Review Article. Penile Carcinoma: Lessons Learned from Vulvar Carcinoma. Michelle J. Longpre,* Paul H. Lange, Janice S. Kwon* and Peter C.

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1 Review Article Penile Carcinoma: Lessons Learned from Vulvar Carcinoma Michelle J. Longpre,* Paul H. Lange, Janice S. Kwon* and Peter C. Black*, From the Department of Urologic Sciences, and the Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, British Columbia, and the Department of Urology, University of Washington, Seattle, Washington Purpose: Penile carcinoma is rare in the developed world and treatment guidelines are often based on marginal clinical data. Prospective controlled studies are virtually absent and meta-analyses are rare. Vulvar carcinoma, on the other hand, has many parallels to penile carcinoma, and the level of evidence for diagnosis and treatment is more robust. Therefore, we assessed the body of literature on vulvar carcinoma to identify potential improvements in the care of patients with penile carcinoma. Materials and Methods: A literature review was performed on vulvar carcinoma and direct comparisons were made to a similar review of the literature on penile carcinoma. Results: Several aspects of vulvar carcinoma management are clearly established and deserve closer evaluation in penile carcinoma. For example, human papillomavirus is identified in a high percentage of patients with vulvar carcinoma but is understudied in penile carcinoma. Further study is of potential clinical value, especially with the development of human papillomavirus vaccines for prevention. Penile carcinoma TNM staging does not adequately stratify survival or risk of advanced disease. Staging of vulvar carcinoma is dependent on tumor size and depth of invasion measured in millimeters, as opposed to the invasion of underlying structures in penile carcinoma. Management of the inguinal nodes is more refined for vulvar carcinoma, where lymphatic mapping has been conducted and sentinel node biopsy has proven to be highly effective in multicenter trials. Finally, the efficacy of adjuvant radiation and chemotherapy has been tested in controlled trials or reported in meta-analyses for vulvar carcinoma, which are both lacking for penile carcinoma. Radiation after inguinal node dissection, for example, has been shown to enhance survival in patients with defined risk factors. Neoadjuvant chemoradiation is recommended before surgery for advanced vulvar carcinoma. Conclusions: Evidence derived from studies on vulvar carcinoma can be extrapolated to penile carcinoma to help guide clinical trials and future research directions to enhance the treatment of these patients. Key Words: penile neoplasms; vulvar neoplasms; carcinoma, squamous cell; neoplasm staging; disease management Abbreviations and Acronyms DSLNB dynamic sentinel lymph node biopsy HPV human papillomavirus ILND inguinal lymph node dissection LN lymph node LND lymph node dissection PC penile carcinoma RCT randomized clinical trial RT radiation therapy SLNB sentinel lymph node biopsy VC vulvar carcinoma Accepted for publication March 29, * Nothing to disclose. Financial interest and/or other relationship with Janssen, LaZure Scientific, Johnson & Johnson and Merck. Correspondence: Department of Urologic Sciences, University of British Columbia, Level 6, 2775 Laurel St., Vancouver, British Columbia V5Z 1M9 Canada (telephone: ; FAX: ; peter.black@ubc.ca). Editor s Note: This article is the first of 5 published in this issue for which category 1 CME credits can be earned. Instructions for obtaining credits are given with the questions on pages 398 and 399. PENILE carcinoma is a disease for which the treatment can be as devastating as the carcinoma itself. It is a rare disease in developed countries with a reported incidence in the United States of 0.58 in 100, The incidence in Asia, Africa and South America is far higher, and accounts for 10% to 20% of all malignancies. 2 Due to its rarity, randomized prospective studies are virtually absent and meta-analyses are rare. Therefore, many controversies exist in the management of PC /13/ /0 THE JOURNAL OF UROLOGY Vol. 189, 17-24, January by AMERICAN UROLOGICAL ASSOCIATION EDUCATION AND RESEARCH, INC. Printed in U.S.A. 17

2 18 LESSONS LEARNED FROM VULVAR CARCINOMA Vulvar carcinoma in women has many similarities to penile carcinoma in men. Both diseases have similar anatomy, histology, risk factors and natural histories. Although VC is also relatively rare in developed countries (2.5/100,000 in the United States), it is a much better studied disease, with a higher level of evidence for guiding diagnosis and treatment. 3 We propose that the body of literature on VC can be used to guide us toward improvement in the management of PC. ANATOMICAL SIMILARITIES The male and female external genitalia develop along a common embryological pathway. The lymphatics from the glans of the penis as well as the clitoris, labia minora and the terminal end of the vagina drain into the deep inguinal nodes and the internal iliac nodes. 4 The penile shaft skin and the labia majora drain into the superficial inguinal nodes. The penis and vulva differ in that the penis often drains bilaterally and the vulva drains unilaterally, except for the midline regions of the vulva. 4 Metastatic spread in vulvar and penile carcinoma via these lymphatics occurs in a predictable pattern without skip lesions. The presence or absence of lymph node metastasis in PC and VC is highly predictive of survival. HISTOLOGY AND HPV ASSOCIATION Penile and vulvar cancers have previously been considered diseases of the elderly with a peak incidence in the sixth and seventh decades. This concept is changing with studies showing a quarter of patients with penile cancer to be younger than 50 years old. 5 A similar decrease in the age of diagnosis has occurred in VC, for which the average age is 55 years. 6 Squamous cell carcinoma is the most common malignancy in penile and vulvar carcinoma, accounting for 90% to 95% of cases. There are 2 main categories of well studied predisposing factors to PC that are paralleled in VC. The first is the HPV related pathway that is associated with HPV 16, 18 and 33. The second is a HPV unrelated pathway that is secondary to chronic inflammation such as lichen sclerosus in VC and balanitis xerotica obliterans in PC. These are considered synonymous conditions characterized by a chronic, progressive, atrophic, sclerosing process found on male and female genitalia. A systematic review of 31 studies including 1,466 men showed that HPV is associated with penile carcinoma in 47% of patients. 7 Similar studies have found 60% of vulvar carcinoma to be associated with HPV. 8 The high rate of HPV association with PC raises the question of the usefulness of the HPV vaccine in males. It is well recognized that the HPV vaccine can effectively reduce the risk of preinvasive cervical and vulvar intraepithelial neoplasia. 9 Until recently there was still no defined role for the use of the HPV vaccine in boys due to the lack of long-term studies on the efficacy, safety and cost-effectiveness of the HPV vaccine. However, a randomized placebo controlled trial of more than 4,000 males age 16 to 26 years found the HPV vaccine (HPV 6, 11, 16, 18) reduced the incidence of external genital lesions by 90.4%. 10 Earlier this year the American Academy of Pediatrics recommended the routine use of the quadrivalent HPV vaccine in boys ages 11 and 12 years, and all boys age 13 to 21 who had not previously been offered the vaccine. Their recommendations were backed by clinical trials showing the vaccine is highly immunogenic, safe and well tolerated by boys and girls alike. The vaccine could prevent up to 47% of PC, 87% of anal cancer and 60% of oropharyngeal cancer, and prevent the transmission of the virus to female partners. STAGING TNM staging of PC is often criticized as being poorly predictive of patient outcome. The TNM staging of VC differs significantly from that of PC and it is possible that it could guide changes to PC staging to improve prognostic value. The principal shortcoming of the TNM system in PC is that it does not adequately stratify the risk of death. In one study there was no significant difference between survival for Tis/Ta and T1, and several studies have shown that the 5-year survival for T3 is the same or better than that for T2 disease. 11 This finding is likely due to the combination of corpus spongiosum and corpus cavernosum into 1 stage (T2), because the ability of a tumor to invade the tunica albuginea and, therefore, into the corpus cavernosum has been postulated to be a marker of aggressiveness with worse prognosis. 12 Stage T3 also combines invasion anywhere along the entire length of the urethra and into the prostate. Invasion into the distal urethra, especially at the glans, has a better prognosis than invasion into the proximal urethra or corpus cavernosum. 11 The prostate is rarely involved in PC and the prognostic value of invasion into the prostate has not been determined. 11 The recent update to the TNM staging split T1 into T1a and T1b based on the absence or presence, respectively, of lymphovascular invasion. On multivariable analysis this has been shown to be an independent predictor of positive LNs in patients with clinically negative LNs. 13 The updated TNM staging also includes grade to differentiate between T1a and T1b (absence or presence of high grade carcinoma). While grade is widely accepted as an important risk

3 LESSONS LEARNED FROM VULVAR CARCINOMA 19 factor in PC, there are conflicting reports based on univariable and multivariable analyses regarding its prognostic value. 14 Furthermore, in patients with intermediate grade (G2) T1 disease, the risk of LN metastasis ranges from as low as 0% to as high as 50%. 15 It would be desirable for the TNM categorization to guide the decision to perform ILND (T1b) or not (T1a), but this is not achieved with the updated system. A solution to this controversy may be to adopt a dichotomous grading system that includes only low and high grade, as we have done with bladder cancer. The FIGO (International Federation of Gynecology and Obstetrics) staging system for VC was also revised in 2009 (Appendixes 1 and 2). 16 The new staging system demonstrates an appropriate stratification of prognostic groupings. Many studies on depth of invasion have shown VC lesions with less than 1 mm invasion to have a negligible risk of nodal metastasis, thereby eliminating the need for LND. 17 Furthermore, on multivariable analysis, depth of invasion has been shown to be one of the only independent predictors of recurrence and positive LNs. Hacker et al reported increasing rates of nodal disease with 1 mm increments in depth of invasion, from 0% if 1 mm invasion or less, to 10.5% if 1.1 to 2 mm invasion to 42.9% if more than 5 mm invasion. 18 A comparable multivariable analysis in PC showed T stage was not a predictor of survival or of positive LNs. In a multivariable analysis of 145 patients only depth of invasion was predictive of survival when comparing 1 to 5 mm vs more than 5 mm invasion. 14 VC staging also differs from PC staging in that invasion into the distal third of the urethra by VC is considered a lower stage (stage II and III) than invasion into the proximal two-thirds of the urethra (stage IV). Modifying the parameters to define depth and location of invasion of PC could enhance the prognostication of PC staging. Clinical and pathological LN staging in PC also has many shortcomings. The use of clinical nodal staging in vulvar and penile carcinoma has been shown to have a high false-negative rate of 16% to 24% and 10% to 60%, respectively. 19,20 Therefore, vulvar carcinoma TNM staging no longer relies on the clinical examination of the locoregional LN (Appendix 2). In PC, guidelines continue to rely on whether lymph nodes are palpable to determine clinical staging and to direct management. If LNs are not palpable and dynamic sentinel lymph node biopsy is not available, the recently updated EAU (European Association of Urology) guidelines suggest using patient risk factors and nomograms to determine if the patient can be surveyed or if ILND is required. However, the sensitivity of published nomograms is less than 80%. The vulvar carcinoma TNM nodal staging system is based on the numbers of LNs as well as the size of the LNs (Appendix 2). A GOG (Gynecologic Oncology Group) study of 385 patients with VC undergoing ILND found the 5-year survival for 1 to 2, 3 to 4, 5 to 6 and more than 7 positive nodes to be 75.2%, 36.1%, 24.0% and 0%, respectively. 21 Another similar study in VC found a 94% survival with 1 positive node, an 80% survival with 2 positive nodes and a 12% survival with 3 or more positive nodes. 22 The size of LN metastasis has also been incorporated into the staging of VC based on data showing a significant survival difference among less than 5 mm, 5 to 15 mm and more than 15 mm nodal involvement. Pathological nodal staging in PC differentiates only single vs multiple or bilateral inguinal lymphadenopathy. This is a fairly crude differentiation since studies in PC have found significant survival differences when accounting for the number of positive nodes found during ILND. In a study of 128 patients with PC who underwent ILND, a multivariable analysis revealed that the number of positive inguinal LNs, bilateral positive LNs, positive pelvic LNs and extranodal spread were independent predictors of survival. However, the number of LNs was only divided into 1 to 3, 4 to 5 and more than 5, which had a 5-year survival of 75.6%, 8.4% and 0%, respectively. 23 It may have been beneficial to differentiate between 2 or fewer LNs vs more than 2 positive LNs. 24 In a similar study of 201 patients Ravi found more than 3 positive LNs to be an independent predictor of survival. 25 This finding was supported by another study showing 2 or fewer nodes vs 3 or more LNs to be an independent predictor of survival. 12 The same study also found extracapsular extension to be an independent predictor of survival on multivariable analysis. 12 We suggest that the current TNM staging should be adjusted to incorporate the number of positive LNs. The use of nodal size has not been adequately studied in PC and further investigations are required before this element can be incorporated. There are conflicting data for vulvar and penile carcinoma regarding the use of bilateral vs unilateral LN involvement as a prognostic factor. The majority of studies on VC have not shown a significant difference in survival if bilateral nodes are involved, and a recent study found bilateral LN metastases only to predict worse survival when the number of LNs was included in the model. 26 For PC, a recent review of the current TNM staging did find a significant difference in survival depending on the laterality of positive LNs. 11 Based on a comparison of the VC and PC literature, we believe there is sufficient evidence to reevaluate PC TNM staging. A proposed variation to the TNM staging is outlined in

4 20 LESSONS LEARNED FROM VULVAR CARCINOMA Appendixes 3 and 4. This proposed revision would of course require validation with clinical data. SENTINEL LYMPH NODE BIOPSY ILND is a potentially morbid procedure. Studies have shown that up to 50% of patients have postoperative complications including wound infection, wound breakdown and lymphedema. 27 Furthermore, up to 80% of patients without clinical evidence of nodal involvement will have no pathological evidence of nodal metastases. A potential method of identifying involved LNs without subjecting all patients to the associated complications of ILND is sentinel lymph node biopsy. SLNB has an established role in VC but its use continues to be debated for PC. SLNB was first described by Cabanas in 1977 for the management of PC. 28 Unfortunately its adoption in penile carcinoma has been slow, whereas VC, melanoma and breast cancers have led the way in the research and use of this technique. The sentinel LN is the first LN in the lymphatic basin that receives primary lymphatic flow from the area of the tumor. SLNB was initially performed using blue dye injected into the tumor, but now uses a combination of blue dye and technetium-99m-labeled nanocolloid (99mTC) that can be located and traced intraoperatively by a gamma ray detector probe. Many of the initial studies in PC with SLNB had unacceptably high false-negative rates (ranging from 10% to 75%). However, many of these studies were small and did not use current methods. 29,30 Results from the Netherlands Cancer Institute have shown that low false-negative rates can be achieved when the optimal technique is applied. 31 In their study of 323 patients the sentinel LN detection rate was 97% with a false-negative rate of 7% and a complication rate of 4.7%. The SLNB technique was modified after the first 157 patients so that these were compared to the subsequent 105 patients. The modifications included preoperative ultrasound in all patients, immediate fine needle aspiration of suspicious LNs and improved histopathology. Any patient with positive cytology went directly on to full ILND. These patients with more substantial LN involvement often have lymphatic rerouting and a higher risk of a false-negative result on SLNB. Therefore, identifying these patients preoperatively increases the sensitivity of SLNB. With this modified approach (dynamic sentinel lymph node biopsy), the false-negative rate decreased from 19% to 4.8%. The same group also compared the traditional EAU risk stratification guidelines to DSLNB and found DSLNB to be superior. 12,32 This technique is being validated in the United Kingdom with a large multicenter series of surgeons performing their first 25 cases using SLNB followed by traditional lymphadenectomy. The data for VC are more robust than for PC and would encourage the further development of the technique for PC. Selman et al systematically reviewed the accuracy of minimally invasive and noninvasive tests to assess the inguinal LN status in VC. 33 They found SLNB with 99mTC nanocolloid to be the most accurate compared to fine needle aspiration, magnetic resonance imaging and positron emission tomography. The pooled sensitivity of SLNB was 97% in this study with an inguinal recurrence rate of only 2.3%. 33,34 In the studies that used intraoperative lymphoscintigraphy and the blue dye method, the detection rates varied from 95% to 100% with no false-negatives. These data can be compared to similar studies using ILND. The false-negative rates for classic ILND were estimated to be between 0% and 4% at the International Sentinel Node Society meeting in An argument against DSLNB in penile carcinoma is the concern that the learning curve is too long for such a rare disease. Van der Zee et al proposed a 10-case learning curve for VC, which is much shorter than for melanoma and breast carcinoma (30 and 40 cases, respectively) due to the predictability of the sentinel LN in VC. 34,36 DSLNB should be performed at large referral centers or centers of excellence in collaboration with gynecologic oncologists where a few surgeons can master the technique. ADJUVANT CHEMOTHERAPY AND RADIATION THERAPY Finally, the use of radiation and chemotherapy in the management of vulvar and penile carcinoma has been advancing with guidance from research on anal carcinoma and cervical carcinoma. There are 3 main areas in which radiation with or without chemotherapy has been studied. The first is the use of RT in place of ILND with low stage and clinically LN negative disease (prophylactic RT) or in clinically LN positive disease (with curative intent). Next is the use of adjuvant and neoadjuvant RT (combined with ILND) to decrease local failures in LN positive disease. Finally, chemoradiation can be used in metastatic disease to improve survival, and avert the need for extensive pelvic resection with urinary and fecal diversion. The use of RT as an alternative to ILND is controversial in penile and vulvar carcinoma. It is not routinely used for PC based on a single prospective nonrandomized study of 64 patients with PC, which found decreased survival for clinically LN negative and LN positive disease treated with RT compared to bilateral ILND. 37 In the context of VC, a growing

5 LESSONS LEARNED FROM VULVAR CARCINOMA 21 body of research supports inguinal RT for clinical N0 and N1 disease. The GOG group originally found RT to be inferior to ILND. 38 After early poor results, recent studies with a superior RT design showed no survival advantage when comparing ILND with RT for clinical N0 and N1 disease. 39 A similar study of 23 patients with locally advanced VC and clinically negative LNs receiving radiation in addition to chemotherapy demonstrated no inguinal recurrence. 40 The GOG now supports the use of prophylactic inguinal RT in women who refuse ILND or who are deemed medically unfit to withstand ILND (National Cancer Institute: PDQ Vulvar Cancer Treatment. Bethesda, MD: National Cancer Institute). The evidence is inadequate to claim that RT should be considered equivalent to ILND in all patients. The toxicity of ILND and RT is similar, with cutaneous toxicity, lymphedema, sepsis and urinary tract infections being the most common adverse effects. Although the studies are small, patients with PC who refuse ILND or are unfit should also be offered the option of RT to manage clinically N0 and N1 disease. The role of neoadjuvant and adjuvant radiation for LN positive disease in PC is much less studied than in VC. 41 In PC a large retrospective series in addition to several small single institutional series addresses this question. However, in VC prospective randomized trials have been completed. The evidence for neoadjuvant RT in penile carcinoma is mixed. In a study of 201 men with clinically metastatic inguinal LNs larger than 4 cm or fixed to the skin who were treated with neoadjuvant RT before LND, the rate of inguinal recurrence decreased from 19% in nonirradiated to 3% in irradiated patients. 42 Other small studies in PC revealed worse outcomes with neoadjuvant RT of positive inguinal LNs as well as increased complications. 43 The Netherlands Cancer Institute Group has adopted the use of adjuvant RT to the inguinal and pelvic LNs if more than 2 LN metastases are found on ILND. 12 The cutoff of more than 2 LNs before adjuvant RT is supported by the VC literature. 44 The most recent guidelines from the EAU, 45 the only organization with guidelines for treating PC, did not address the use of neoadjuvant RT to inguinal LNs, but did state that adjuvant RT may improve locoregional control in patients with extensive metastases (extent not specified) or extranodal spread. 45 Based on data from 2 RCTs, patients with stage III VC who undergo ILND and are found to have positive LNs are offered adjuvant inguinal and pelvic radiation. An initial RCT by the GOG randomized 114 patients to radiation of the pelvis and inguinal or pelvic node resection if ILND revealed inguinal LN metastases. 44 There was a statistically significant increase in overall survival after 2 years in the radiation group. A second RCT was conducted to study long-term outcomes. After a 6-year followup the cancer related death rate was significantly higher for pelvic LND compared with radiation (51% vs 29%). This study also found that if the ratio of positive LNs-to-total LNs removed is greater than 20%, there is a significantly increased risk of contralateral LN metastasis, relapse and cancer related death. 23 The Society of Obstetricians and Gynaecologists of Canada practice guidelines state that patients with 3 or more micrometastases in the groin, with LNs larger than 10 mm, with extracapsular spread or with bilateral microscopic metastases, should receive postoperative bilateral inguinal and pelvic radiation. Pelvic LND is rarely performed in the setting of regional LN metastasis in VC, whereas it is still the recommended practice in PC. Lastly, preoperative chemoradiotherapy for advanced VC has been shown to reduce the need for more radical surgery. A GOG prospective multicenter phase II study found that when patients with stage III or IV VC were treated with cisplatin/5- fluorouracil and radiation followed by surgical excision, 68 of 71 were able to preserve urinary and/or gastrointestinal continence. 46 Of these 71 patients 33 had no detectable VC at the time of planned surgery. A randomized phase III controlled trial comparing RT alone to RT and chemotherapy with fluorouracil/mitomycin for locally advanced anal carcinoma found that the rate of complete response increased from 54% to 80% in the combination group. Furthermore, event-free survival (defined as free of locoregional progression, no colostomy and no severe side effects or death) showed significant improvement with chemoradiotherapy. 47 A prospective phase II trial in VC is under way by the GOG that will investigate the use of weekly cisplatin with daily high dose radiation followed by resection of residual tumor (GOG protocol 205). To our knowledge no trials have evaluated the use of combination chemoradiotherapy in advanced PC but studies of the individual components have shown some promising results. Several studies have investigated the use of single agent and multi-agent chemotherapy in advanced PC to facilitate curative surgery and improve overall survival. The most successful regimens have included cisplatin combined with bleomycin and methotrexate or with paclitaxel and ifosfamide. 12,48 Preliminary studies on paclitaxel combined with 5-fluorouracil have shown promising results. 49 CONCLUSIONS PC is a rare but devastating disease. Due to its rarity, clinical trials are sparse and have included

6 22 LESSONS LEARNED FROM VULVAR CARCINOMA few patients. Fortunately VC has many parallels to PC, with more robust clinical research supporting treatment choices. We believe that the evidence available for the management of VC offers valuable lessons to guide new research in PC and improve the management of this disease. A rational argument can be made for the administration of the HPV vaccine in males and it is now recommended by the American Academy of Pediatrics. The current TNM staging system provides inadequate prognostication for PC and may be enhanced by using principles from VC staging. A new TNM staging system is proposed in this review but further investigation is required to determine if it is able to better predict patient survival. Dynamic sentinel lymph node biopsy has an established role in VC, breast cancer and melanoma, but its use in PC continues to be debated. Recent evidence supports its use, but implementation is difficult due to the low patient numbers that prevent most centers from gaining adequate experience with the technique. By combining our efforts with gynecology at larger centers we would be able to overcome the learning curve more rapidly. Lastly, radiation and chemotherapy are underused in PC. The use of radiation in clinically LN negative cases for prophylaxis needs to be reevaluated in a larger study as it has shown noninferior results compared to ILND in vulvar carcinoma. The use of radiation, particularly in LN positive cases, has replaced the morbid pelvic LND in vulvar carcinoma, and should be studied as a treatment option for high stage PC. The combination of chemotherapy and radiation may be able to reduce the need for extensive pelvic surgery in cases of advanced disease as well as improve overall progression-free survival. APPENDIX 1 Vulvar carcinoma TNM tumor staging 16 STAGE Tis T1a T1b T2 T3 DESCRIPTION Carcinoma in situ Lesion 2 cm or smaller confined to the vulva or perineum with stromal invasion 1.0 mm or less* Lesion larger than 2 cm or with stromal invasion greater than 1.0 mm, confined to the vulva or perineum Lesion of any size with invasion into perineal structures (lower/distal third urethra or vagina, or any anus involvement) Lesion of any size with invasion into the upper/proximal two-thirds of urethra and/or vagina, bladder or rectal mucosa, or fixed to pelvic bone * Depth of invasion defined as the measurement of the tumor from the epithelialstromal junction of the most adjacent superficial dermal papilla to the deepest point of invasion. APPENDIX 2 Vulvar carcinoma TNM nodal staging 16 STAGE NX N0 N1a N1b N2a N2b N2c N3 NODAL (N- Stage) Regional lymph nodes cannot be assessed No regional lymph node metastasis One or 2 regional lymph node metastases, each 5 mm or less One lymph node metastasis 5 mm or greater Three or more lymph node metastases each less than 5 mm Two or more lymph node metastases 5 mm or greater Lymph node metastasis with extracapsular spread Nixed or ulcerated regional lymph node metastasis APPENDIX 3 Current and proposed T categories in penile carcinoma 50 CURRENT T CATEGORY PROPOSED T CATEGORY T0 No evidence of primary tumor No evidence of primary tumor Tis Carcinoma in situ Carcinoma in situ Ta Noninvasive verrucous carcinoma Noninvasive verrucous carcinoma T1 T1a Invades subepithelial connective tissue without lymphovascular invasion and is not poorly differentiated or undifferentiated (not grade 3 4) T1b Invades subepithelial connective tissue with lymphovascular invasion, or is poorly differentiated or undifferentiated T2 Tumor invades corpus spongiosum or corpus cavernosus T1a Lesion 2 cm or smaller with 1 mm or less of stromal invasion T1b Lesion larger than 2 cm or with more than 1 mm stromal invasion, or presence of lymphovascular invasion Tumor invades corpus spongiosum or glandular urethra T3 Tumor invades urethra or prostate Tumor invades corpus cavernosum T4 Tumor invades adjacent structures T4a Tumor invades pendulous urethra T4b Tumor invades adjacent structures or prostate APPENDIX 4 Current and proposed pathological N categories in penile carcinoma 50 CURRENT PATHOLOGICAL TNM NODAL STAGING PROPOSED PATHOLOGICAL TNM NODAL STAGING N0 No regional LNs No regional LNs N1 Intranodal metastasis in a single inguinal lymph node 2 or fewer inguinal LNs with intranodal metastasis N2 Metastasis in multiple or bilateral inguinal lymph nodes 3 or more inguinal LNs or bilateral inguinal LNs with intranodal metastasis N3 Metastasis in pelvic lymph node(s), unilateral or bilateral or extranodal extension of regional lymph node metastasis Extranodal extension or pelvic lymph node(s) Proposed nodal staging to be based on surgical and pathological findings.

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