Optimal surgical margin for penile‐sparing surgery in management of penile cancer—Is 2 cm really necessary?

Abstract Introduction Classical teaching of a 2 cm macroscopic surgical margin for surgical treatment of primary penile cancer is overly aggressive. Contemporary evidence suggests narrow but clear margins have similar survival outcomes for localized disease. This study aims to determine the oncological outcome of using a risk‐adapted algorithm to selection of macroscopic surgical margin based on biopsy grade of disease: 5 mm margin for grade 1, 10 mm margin for grade 2, and 20 mm margin for grade 3. Methods This is a retrospective case series of patients who underwent penile‐sparing surgery for biopsy‐proven penile SCC by a single surgeon from May 2010 through to January 2019. Clinicopathological data were extracted from medical records. Primary outcome was the positive margin rate. Secondary outcomes were overall survival (OS), cancer‐specific survival (CSS), metastasis‐free survival (MFS), and local recurrence‐free survival (RFS). Kaplan‐Meier survival analysis was used to determine survival outcomes. Results A total of 21 patients were included in this study. The median age was 65. Pre‐operative biopsy grade was grade 1 in 19.1% of patients, grade 2 in 47.6%, and grade 3 in 33.3%. The median size of tumor on examination was 20 mm. Using a grade‐stratified algorithm for macroscopic surgical margin, only one patient (4.8%) had a positive margin. This patient had G1T3 disease and proceeded to have a total penectomy for oncological clearance. The median margin clearance was 7 mm. The 12‐month OS, CSS, MFS, and local RFS were 94.6%, 94.6%, 81.0%, and 92.3%, respectively. Conclusion This study suggests that using a grade‐stratified approach to aim for a narrower macroscopic surgical margin does not appear to significantly alter the oncological outcome, with a negative margin rate of 95.2% in our this series. This enables more men to be eligible for organ preserving surgery and thereby improve their quality of life in the urinary function and sexual function domain. Larger prospective studies are warranted to confirm these findings.


| INTRODUC TI ON
Penile cancer is a rare form of cancer with an incidence of 0.66- 1.44 per 100 000 men. [1][2][3] The majority of penile cancer can be histologically classified as squamous cell carcinoma. 2 The goal of local management for penile cancer is to achieve complete tumor removal as the most important priority followed by organ preservation to achieve a better functional and cosmetic outcome. 4,5 The majority of penile cancer are located on the glans or foreskin, making them amenable to organ-sparing surgery. 2 Traditional teaching recommends a 2 cm macroscopic surgical margin for all tumors, which significantly limits the number of men suitable for penile-sparing surgery. [6][7][8] was the first to propose that local oncological control can be obtained with margins less than 15 mm. 9 More contemporary case series of partial and total penectomy have demonstrated that none of the grade 1 or 2 lesions microscopically extended beyond 10 mm proximal to the visible margin, and none of the grade 3 lesions extended beyond 15 mm. 10 Furthermore, Phillipou et al found that the extent of microscopic clear excision margin of 5 mm or less versus greater than 5 mm was not an independent predictor of local recurrence. 11 With the use of intra-operative frozen section and ability to re-operate in the event of positive margin, we can be less aggressive with our macroscopic margin and not subject all patients to a 2 cm macroscopic surgical clearance. 12 This will allow more patients to be suitable for penilesparing surgery leading to a better functional outcome and quality of life. This study used a risk-adapted approach to the selection of macroscopic surgical margin to achieve based on pre-operative biopsy tumor grade: 5 mm macroscopic surgical margin in grade 1 disease, 10 mm margin in grade 2 disease, and 20 mm margin in grade 3 disease. This study aims to assess the oncological outcomes of this riskadapted algorithm to the selection of macroscopic surgical margin.

| ME THODS
This is a retrospective single surgeon case series. From January 2009 to January 2019, all patients who underwent penile-sparing surgery for management of biopsy-proven penile squamous cell carcinoma were included in this study. All cases were performed by a single surgeon who is the sole provider of penile cancer surgery at the included institutions. All patients underwent biopsy of the primary tumor prior to definitive surgery. Biopsy was either performed in the office setting or in theatre for patients who choose Using this study's risk-adapted algorithm for macroscopic surgical margin, positive surgical margin was present in only one patient (4.8%). This patient had biopsy diagnosed grade 1 disease but was found to have T3 cancer on his partial penectomy histopathology.
He subsequently underwent a total penectomy to achieve local clearance of tumor. He did not have any further recurrences or metastasis and was alive at last follow-up of 94 months. The median microscopic margin clearance in this study was 7 mm (IQR 2-10).
Over the study period, two patients developed local recurrence.
The first patient had recurrent CIS that was excised. The second

| D ISCUSS I ON
Currently, there is no clear evidence regarding the optimal width of clear surgical margin for best oncological outcome in penile cancer surgery. 15 Conventionally, a 2 cm surgical margin is advocated for all penile cancers, which limits the number of men suitable for organ-sparing surgery. [6][7][8] A study has shown that the extent of microscopic surgical margin of 5 mm or less versus greater than 5 mm was not a predictor of local recurrence. 11 Therefore, achieving a clear surgical margin even if less than 5 mm does not compromise local control. 11 Another study, by Sri et al, further suggested that a deep clear margin of >1 mm is adequate and has a low risk of local recurrence. 16 As such EAU guidelines have recommended that a 3-5 mm width of negative histopathological margin is adequate. 15 Although the EAU guideline did comment on the use of a grade-based approach to determine the width of negative surgical margin to achieve, it was unclear whether this referred to macroscopic margin to aim for or microscopic margin identified on histology. Furthermore, this recommendation is based on expert opinion of the panel. This study supports the expert opinion, demonstrating that with a risk-adapted approach to the selection of target macroscopic resection margin, the risk of positive margin is low. For these small percentage of patients, they can undergo further resection to achieve negative surgical margin. 11 Even in the event of local recurrence, CSS does not appear to be adversely affected. 11,15,17  these studies and has shown local recurrence to be a significant predictor of decreased OS and CSS on multivariate analysis. 18 Nodal disease 18 and regional recurrence are more well-established determinants of poor CSS, with a 5-year CSS of 32.7%-38.4% in patients with regional recurrence. 11,17 These findings suggest that mortality relating to penile cancer is more closely related to nodal and metastatic disease than local recurrence. Therefore, it is unnecessary to achieve a 2 cm macroscopic resection margin for all patients. A risk-adapted algorithm like the one used in this study would allow more men to be eligible for organ-sparing treatment without compromising oncological outcome.
Organ preservation surgery is associated with better functional and psychological outcomes compared with more mutilating resections. 19 Keiffer et al found that men who underwent partial penectomy compared with penile-sparing surgery had more problems with orgasm, appearance concerns, life interference, and urinary function, 20 and only 10%-20% of men post total penectomy engage in any form of sexual activity. 21 Significant psychological harm also appears to be associated with more aggressive resections. 22 Ficarra et al found that following partial penectomy, men had a measurable impairment to their psychological well-being compared to control group. 23 In addition, a prospective Chinese study found that following a partial penectomy, 39% of men had depression and 58% suffered from anxiety. 24  The findings of this study will add to the weight of the existing literature on surgical margins in penile-sparing surgery, and support the grade-based approach to selection of surgical resection margin suggested by the EAU guidelines. 15

| CON CLUS ION
Conventional teaching of a 20 mm macroscopic resection margin for all penile cancers is likely over-aggressive. This study suggests that a risk-adapted algorithm to macroscopic resection margin based on biopsy tumor grade can achieve a low positive surgical margin rate, which can be further surgically treated to achieve a clear margin. The algorithm suggested in this study of aiming for a macroscopic resection margin of 5 mm for grade 1 disease, 10 mm for grade 2 disease, and 20 mm for grade 3 disease may provide a good balance between achieving a good oncological outcome and F I G U R E 1 Survival curves for men who underwent penile-sparing surgery in this case series. (A) Overall survival, (B) Cancer-specific survival, (C) Metastasis-free survival, and (D) Local recurrence-free survival functional outcome from organ preservation. The findings of this study should be confirmed with larger prospective randomized trials with comparative groups.