin graft for the treatment of penile carcinoma. Int J Impot Res. 2009;21:311-314. Brown GM, Khadra A, Abdelraheem A, et al. Predictors of penile cancer recurrence following conservative surgical resection. J Urol. 2009;181:202, [Abs.:566]. Pietrzak P, Corbishley C, Watkin N. Organ-sparing surgery for invasive penile cancer: early follow-up data. BJU Int. 2004;94: 1253-1257.
UROLOGY 78 (5), 2011
RESULTS
CONCLUSION
To evaluate the complications and outcomes of organ-sparing surgery in penile cancer. Thirty-two penile cancer patients had undergone organ-sparing surgery between 2006 and 2010 in Fudan University Shanghai Cancer Center. Applied surgical techniques included radical circumcision and/or wide local excision. Intraoperative frozen section analyses of circumference and deep margins were performed to guarantee complete removal of cancerous tissue. Complications and oncological and functional outcomes were recorded prospectively. Bilateral inguinal lymphadenectomy was routinely performed in patients with invasive penile cancer. Of 32 patients, 8 underwent radical circumcision, 18 were treated with wide local excision, and 6 received wide local excision and circumcision. Postoperatively, only 3 (9.4%) patients had minor complications. With a median follow-up of 26.5 months, local control was achieved in 29 (90.6%) patients, and 3 patients (9.4%) with positive lymph nodes died of disseminated disease. Of 29 patients who completed follow-up surveys of functional outcome, only 1 (4.5%) claimed decreased sexual function and all reported satisfied urination. Organ-sparing surgery, such as radical circumcision and wide local excision is an appropriate treatment option for selected penile cancer patients. It preserves sexual and urination function without significantly increasing the risk of recurrence. UROLOGY 78: 1121–1124, 2011. © 2011 Elsevier Inc.
P
enile cancer is a rare disease in urban Shanghai, accounting for ⬍1% of all male malignancies.1 However, in certain areas where hygiene and health conditions are poor, it is still a substantial health problem, constituting up to 10% of cancers in men.2 For the management of invasive disease, partial or total penectomy with a 2-cm margin has historically been considered the gold standard. With complete extirpation of the penile lesion, radical surgery results in a high local control rate of nearly 90%.3,4 However, these treatments also have a significant negative impact on the patient’s sexual function, quality of life, social interactions, selfimage, and self-esteem.5-7 Several penis-preserving strategies were attempted for penile cancer patients, especially those with early localized disease (ⱕT2).8 Detailed pathologic examinations of the primary disease revealed that microscopic extension of penile cancer was mostly confined within 1 cm of the clinical edge.9-11 For poorly defined boundaries, intraoperative frozen section analyses are helpful to ensure a tumor-free surgical margin.12 These findings provide a rational basis for the Jian Li and Yao Zhu contributed equally to this work. From the Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China; Department of Urology and Department of Pathology, Fudan University, Shanghai Cancer Center, Shanghai, China Reprint requests: Ding-Wei Ye, M.D., Department of Urology, Fudan University, Shanghai Cancer Center, No. 270 Dong’an Road, Shanghai, 200032, People’s Republic of China. E-mail: [email protected]. Submitted: May 10, 2011, accepted (with revisions): August 1, 2011
© 2011 Elsevier Inc. All Rights Reserved
recommendation of local resection in selected patients. In the literature, radical circumcision, wide local excision, and glansectomy are all feasible procedures for the conservative management of primary disease.13 There were, however, limited studies that comprehensively discussed the complications, oncological and functional outcomes of organ-sparing surgery. To provide more data on this topic, we present our experience of conservative management of primary disease.
MATERIAL AND METHODS Patients and Surgical Procedures Thirty-two Chinese penile cancer patients received organ-sparing surgery in Fudan University Shanghai Cancer Center from March 2006 to May 2010. Clinicopathological records were prospectively collected in the database. In our center, conservative treatment was only recommended to patients who refused extirpative surgery. Risk of recurrence was thoroughly discussed before informed consent was obtained. The types of organ-sparing surgery were radical circumcision and wide local excision, which were described in a review.13 Patients with small and localized lesions in the foreskin were treated with radical circumcision, whereas those with tumor situated at the glans underwent wide local excision. Incisions were made with a clinical tumor-free margin of at least 5 mm. Intraoperative frozen section analyses of circumference and deep margins were performed to guarantee complete removal of cancerous tissue. Suspicious skin changes were also evaluated by pathologic examination to exclude multifocal lesions. After satisfactory he0090-4295/11/$36.00 doi:10.1016/j.urology.2011.08.006
1121
Figure 1. (A) Preoperative appearance of a lesion in the foreskin; (B) radical circumcision; (C) primary closure of the defect; (D) appearance 3 months postoperatively; (E) preoperative appearance of a lesion involving foreskin and glans; (F) wide local excision, cautery was used for hemostasis; (G) defect covered by skin flap; and (H) appearance 3 months postoperatively.
mostasis, surgical defects were closed by primary closure or skin flap.14,15 Representative cases were shown in Figure 1. Postoperatively, antibiotics were used for prophylaxis of infection. No adjuvant therapy before or after the surgery was given in this series. Patients with invasive penile cancer underwent bilateral inguinal lymphadenectomy, which was a routine practice in our center. The study was approved by the institutional review board, and written informed consent was obtained from each patient. Complications within 30 days of surgery were prospectively recorded and graded according to the Clavien classification.16 Intervention-related complications included bleeding, wound dehiscence, skin/flap necrosis, hematoma, abscess, and wound infection.
or wide local excision according to the lesion size, depth of invasion, and patient’s willingness. Local recurrence-free survival was calculated from the date of operation to the date of local recurrence or last follow-up. Sexual function was assessed preoperatively using the simplified International Index of Erectile Function (IIEF-5). Three months after the operation, patients were invited to complete a follow-up questionnaire. Erectile dysfunction (ED) severity was classified into 5 categories based on IIEF-5 scores from none (22-25) through severe (5-7).19 Urination was another functional outcome in this study. Satisfied urination was defined as patients who could urinate as before without stenosis of the urethral meatus.
Statistical Analysis Pathology and Immunohistochemistry Pathologic slides of the primary disease were independently reviewed by 2 pathologists without clinical data. Tumors were staged according to AJCC 2002 staging system.17 Histologic grade was classified according to the percentage of undifferentiated cells: G1, ⬍25%; G2, 25-50%; and G3, ⬎50%. Lymphovascular embolization was defined by the presence of tumor emboli within endothelium-lined spaces bounded by a thin wall. All discrepancies were resolved by joint review of the slides in question. For those patients who had recurrent disease in the penis, the primary and recurrent diseases were submitted for immunostaining. As previously described, two-step EnVision/horseradish peroxidase technique (Dako, Glostrup, Denmark) was used to detect p53, p16INK4a, epithelial growth factor receptor (EGFR), and cyclin D1 protein expression.18
Assessment of Outcomes Follow-up examinations were performed every 3 months in the first 2 years and every 6 months in the following 3 years. Biopsy-confirmed recurrent disease was treated with penectomy 1122
For comparisons of proportions, Fisher’s exact test was used. The level of statistical significance was taken to be P ⬍.05. Statistical analysis was performed using R 2.12.1.20
RESULTS Demographic data of patients and tumors are shown in Table 1. Of 32 cases, 8 underwent radical circumcision, 18 were treated with wide local excision, and 6 received wide local excision and circumcision. Complete removal of the tumor was accomplished in all patients with negative margins on both frozen sections and final permanent sections. Postoperative recovery was uneventful in 29 (90.6%) patients. Of 3 patients with surgical morbidity, 2 had grade I wound dehiscence and 1 had grade II abscess. With a median follow-up of 26.5 months (range 2-61), local control was achieved in 29 (90.6%) patients. All 3 recurrences occurred within 6 months after surgery and were treated with wide local excision (1 patient) or total UROLOGY 78 (5), 2011
Table 1. Demographic data of penile cancer patients and tumors Median age (range) T stage (%) Tis Ta T1 T2 Grade (%)* G1 G2 G3 Lesion location (%) Foreskin Glans Penile shaft No. lymphovascular embolization (%) No. lymph node metastases (%)
45.5
(24-70)
2 5 23 2
(6.3%) (15.6%) (71.9%) (6.3%)
21 3 1
(65.6%) (9.4%) (3.1%)
10 20 2 3 5
(31.3%) (62.5%) (6.3%) (9.4%) (15.6%)
* Grade was reported in 25 T1/T2 disease.
penectomy (2 patients). Except for 1 man who died of disseminated disease shortly after surgery, salvage penile surgery was successful with a minimal follow-up of 12 months. The comparisons of histopathological characteristics between primary and recurrent tumors showed 2 patients had upstaging (from T1 to T2 disease) and 1 case had increased expression of EGFR in recurrent disease. Tumor grade and the expression of other molecular markers were similar in the primary and recurrent tumors. At last visit, 1 patient with local recurrence and 2 patients without local failures had died from penile cancer. All 3 men had pathologically positive lymph nodes at initial lymphadenectomy. Except for 3 patients who had poor performance status because of metastatic disease, follow-up sexual function evaluations were available for 29 cases. Before surgery, 7 (24.1%) patients reported having moderate to severe ED, and 22 (75.9%) reported having none to mild ED. In the latter group, only 1 (4.5%) man claimed to have mildmoderate ED after the operation and the other 21 cases had the same ratings of sexual function as before. All responding patients reported satisfied urination in the postoperative survey. In the same period, 84 patients received partial/total penectomy at our institution. Eleven (13.1%) patients had recorded postoperative morbidity, which included hematoma, abscess, wound infection, and urethra orifice necrosis. After partial/total penectomy, recurrence in the penis was found in 6 patients (7.1%). There was no statistically significant difference in rates of recurrence and morbidity between extirpative surgery and conservative treatment (P ⫽ .71 and 0.75, respectively).
COMMENT For primary disease of penile cancer, partial and total penectomy achieved excellent local control rates and remains the oncological “gold standard.”3,4 In the last decade, because of improvements in treatment techniques and growing attention to functional issues, the UROLOGY 78 (5), 2011
management of primary tumors has started to evolve in favor of conservative surgery. Recently, European guidelines have recommended an organ-sparing approach for early stage penile cancer whenever possible.21 Although several surgical procedures were introduced, there were few studies evaluating the strategy in a scientifically rigorous manner.21 In this study, we prospectively assessed the complications and outcomes of penis-preserving surgery in a series of Chinese patients. Several surgical procedures have been established for achieving the goal of eliminating disease without severe sacrifice of the penis.8 The selection of appropriate techniques depends mainly on the invasive depth, extent, and location of disease. Total glans resurfacing is an effective treatment for carcinoma in situ, especially after failure of topical chemotherapy. The local recurrence rate was 4% in a recent study of 25 patients with carcinoma in situ.22 Noninvasive verrucous carcinoma and small T1/2 disease can be managed with wide local excision. Although local excision is easy to perform, special care should be taken to ensure adequate tumor-free margins. Bissada et al reported a recurrence rate of 7.7% in 26 patients with solitary disease.23 Consistent with their findings, the local recurrence rate after radical circumcision and/or wide local excision was 9.4% in our series. For large or multifocal T1/2 penile tumors limited to the glans, glansectomy and resurfacing were advocated as an alternative to penectomy with similar oncological outcome and satisfactory esthetic results.24,25 With a mean follow-up of 27 months, the recurrence rate after glansectomy was 4% in a cohort of 72 patients.24 The procedure, however, had disadvantages such as reduced glans sensitivity, the spraying of urine when voiding, and the complications of a more technically complex procedure, including graft failure and infection.24 More advanced disease as T2 tumors with corpora cavernosa invasion or T3/4 tumors often requires penectomy and reconstruction to achieve better oncological and functional outcome. Functional outcome is an important measurement of organ-sparing surgery. Unfortunately, no previous study formally assessed sexual function changes with a multidimensional scale. Our results showed that 95.5% of the patients with none to mild ED maintained their sexual function after the operation. By using the IIEF questionnaire, Romero et al evaluated erectile function and satisfaction in 18 Brazilian patients treated with partial penectomy.7 Although all patients reported that they were moderately or very satisfied with sexual function before surgical treatment, only 6 (33.3%) sustained their degree of satisfaction after. The reasons for ED included small size of the penis, an absence of the glans, and surgical complications. To achieve the functional goal of penis-preserving surgery, these reasons should be taken into account. Consistent with previous studies, satisfied urination was reported by all patients. This is the advantage of surgery compared with radiotherapy, which may lead to urethral stenosis and urethral fistula. 1123
Local recurrence was the main concern of organ-sparing strategy. Although salvage surgical intervention is mostly successful for the primary disease, it may subsequently result in higher mortality by nodal or systematic spread.3,26 Lont et al reviewed 157 T1-T2 penile cancer patients treated with various penis-preserving approaches over a nearly 50-year span.3 The 5-year local recurrencefree rates were 63% and 88% for conservation management and partial amputation, respectively. In multivariate analysis, only a microscopically incomplete resected primary tumor was an independent prognostic factor for local recurrence. Because of the improvement of surgical technique and meticulous pathologic examination, the local recurrence rates have decreased to approximately 10% in recent reports.24-27 Brown et al analyzed the histopathological factors for predicting local recurrence after conservative resection in a large cohort.26 They found higher tumor stage (ⱖpT2), lymphovascular invasion, and lymph nodes metastases were independently associated with a greater incidence of local tumor recurrence. Because of a limited number of patients, we were unable to perform robust analysis for possible predictors of local recurrence. Because all recurrence occurred within 6 months and had similar pathologic characteristics to primary disease, the recurrences were most likely a result of residual disease rather than second primary disease. Thus, factors affecting the completeness of surgical excision may be important predictors of local recurrence. Our study is not without limitations. After patients were informed of the risks, benefits, and alternatives to organ-sparing surgery, the number enrolled in this study was limited. With more evidence of safety and efficacy, the procedure may be appropriate treatment options for select penile cancer patients in the future.
CONCLUSION
7. 8.
9.
10.
11.
12.
13.
14.
15.
16.
17. 18.
19.
20.
Organ-sparing surgery, such as radical circumcision and wide local excision, is an appropriate treatment option for selected penile cancer patients. It preserves sexual and urination function without significantly increasing the risk of recurrence.
21.
References
23.
1. Jin F, Devesa SS, Zheng W, et al. Cancer incidence trends in urban Shanghai, 1972-1989. Int J Cancer. 1993;53:764-770. 2. Misra S, Chaturvedi A, Misra NC. Penile carcinoma: a challenge for the developing world. Lancet Oncol. 2004;5:240-247. 3. Lont AP, Gallee MP, Meinhardt W, et al. Penis conserving treatment for T1 and T2 penile carcinoma: clinical implications of a local recurrence. J Urol. 2006;176:575-580; [Discussion:580]. 4. Korets R, Koppie TM, Snyder ME, et al. Partial penectomy for patients with squamous cell carcinoma of the penis: the Memorial Sloan-Kettering experience. Ann Surg Oncol. 2007;14:3614-3619. 5. D’Ancona CA, Botega NJ, De Moraes C, et al. Quality of life after partial penectomy for penile carcinoma. Urology. 1997;50:593-596. 6. Maddineni SB, Lau MM, Sangar VK. Identifying the needs of penile cancer sufferers: a systematic review of the quality of life,
1124
22.
24.
25.
26.
27.
psychosexual and psychosocial literature in penile cancer. BMC Urol. 2009;9:8. Romero FR, Romero KR, Mattos MA, et al. Sexual function after partial penectomy for penile cancer. Urology. 2005;66:1292-1295. Shapiro D, Shasha D, Tareen M, et al. Contemporary management of localized penile cancer. Expert Rev Anticancer Ther. 2011;11:29-36. Hoffman MA, Renshaw AA, Loughlin KR. Squamous cell carcinoma of the penis and microscopic pathologic margins: how much margin is needed for local cure? Cancer. 1999;85:1565-1568. Minhas S, Kayes O, Hegarty P, et al. What surgical resection margins are required to achieve oncological control in men with primary penile cancer? BJU Int. 2005;96:1040-1043. Agrawal A, Pai D, Ananthakrishnan N, et al. The histological extent of the local spread of carcinoma of the penis and its therapeutic implications. BJU Int. 2000;85:299-301. Algaba F, Arce Y, López-Beltrán A, et al. Intraoperative frozen section diagnosis in urological oncology. Eur Urol. 2005;47:129136. Hegarty PK, Shabbir M, Hughes B, et al. Penile preserving surgery and surgical strategies to maximize penile form and function in penile cancer: recommendations from the United Kingdom experience. World J Urol. 2009;27:179-187. Ubrig B, Waldner M, Fallahi M, et al. Preputial flap for primary closure after excision of tumors on the glans penis. Urology. 2001; 58:274-276. Brown CT, Minhas S, Ralph DJ. Conservative surgery for penile cancer: subtotal glans excision without grafting. BJU Int. 2005;96: 911-912. Dindo D, Demartines N, Clavien PA. Classification of surgical complications: a new proposal with evaluation in a cohort of 6336 patients and results of a survey. Ann Surg. 2004;240:205-213. Greene FL. AJCC Cancer Staging Manual. New York, NY: Springer; 2002. Zhu Y, Zhou XY, Yao XD, et al. The prognostic significance of p53, Ki-67, epithelial cadherin and matrix metalloproteinase-9 in penile squamous cell carcinoma treated with surgery. BJU Int. 2007;100: 204-208. Rosen RC, Cappelleri JC, Smith MD, et al. Development and evaluation of an abridged, 5-item version of the International Index of Erectile Function (IIEF-5) as a diagnostic tool for erectile dysfunction. Int J Impot Res. 1999;11:319-326. Team RDC. R: A language and environment for statistical computing. Vienna, Austria: R Foundation for Statistical Computing; 2010. Pizzocaro G, Algaba F, Horenblas S, et al. EAU penile cancer guidelines 2009. Eur Urol. 2010;57:1002-1012. Shabbir M, Muneer A, Kalsi J, et al. Glans Resurfacing for the Treatment of carcinoma in situ of the Penis: Surgical Technique and Outcomes. Eur Urol. 2011;59:142-147. Bissada N, Yakout H, Fahmy W, et al. Multi-institutional longterm experience with conservative surgery for invasive penile carcinoma. J Urol. 2003;169:500-502. Smith Y, Hadway P, Biedrzycki O, et al. Reconstructive surgery for invasive squamous carcinoma of the glans penis. Eur Urol. 2007; 52:1179-1185. Morelli G, Pagni R, Mariani C, et al. Glansectomy with splitthickness skin graft for the treatment of penile carcinoma. Int J Impot Res. 2009;21:311-314. Brown GM, Khadra A, Abdelraheem A, et al. Predictors of penile cancer recurrence following conservative surgical resection. J Urol. 2009;181:202, [Abs.:566]. Pietrzak P, Corbishley C, Watkin N. Organ-sparing surgery for invasive penile cancer: early follow-up data. BJU Int. 2004;94: 1253-1257.
UROLOGY 78 (5), 2011