Penile cancer: organ-sparing techniques

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1 Reviews Penile cancer: organ-sparing techniques Paul K. Hegarty, Ian Eardley*, Axel Heidenreich, W. Scott McDougal, Suks Minhas, Philippe E. Spiess, Nick Watkin** and Simon Horenblas Department of Urology, Mater Misericordiae University Hospital and Mater Private, Dublin, Ireland, *Department of Urology, St James's University Hospital, Leeds, UCLH Institute of Urology London, London, **Department of Urology, St. Helier Hospital, Carshalton, Surrey, UK, Department of Urology, RWTH University Aachen, Aachen, Germany, Massachusetts General Hospital Department of Urology, MA, Department of Urology, H Lee Moffitt Cancer Center, Tampa, FL, USA, and Department of Urology, Netherlands Cancer Institute, Amsterdam, The Netherlands To compare the oncological safety of treating patients with penile cancer with conservative techniques developed to preserve function, cosmesis and psychological well-being with more radical ablative strategies. We conducted an extensive review of the literature of penile-preserving and ablative techniques and report on the oncological as well as functional outcomes. There were no randomised studies comparing penile-preserving and ablative techniques. Most studies consisted of retrospective cohorts. The quality of evidence was level 3 at best. Cancer-specific survival is similar in penile-preserving and ablative approaches for low-stage disease. Penile preservation is better for functional and cosmetic outcomes and should be offered as a primary treatment method in men with low-stage penile cancer. Keywords penile cancer, surgery, treatment, organ preservation, review Introduction Penile cancer is a rare malignancy in the Western world, with an incidence in the 0.3 to 1/ males. The highest cumulative rate of 1% before the age of 75 years is seen in parts of Uganda, compared with the lowest cumulative rate of 300-times less amongst Israeli Jews [1,2]. The incidence increases with age. Areas where there is a higher incidence also have a greater proportion of young men with penile cancer [3]. The rarity of this disease has limited data acquisition and standardisation in clinical practice. Guidelines are often based on small retrospective reports. For example in the UK, the National Institute for Clinical Excellence (NICE) recommends that patients be referred to supra-regional centres that treat 25 new cases per annum [4]. The evolution of such referral centres across Europe has allowed standardisation of treatment pathways to develop [5]. The European Association of Urology has published a series of guidelines on the management of penile cancer [5 7]. Penile preservation techniques have been used more commonly in recent years, as it has been recognised that this type of surgery for the primary cancer is associated with better functional outcomes and psychological well-being [8]. While an exact definition of organ sparing is still required the oncological rationale for these developments needs to be clarified. The present review aimed to gather current evidence-based recommendations for the management of primary penile tumours. We first discuss the pattern of tumour margins and local recurrence, which then lead to strategies for organ-preservation. Evidence Acquisition Relevant online search was made of Medline using the terms penile cancer, organ-preservation, management, topical, laser, surgery, radiation. Articles were confined to the English language. An exception to this was the first description of glans excision, which was in German [9]. A direct search was also made of the last 3 months in the major urology and oncology journals. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist was used [10]. The principle summary measure was local recurrence. Studies were limited to those with 24 months follow-up. In all, 134 articles were retrieved and after case reports and articles that pertained to the management of lymph node or metastatic disease were excluded, 48 articles were left. These were then analysed as to the level and quality of evidence and recommendations made according to the International Consultation on Urological Diseases (ICUD) guideline [11]. All evidence quoted is Level 3 unless otherwise stated. The low level of evidence precluded a systematic BJU International 2013 BJU International doi: /bju BJU Int 2014; 114: Published by John Wiley & Sons Ltd. wileyonlinelibrary.com

2 Review review. The review investigates the role of the surgical margin, which leads to the current management strategies according to T stage. Margins Historically, excision of the primary lesion, with a 2-cm margin proximal to the macroscopic lesion meant that the choice of surgical technique was limited to either partial penectomy, where some shaft is preserved, or total penectomy with formation of a perineal urethrostomy. The evidence base for using a 2-cm clearance margin is unknown. There have been a few studies analysing the microscopic extension of tumour in squamous cell carcinoma of the penis. A retrospective review of 64 partial and total penectomy specimens examined the microscopic spread of tumour beyond the visible tumour margin [12]. Firstly, they found that only 12 of 64 tumours (19%) had microscopic extension beyond the gross tumour margin. Of these, only three of 12 tumours (2% of the group) had extension of mm from the edge of the visible tumour, all were grade 3. The remaining nine tumours had microscopic extension limited to 5 10 mm from the macroscopic edge. There were no cases of discontinuous spread. This would imply that if a clear margin is confirmed at the time of excision, the surgeon can be confident that the primary lesion has been fully removed. A further study analysed excisional margins in 51 cases treated by penile conservation or partial penectomy [13]. In all, 48% of patients had clear surgical margins of 10 mm, while 90% had margins of <20 mm. At a mean follow-up of 26 months only 4% of cases had local recurrence, managed successfully with further local excision. The authors concluded that adequate oncological control is achieved with excision margins of only a few millimetres. What is clear from these two studies is that within strategies of organ-preserving surgery, there may be a role for perioperative frozen section histopathological assessment, although the accuracy of this technique is as yet, unproven in this context and requires further study. Local Recurrence When cancers do recur adjacent to where a previous excision has been performed, the question arises whether this is the same cancer that was left behind, a second cancer that was already present (synchronous) or a new cancer that has developed (metachronous). Some authors define recurrence as residual disease if occurring at 3 months of the original surgery [14]. The number of local recurrences in each reported case series is small, and there has not been a report comparing the tumour biology/signature of recurrence with that of the original tumour. In most prior studies, local recurrences have been amenable to further conservative techniques. It is possible local recurrences after organpreserving cancer surgery is preservation of skin with a genetic predisposition to carcinogenesis, i.e. field change, although there is no current scientific evidence for this. Techniques of wide local excision, such as circumcision or partial glans excision, leave glans skin that has an increased potential for developing cancer. This raises the question as to whether a prophylactic glans resurfacing should be performed at the same time as the primary tumour local excision, particularly for small lesions on the glans or foreskin. This question remains unanswered and awaits further study. A two centre series examined the recurrence pattern in 700 men after a range of treatments (laser, radiation, conservative surgery, amputation), treated between 1956 and 2006 [14]. The object of the study was to determine the time to recurrence (local, regional and distant) so as to inform clinicians on how to follow-up their patients. In that series, 105 patients had organ-preserving surgery. The use of frozen section and margin status were not described. Local recurrence for the 415 patients who underwent penile preserving strategies (including laser ablation, organpreserving surgery and radiation) was 27.7%. The outcome of the 105 who had organ-preserving surgery was not specified. The local recurrence for those undergoing partial or total penectomy was 5.3%. In the series, local recurrence on the penis was associated with a 92% 5-year cancer-specific survival (CSS) and 92.2% of local recurrences occurred 5 years of treatment. The authors describe follow-up regimes according to treatment, up to 5 years and advised involving the patient more in follow-up through instruction in self-examination. Furthermore, Lont et al. [15] examined the outcome of local recurrence in T2 tumours relative to the risk of developing lymph node metastases and survival. In that series there was close follow-up and men with recurrence were treated early. They found no evidence of an increased risk of lymph node disease or mortality, with such a strategy. A more recent study looked specifically at local recurrence in 179 men undergoing organ-preserving surgery between 2002 and 2010 [16]. The 5-year local recurrence-free survival was 86.3%. Most recurrences were surgically salvageable. The 5-year CSS for an isolated local recurrence was 91.7%. Thus local recurrence after organ-preserving surgery does not appear to have a negative impact on survival. Another recent study of 65 men treated with a range of organ-preserving surgeries also reported a similar low local recurrence rate, at 6% over 40 months of follow-up [17]. A series of 56 men (28 with carcinoma in situ [CIS]; 28 with T1) were followed-up for between 6 months and 16 years [18]. Many cases were managed by wide local excision. The rate of local recurrence was 21.4% for cases of both CIS and T1. The mean time to recurrence was surprisingly long at 4.28 years, with 25% of recurrences at >5 years after being treated. Again this raises the issue of what is actually meant by a recurrence. In a series of 15 cases treated by glansectomy and skin grafting, no local 800 BJU International 2013 BJU International

3 Penile cancer: organ-sparing techniques Table 1 Outcomes of local control according to stage and treatment method. All series were cases series in design some with comparisons between features such as stage and grade. While some data were prospectively acquired most were retrospective. Each study amounted to level 3 evidence. Reference N Years Treatment method Stage Mean follow-up, months Local recurrence, % van Bezooijen et al. [24] Laser CIS Meijer et al. [25] Laser CIS-T2 48 Shabbir et al. [26] Glans resurfacing, glansectomy CIS, T Philippou et al. [16] Organ-preserving surgery CIS-T Veeratterapillay et al. [17] Organ- preserving surgery CIS-T2 Median Feldman et al. [18] Organ- preserving surgery CIS-T Leijte et al. [14] laser, radiation, organ-preserving surgery, amputation CIS-T4 Median Rozan et al. [27] Brachytherapy, Surgery and brachytherapy, EBRT and brachytherapy CIS-T Crook et al. [28] Brachytherapy CIS-T recurrence was identified during the 3-year follow-up [19]. The most recent report is a retrospective study of 859 patients treated in a single centre between 1956 and There was a progressive trend towards performing penile-sparing surgery. When controlled for stage/grade and patient factors there was no difference in CSS between those undergoing penile-sparing surgery and partial/total penectomy. Local recurrence following penile-sparing surgery did not affect CSS [20]. Table 1 lists the reported rate of local recurrence from different groups/techniques. When there is tumour recurrence after the organ-preserving technique, it is may be possible to achieve control of the cancer by further local excision if the corpora cavernosa are not involved, as per European guidelines [7]. Organ-Sparing Techniques Partial or total penectomy has excellent local control rates [14] at the cost of significant psychological morbidity and sexual dysfunction [21,22]. The penis may also be preserved using radiotherapy; however, local recurrence is seen in 10 40% of cases (see below). Furthermore, salvage therapy is difficult requiring amputation and often emasculating surgery [23]. A range of operative techniques has recently been developed to overcome these problems. They aim to preserve penile tissue and functional integrity, without compromise of oncological control. This is possible with early diagnosis and accurate staging. In the UK only 15% of tumours invade the corpora at presentation. In the Netherlands, most tumours were staged T1/T2 (61%) [24]. The vast majority of cancers of the penis are amenable to organ-preserving surgery. This is probably also true for all countries with well-developed healthcare, where patients are referred to specialised centres. Organ-Preserving Strategies Based on Disease Stage and Location The choice of surgery is largely determined by the location of the tumour, the ability to achieve clear surgical margins and the structures that can be preserved/reconstructed. These techniques are discussed elsewhere [25]. The reported series are summarised in Table 1 [14,16 18,26 30]. These series are comprised of different populations and treatments that greatly limit meaningful comparison. While any surgical procedure that preserves some or all of the glans penis, or preserves all of the corporal bodies is quite reasonably thought of as organ-preserving, the degree to which a partial penectomy, even with some reconstruction is truly organ-preserving is more controversial. The distinction between a partial penectomy that preserves the organ, and a partial penectomy that does not, is not clear and has almost certainly been interpreted differently by different authors. There is a case for a more clearer definition of what is truly organ-preserving and such a definition should probably be informed by functional outcomes. CIS and Superficial Verrucous Carcinoma (Tis and Ta) The non-invasive nature of CIS (Tis) makes it amenable to curative treatment with preservation of the penis. If there is no invasive carcinoma, first-line treatment is the application of topical chemotherapeutic agents such as 5% 5-fluorouracil (5-FU) cream for 6 weeks on alternate days. Small studies (n<10) have reported sustained response rates approaching 100% at 5 years [31]. A more recent and larger study reported the 10-year retrospective outcome of 86 cases of primary or recurrent CIS of the glans treated topically with either 5-FU or imiquimod [32]. There was a complete response in 25 of the 44 men treated with 5-FU (57%). Nevertheless, this is a safe treatment with low morbidity and minimal systemic absorption. Those that do not have a complete response can be treated with topical imiquimod for a similar duration, although outcomes are mostly based on case reports [33]. Alternatively, carbon dioxide and neodymium:yttriumaluminum-garnet (YAG) lasers may be used as first-line therapy with favourable cancer control rates and good cosmetic results. In a series of 19 patients with Tis treated with laser therapy, 26% of patients had successful retreatment for histologically confirmed Tis recurrence at 32 months of BJU International 2013 BJU International 801

4 Review follow-up. One patient (5%) progressed to invasive disease [26]. However, another study of 44 patients with tumours ranging from Tis to T2 treated with laser had a local recurrence rate of 48%. Of more concern was the progression to nodal disease seen in 23% of cases; 80% of these were in patients with T2 disease [27]. This substantiates the premise that laser should not be used in more advanced disease. Failure to respond to topical or laser therapy may be managed by local excision or total glans resurfacing as developed by Depasquale et al. [34] in the management of severe balanitis xerotica obliterans. This involves removal of the epithelium and subepithelium from the glans spongiosus by sharp dissection under tourniquet haemostatic control. The tissue is usually removed in quadrants beginning at the urethral meatus and extended to 1 cm beyond the coronal sulcus. The exposed surface is then covered using a split-thickness skin graft (STSG). The graft take is excellent achieving a practically normal cosmetic appearance 6 weeks after surgery. The short-term results of this technique were reported in There was an excellent functional outcome with no local recurrence [35]. However, in a series of 25 men with biopsy confirmed Tis, five cases (20%) had unexpected invasive disease in the final pathology [28]. This may explain local recurrences in non-excisional strategies. The overall local recurrence in this series was 4%. T1 Lesions of the Foreskin Circumcision may achieve a curative wide local excision, if adequate clearance margins are confirmed [36]. For more proximal lesions, excision may have to be extended to the shaft of the penis to ensure negative margins [37] and a STSG can be used to replace skin. As there is risk of local recurrence of the preserved glans close follow-up is required. Recurrence may be treated by resurfacing or resection depending on the pattern of disease spread. Small T1 Tumours on the Glans Penis Management of small T1 lesions on the glans is debatable. It may be possible to perform a wide local excision with primary closure of the defect if the lesion is small and not too close to the urethral meatus [38]. However, closing the defect from larger lesions may lead to tilting of the glans and may affect the direction of micturition. In such cases, skin grafting may be required to cover the defect. However, as with tumours of the foreskin, there is a risk of metachronous tumours on the glans. Clear margins should be achieved at the time of surgery and should not be performed in the presence of field change, i.e. CIS. Recurrence rates of up to 50% have been reported, most occurring 2 years of initial surgical resection [39]. Thus, close follow-up is needed. Fortunately, salvage surgery has a high success rate and does not affect CSS [15,40]. This strategy is offered to patients with well differentiated tumours, absence of concurrent Tis and an otherwise normal looking glans. It requires careful patient selection, education and commitment to follow-up to ensure early detection and treatment of local recurrence. As mentioned above an alternative strategy would be to perform a total glans resurfacing at the same time as excision of the primary cancer. This requires further evaluation. T2 Disease Confined to the Glans Penis Historically the choice of treatment for these tumours consisted of either penile amputation or radiotherapy. These patients may now be offered glansectomy and skin grafting. The anatomical distinction between the corpora cavernosa and corpus spongiosum led to the concept of glansectomy as an effective option for penile cancer confined to the glans penis [41]. Not only did Bracka [9] describe total glans resurfacing, he also described glansectomy and skin grafting. The details of this technique have been more recently illustrated [42]. Davis et al. [43] reported on the successful treatment of three patients with verrucous carcinoma, angiosarcoma and melanoma limited to the glans, using glansectomy. In all three pathologies there were clear surgical margins and no local recurrence. Furthermore, normal sexual and urinary function was maintained in all three cases. Another series of seven cases of verrucous carcinomas were managed by glansectomy [44]. One patient required further resection at 3 months for a local recurrence. A cohort of 72 patients, including seven salvage cases following radiotherapy, were treated by glansectomy and STSG. At 27 months follow-up, the local recurrence rate was 4% [45]. T2 Tumours Involving Corpora Cavernosa and T3 Tumours When penile cancer involves the corporeal bodies, urethra or both, a more extensive resection is strongly advised. Provided there is a reasonable shaft to allow voiding and/or sexual activity a partial penectomy is indicated. Successive frozen sections may be required to achieve negative margins. The penis is then assessed as to whether preservation is possible. Dividing the suspensory ligaments just below the pubic arch may provide up to 2 cm of additional penile length via mobilisation either at the time of surgery or as a delayed procedure. If sufficient shaft is preserved then the corpora can be reconstructed to create a neo-glans. The exposed corporal tips may be covered with a STSG. Use of skin grafting instead of bringing the shaft skin to the new urethral meatus prevents retraction of the residual shaft and the cosmetic outcome is better than with the traditional approach of total penectomy. However, with more extensive disease, a total penectomy may be indicated. As with all organ-preserving techniques, case selection and close surveillance, including self-examination, is necessary as late recurrences have been reported and their 802 BJU International 2013 BJU International

5 Penile cancer: organ-sparing techniques early recognition may optimise their resulting treatment outcomes [14]. Salvage for Local Recurrence after Radiotherapy Local recurrence after radiotherapy occurs in 10 40% of cases [30,46]. It may be difficult to distinguish a local recurrence from chronic skin changes secondary to radiotherapy. Areas of non-healing ulcers should be biopsied as a general rule. In many cases, penile-preserving techniques as described above can be used. In a recent study, the outcome of patients referred with chronic or recurrent ulceration after radiotherapy was assessed [47]. In all, 15 of the 17 (88%) patients were found to have invasive cancer; 14 underwent glansectomy and reconstruction. Despite the challenges of healing in an irradiated field, all cases had successful take of the graft. One case had ensuing sarcomatoid changes and the patient died of brain metastases 1 year of surgery. The remaining 16 of the 17 patients had no evidence of disease at a mean follow-up of 3 years. Brachytherapy Although brachytherapy is not a form of surgery it is an option in the management of the primary tumour that is worthy of consideration. In a multicentre study of 259 patients comprised of CIS (6.8%), T1 (41%), T2 (41.5%) and T3 (10.7%) primary tumours [27], 56 (22%) had some form of surgery before brachytherapy. In all, 36 patients had excisional surgery by circumcision whereas 106 underwent circumcision to expose the tumour before treatment. In all, 26 (10%) underwent external beam radiotherapy before brachytherapy. Thus, 184 patients underwent brachytherapy as a monotherapy and 75 had brachytherapy combined with surgery or external beam radiotherapy. Local recurrence occurred in 41 patients (16%); 31 of these were managed by salvage surgery, i.e. local excision in three, partial penectomy in 16 and total penectomy in 12. There was no recurrence in any patient with CIS. There was no statistical difference between other T stages for local control. Larger or infiltrating tumours were more likely to recur. In all, 61% of patients had side-effects, the most common being urethral stenosis, which occurred in 30% of patients. A more recent study by Crook et al. [30] describes 49 patients treated by brachytherapy. It included patients with CIS (4%), T1 (51%), T2 (33%) and T4 (8%) tumours. The median (range) follow-up was 33.4 (4 140) months. Five men had local recurrence, all salvaged with either partial or total penectomy. In all, 42 of the 49 patients had an intact and cancer-free penis at the time of last follow-up. Side-effects were soft tissue necrosis in 16% and urethral stenosis in 12%. Of the 27 patients with normal erectile function before treatment, 22 reported satisfactory erections after brachytherapy. Functional Outcomes and Quality of Life An extensive review has been published by Maddineni et al. [48]. They found that much of the data on quality of life are retrospective in nature, with significant differences in methodology. Despite these limitations some patterns are clear. Penile cancer causes a negative impact on well-being in up to 40% of patients. Men who have undergone more mutilating surgery are more likely to have impaired well-being. Furthermore, symptoms of psychiatric illness areseenin 50%, amounting to post-traumatic stress disorder in two of 30 sufferers in one study [49]. Sexual function may be impaired in up to two thirds of sufferers. Those who had received organ-preserving treatment appeared to have better sexual function. Finally, it may be difficult to assess whether negative psychological effects are a result of the disease or its treatment; however, it was noted that relationships with family or partner were improved after treatment. A further issue that can affect the functional outcome of penile-preserving surgery is the potential need for treatment of the inguinal nodes. Even the most refined penile-preserving approach is negated if the patient requires bilateral inguinal lymphadenectomy, and then goes on to develop significant scrotal lymphoedema. While such lymphoedema often settles with time, in a proportion it will persist, and such issues are not typically reported. Regardless of how the primary is managed the lymph nodes should be managed according to agreed guidelines [7]. Conclusions Historically the rarity of penile cancer has delayed innovation; however, the past decade has seen a trend towards conservative management of the primary lesion. There remains a lack of level 1 evidence comparing the available treatment options but the experience at large tertiary care referral centres has improved our understanding on how to manage penile cancer. Studies have shown the safety of reducing the size of required negative surgical margins leading to the development of penile-preserving techniques. When the glans skin is removed, local recurrence rates are estimated to be 4%, which is similar to the 5% recurrence rate seen with partial/total penectomy within similar cohorts of patients with penile cancer. A clear definition of what is meant by organ sparing is not yet available in the area of penile cancer but such surgery should protect functional and psychological integrity, with selection of the specific technique dependent on the tumour stage and local anatomy. Careful assessment of individual tumour biology and sensible choice of technique is needed. Close surveillance is also required while the long-term recurrence rates for these techniques remain to be defined. BJU International 2013 BJU International 803

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