Version May 2024
INTRODUCTION — Cancers of the penis are rare in the United States, Europe, and other industrialized countries. However, the incidence of penile carcinoma is much higher in parts of South America, Africa, and Asia. (See "Carcinoma of the penis: Epidemiology, risk factors, and pathology".)
The treatment of squamous cell carcinoma of the penis is reviewed here. Related topics include:
●(See "Carcinoma of the penis: Epidemiology, risk factors, and pathology".)
●(See "Carcinoma of the penis: Clinical presentation, diagnosis, and staging".)
TREATMENT OVERVIEW — The American Joint Committee on Cancer (AJCC) tumor, node, metastasis (TNM) eighth edition staging system (table 1) is used for staging carcinoma of the penis. (See "Carcinoma of the penis: Clinical presentation, diagnosis, and staging", section on 'TNM staging evaluation'.)
Following initial evaluation, staging and treatment of the primary lesion and the regional lymph nodes are performed separately. Our overall approach is as follows:
●Primary tumor – In general, men with a low risk of recurrence are candidates for organ-preserving treatment, whereas men with a high risk of recurrence should be treated by penile amputation (algorithm 1). (See 'Treatment of the primary tumor' below.)
•For men with a small distal, noninvasive, or minimally invasive primary tumor, treatment depends on whether the lesion can be adequately controlled with topical therapy, limited excision techniques, or radiation therapy (RT) in an effort to preserve penile form, function, or both (figure 1A-B).
•For men with bulky stage T2 to T4 primary tumors, primary tumor control essentially requires amputation to achieve tumor-free margins and low rates of local recurrence.
●Regional lymph nodes – The need for surgical staging and subsequent treatment of the regional lymph nodes is based upon characteristics of the primary tumor (ie, grade, stage, lymphovascular invasion, perineural invasion) as well as the presence or absence of palpable inguinal lymphadenopathy (algorithm 2 and algorithm 3 and algorithm 4). (See 'Approach to the regional nodes' below.)
●Locally advanced disease – Men with locally advanced disease (ie, unresectable primary tumor and/or bulky lymphadenopathy) should be treated initially with systemic or multimodal therapy rather than surgery or RT alone. (See 'Neoadjuvant chemotherapy for locally advanced or unresectable disease' below.)
●Recurrent or metastatic disease – The approach to men with recurrent or metastatic penile carcinoma depends upon whether disease is localized and potentially curable, whether adjacent structures are involved (ie, major blood vessels, vital organs), or whether distant metastatic disease is present. (See 'Recurrent or metastatic disease' below.)
TREATMENT OF THE PRIMARY TUMOR
Tumors with a low risk of recurrence — Primary tumors with a low risk of recurrence include Tis involving shaft skin and glans penis, Ta lesions involving the glans only, and T1a and T1b lesions involving the shaft skin and glans alone (figure 1A-B and table 1).
Limited excision — The objective of a limited excision is to preserve as much of the anatomy of the penis as possible in order to maintain penile length and sexual function while not compromising complete resection of the cancer. Minimally invasive tumors involving the glans (Tis, Ta, T1) and foreskin are most amenable to these techniques. However, small distal T2 glanular lesions can sometimes be resected with negative margins using a glans-sparing technique or with complete glans resection alone, sparing the corporal bodies.
The results with a conservative surgical procedure are illustrated by a study from the United Kingdom that analyzed outcomes among 179 patients treated over an eight-year period [1]. Surgical procedures used in this series included circumcision, wide local excision with primary closure or skin graft placement, removal of the glans, or removal of the glans and distal corpora. The mean distance between the microscopic tumor and the resection margin was approximately 5 mm. At a median follow-up of 39 months (range 4 to 107), the local recurrence rate was 9 percent, with a projected five-year freedom from recurrence rate of 86 percent. Predictors of local recurrence were tumor grade and lymphovascular invasion. However, distance to the resection margin was not a significant predictor of recurrence.
Excision to negative margins is critical, with a minimum tumor-free margin of 1 mm or greater. One study from the United Kingdom evaluated the issue of distance of tumor from a negative margin and the risk of recurrence. Among a cohort of 332 patients undergoing organ-sparing surgical procedures in whom the surgical margins were negative, the recurrence rate was 6.4 percent. However, among the cohort of patients with less than a 1 mm tumor-free surgical margin, the incidence of recurrence was approximately six times greater than those with a margin distance >1 mm [2]. In another study of 64 penectomy specimens, histologic grade was highly correlated with microscopic tumor extension beyond the grossly negative margin [3]. The maximum tumor extension was 5 mm for grade 1 to 2 tumors and up to 10 mm for grade 3 tumors. A historically recommended surgical margin of 2 cm is no longer mandated.
Alternative organ-preserving strategies — In general, alternative organ-preserving strategies should be reserved for men with small, low-stage primary (Tis, Ta, T1) penile tumors. Available options include the following:
●Topical therapy, laser ablation, and total glans resurfacing (TGS) are primarily used for Tis lesions (ie, penile intraepithelial neoplasia).
●Mohs micrographic surgery (MMS) is sometimes used for Tis to T1 lesions. (See "Mohs surgery".)
●Penile radiation therapy (RT; external beam or interstitial brachytherapy) can be used for Tis, T1, and T2 lesions <4 cm.
The choice of treatment approach depends upon the available local expertise and patient preference.
Topical therapy — Both fluorouracil (5 percent cream applied every other day for four to six weeks) and imiquimod (5 percent cream applied five days a week for four to six weeks) are used topically to treat carcinoma in situ. However, data on long-term outcomes with topical treatment are limited due to the small sample sizes in single-institution studies [4,5].
In one of the largest reports, 44 men received topical therapy for carcinoma in situ, with fluorouracil used as first-line treatment and imiquimod as second-line therapy [5]. With a mean follow-up of 34 months, 31 men had a response to treatment, and in 25, it was a complete response. With a median follow-up of 34 months (range 12 to 180), 20 men remained in remission.
Laser ablation — Laser ablation utilizes a laser energy source to penetrate and ablate the tumor. Commonly used energy sources include carbon dioxide (CO2), argon, neodymium-doped yttrium aluminium garnet (Nd:YAG), and potassium titanyl phosphate [6].
Laser ablation is associated with a high rate of resumption of sexual activity and sexual satisfaction [7], but its use appears most successful among patients with carcinoma in situ. For men considering laser ablation, the penis must be examined after application of 5 percent acetic acid to identify premalignant areas that will require treatment [8,9].
Several retrospective series have provided information about long-term outcome after laser therapy [10-12]. As an example, in one series that evaluated 104 patients treated with excision plus laser therapy, there was a higher local recurrence rate compared with that of 100 men managed with partial amputation (38 versus 10 percent) [10]. However, local control was achieved in more than 90 percent of those who experienced a local recurrence.
Total glans resurfacing — TGS removes the skin and lamina propria layers of the glans penis down to the corpus spongiosum, followed by placement of a skin graft [13].
The evidence to support its use in low-risk penile carcinoma is limited to single-institution case reports and small series [13-15]. As an example, in one report, 25 men with carcinoma in situ were treated with either TGS or partial glans resurfacing [14]. With a mean follow-up of 29 months (range 2 to 120), 24 men had excellent graft take. However, seven men (28 percent) required further surgery, and in five of these cases, it was due to incidental detection of invasive disease. However, the overall local recurrence rate was only 4 percent. In another series, excellent skin graft take was observed in 19 patients. At mean follow-up of 23 months, the recurrence incidence was 5 percent [15]. Additionally, excellent sexual function was noted using International Index of Erectile Function scores [15]. Additional follow-up will be required to determine the long-term efficacy of TGS.
Mohs micrographic surgery — MMS involves layer-by-layer excision of the penile lesion. It is performed in multiple sessions and provides improved precision while maximizing organ preservation. MMS is performed by a dermatologic surgeon with specific training but requires careful coordination between the MMS surgeon and the urologist to optimize patient care.
The results with MMS are illustrated by a series of 33 patients (15 with invasive lesions) who underwent 41 MMS procedures between 1988 and 2006 at a single institution [16]. Overall, eight patients (24 percent) had a local recurrence, of which seven were managed with repeat MMS. Only one patient ultimately required penectomy, and one patient died of metastatic penile cancer.
Radiation therapy — Penile RT can be administered by either external beam or interstitial brachytherapy techniques. However, the rate of tumor control using external beam RT appears to be inferior to interstitial brachytherapy, as noted in a 2009 review [17].
The most extensive experience with brachytherapy comes from a subsequent series of 201 patients with invasive squamous cell carcinoma of the glans penis treated at a French center over a period of 45 years [18]. With a median follow-up of 10.7 years, the estimated five-year local control rate was 82 percent, and the five-year overall survival rate was 79 percent. Local relapse was the initial site of recurrence in 37 cases (19 percent), and 24 of the 31 patients (77 percent) who recurred locally and received additional therapy remained in complete remission. At last follow-up, 25 patients had undergone partial surgical resection of the penis, and seven required total penectomy.
High doses of RT are generally needed to eradicate penile squamous cell carcinoma. Because of this, complications are common, including urethral mucositis, edema, and secondary infection [19]. Late complications (eg, telangiectasia, dyschromia, superficial necrosis, urethral stricture, fistula formation, meatal stenosis) can also occur [19-23].
Prognostic factors for a poor response among patients treated with RT include [17,24-26]:
●Total treatment dose less than 60 Gy or use of daily fractions less than 2 Gy
●Protracted treatment time greater than 45 days
●T3 or greater tumor
●Tumor larger than 4 cm
●High tumor grade
Circumcision is necessary prior to RT to ensure full exposure of the penile cancer, allow resolution of any surface infection, and prevent maceration and preputial edema. For men who undergo RT, careful follow-up is still required given the risk of local recurrence. Such recurrences may be successfully treated with surgery if diagnosed early. (See 'Posttreatment surveillance' below and 'Localized recurrence' below.)
Tumors with a higher risk of recurrence — Patients with bulky T2 to T4 tumors (table 1) are considered to have a high risk of recurrence without adequate treatment.
Most of these patients will require penile amputation and are not candidates for a limited excision or organ preservation (see 'Penile amputation' below). There are some exceptions:
●Distal, smaller, T2 tumors can be successfully treated with limited excisions as long as a tumor-free margin can be achieved. (See 'Limited excision' above.)
●Interstitial brachytherapy may be an option in select patients who refuse surgery. (See 'Radiation therapy' above.)
Patients with large, invasive (ie, bulky stage T2 to T4), or destructive tumors (ie, bulky stage Ta, verrucous cancers) should be treated with penile amputation in order to achieve rapid control of the primary tumor and to identify those patients requiring additional staging of the inguinal and regional nodes. (See 'Approach to the regional nodes' below.)
Penile amputation — Penile amputation includes either partial or total removal of the penis, which is determined by the location and extent of the primary tumor [27]:
●Partial amputation – A partial amputation involves the removal of the glans penis with or without a portion of the underlying corpora cavernosa. This procedure is usually performed for distal invasive tumors in situations where resection of the tumor may leave the patient with sufficient penile length to enable micturition while standing. In addition, preservation of penile length may be possible for select men with distal tumors amenable to removal of the glans alone [3,28-30]. (See 'Limited excision' above.)
●Total amputation – A total amputation involves removal of the glans penis and most, if not all, of the underlying corporal bodies. The urethra is brought out on the perineum as a urethrostomy in order to facilitate voiding in a sitting position. Total amputation is indicated if the tumor cannot be controlled while sparing sufficient length for the patient to stand and void. This is often the case for very large tumors extending down the shaft.
Partial penectomy is performed more commonly [27,31]. In a review of seven surgical series, total penectomy accounted for 23 percent of 1176 procedures, with the remainder consisting of partial penectomy [27]. Local recurrence rates following penectomy range from 3 to 33 percent, with most series reporting recurrence rates of ≤10 percent. The most common complication of penectomy is meatal stenosis, which occurs in 4 to 9 percent of cases.
Men who undergo amputation should be counselled regarding the option of penile reconstruction [32]. Whether this is an option and the technical aspects of penile reconstruction are highly dependent upon the type of surgery performed and the risk of recurrence following surgery.
APPROACH TO THE REGIONAL NODES — Penile cancer progresses in a predictable manner [33]. There is a prolonged locoregional phase characterized by sequential involvement of the inguinal and pelvic nodes. Distant metastases generally develop following nodal metastases. The presence and extent of inguinal node metastases are the most important prognostic factors for long-term survival [31,34,35].
There are multiple techniques used to evaluate and document the histology of the inguinal nodes, including ultrasound with fine needle aspiration (FNA), dynamic sentinel node biopsy (DSNB), and superficial inguinal lymph node dissection (LND). Patients with disease identified in a pathologically positive sentinel node, superficial dissection, or a positive FNA require further surgical resection of the regional nodes. Staging approaches using FNA, DSNB, and superficial inguinal LND (SILND) are discussed separately. (See "Carcinoma of the penis: Clinical presentation, diagnosis, and staging", section on 'Staging techniques'.)
Clinically negative examination — Men with a clinically negative inguinal node examination may need inguinal node staging based upon the estimated risk of tumor metastasis (algorithm 2) or imaging.
Prognostic factors — Several factors help predict the risk of microscopic inguinal lymph node metastases and are incorporated into the eighth edition of the tumor, node, metastasis (TNM) staging system [36]:
●Primary tumor pathologic stage – Penile carcinoma in situ (Tis), verrucous carcinoma, and low-grade noninvasive carcinomas (Ta) are rarely (if ever) metastatic [33,36]. However, tumors that involve the subepithelial connective tissue alone are heterogeneous for metastatic potential. As an example, the reported incidence of inguinal metastases for stage T1a tumors are 10 to 18 percent [37]. However, among those with stage T1b tumors, the reported inguinal metastatic rates range between 33 and 50 percent, which is similar to the rates seen among men with pT2-4 primary tumors (33 to 52 percent) [37].
●Tumor grade – In addition to tumor stage, metastatic potential is associated with high tumor grade. The reported risk of nodal invasion ranges from 0 to 48 percent for grade 1, 32 to 79 percent for grade 2, and 47 to 100 percent for grade 3 tumors [38]. In one study, men with moderate- and high-grade tumors had a significantly worse survival rate at 10 years compared with those with well-differentiated carcinoma [31].
The reproducibility of the current grading system for penile cancer has come into question in a study from Germany [39]. In addition, the World Health Organization (WHO) and the International Society of Urologic Pathology (ISUP) have recommended that any proportion of anaplastic cells now be designated as grade 3 as part of the eighth edition TNM system [36]. This may facilitate more-uniform identification of tumors with aggressive biology.
●Presence or absence of lymphovascular or perineural invasion – The presence of lymphovascular invasion within the primary tumor is the strongest prognostic factor for lymph node metastases, with an associated risk ranging from 60 to 80 percent [38]. In another study, perineural invasion was found to significantly increase the risk of metastatic disease (69 percent of patients) [40].
Risk stratification — Based upon these prognostic factors, penile cancer guideline panels have stratified men into low- and high-risk groups, which determine the approach to the regional nodes [41,42].
●Low risk – Men with Tis, Ta, and T1a tumors exhibiting no lymphovascular or perineural invasion and that are not grade 3 (using the eighth edition TNM definition (table 1) [36]) and who have no palpable inguinal adenopathy are considered to be at low risk for nodal metastases. The approach to regional nodes in these low-risk patients is discussed below. (See 'Treatment of low-risk disease' below.)
●High risk – In contrast, men with grade 3 tumors, lymphovascular or perineural invasion (≥T1b), and T2 or higher stage are all considered to be at high risk for nodal involvement. The approach to regional nodes in these high-risk patients is discussed below. (See 'Treatment of high-risk disease' below.)
Inguinal staging procedures — DSNB, SILND and modified inguinal LND have been utilized to determine the presence of microscopic metastases among patients with invasive penile tumors and no palpable inguinal adenopathy. All are acceptable alternatives according to treatment guidelines [42-48]. We prefer either DSNB or complete superficial dissection over modified dissections, as the latter had an inguinal recurrence risk of 21 percent in one series [34]. (See "Carcinoma of the penis: Clinical presentation, diagnosis, and staging", section on 'Regional lymph node assessment'.)
Dynamic sentinel node biopsy (DSNB) — The approach to dynamic sentinel lymph node biopsy is discussed separately. (See "Carcinoma of the penis: Clinical presentation, diagnosis, and staging", section on 'Dynamic sentinel node biopsy (DSNB)'.)
Superficial inguinal lymph node dissection — For patients undergoing an SILND, intraoperative frozen sections are performed and, if a positive node is found, a therapeutic inguinal LND should be performed, which involves removal of those nodes deep to the fascia lata contained within the femoral triangle. A pelvic lymphadenectomy should also be performed in the case of advanced inguinal disease (algorithm 2).
●Minimally invasive surgical techniques – Both laparoscopic (LAP) and robotic-assisted inguinal lymphadenectomy (RAIL) have an emerging role as minimally invasive staging procedures to remove the inguinal nodes, especially among patients with clinically negative nodes (cN0) and those with minimal palpable adenopathy. Data suggest that such procedures are safe and can adequately remove the regional nodes, as judged by inguinal lymph node counts [49-54]. As an example, one observational series compared RAIL to standard open inguinal lymphadenectomy among 151 patients with cN0 to minimal palpable adenopathy [52]. Compared with the standard surgery group, patients treated with RAIL experienced slightly longer operating room time but a significantly lower incidence of major complications. Both groups had similar lymph node yields and no inguinal recurrences at approximately 40 months of follow-up.
Further details on SILND for inguinal staging in patients with carcinoma of the penis are discussed separately. (See "Carcinoma of the penis: Clinical presentation, diagnosis, and staging", section on 'Superficial inguinal lymph node dissection (ILND)'.)
Treatment of low-risk disease — The risk of inguinal metastases among men with low-risk disease ranges from 0 to 18 percent [37,41,42,55]. We agree with recommendations from the European Association of Urology (EAU) and the National Comprehensive Cancer Network (NCCN) and offer these men surveillance rather than surgical staging, provided they are able to comply with follow-up recommendations (algorithm 2). (See "Carcinoma of the penis: Clinical presentation, diagnosis, and staging", section on 'Clinically negative inguinal examination'.)
Men who are unable or unwilling to proceed with surveillance should undergo bilateral inguinal node staging by DSNB or SILND. Based on available data, for men with cN0 status, we also believe that minimally invasive RAIL or LAP inguinal removal in experienced hands is a reasonable approach [49-52]. Additional treatment is based upon the results of that staging. (See 'Treatment of high-risk disease' below and "Carcinoma of the penis: Clinical presentation, diagnosis, and staging", section on 'Dynamic sentinel node biopsy (DSNB)'.)
Treatment of high-risk disease — Men at high risk should undergo either DSNB or open SILND. Both RAIL and LAP approaches are also acceptable (provided the expertise and the facilities are available) (algorithm 2). (See "Carcinoma of the penis: Clinical presentation, diagnosis, and staging", section on 'Clinically negative inguinal examination'.)
Further treatment of the regional nodes is guided by the pathologic findings:
●Patients with negative inguinal nodes following either open bilateral SILND, minimally invasive LND, or DSNB require no further therapy. We recommend posttreatment surveillance. (See 'Posttreatment surveillance' below.)
●Patients with one pathologically involved inguinal node and without extranodal extension require a complete ipsilateral inguinal LND. (See 'Therapeutic inguinal node dissection' below.)
●Patients with two or more pathologically involved inguinal nodes, or with one involved node and evidence of extranodal extension should undergo a therapeutic ipsilateral inguinal LND and unilateral or bilateral pelvic LND [56]. Adjuvant therapy (eg, chemotherapy, radiation, or chemoradiation) should be offered. (See 'Therapeutic inguinal node dissection' below and 'Pelvic node dissection' below and 'Adjuvant therapy' below.)
Clinically suspicious examination — We stratify our approach to men who present with palpable inguinal adenopathy based upon the clinical examination and/or imaging, and the results of FNA (algorithm 3). (See "Carcinoma of the penis: Clinical presentation, diagnosis, and staging", section on 'Fine needle aspiration'.)
Enlarged, unilateral inguinal node present — For men who present with a unilateral, solitary inguinal node <4 cm in size, we suggest FNA of the palpable inguinal node.
●If the FNA is positive, a complete (ie, superficial and deep) inguinal LND should be performed as it may provide therapeutic benefit in men with pathologically involved lymph nodes. (See 'Therapeutic inguinal node dissection' below.)
We prefer an open surgical approach, given the limited experience and follow-up using RAIL or LAP techniques in the setting of clinically positive nodes. However, minimally invasive (eg, RAIL or LAP) surgical techniques are an alternative option in centers with appropriate expertise.
A therapeutic open fascial-sparing, saphenous-sparing approach has also been reported with longer-term follow-up [57]. This dissection is similar to SILND because it spares the fascia lata of the thigh and preserves the saphenous vein, but it also obviates the need for frozen sections because it removes the deep nodes within the fossa ovalis around the femoral vessels. In one study evaluating this approach, 104 patients underwent 201 inguinal dissections for cN0-cN2 (minimal disease). At a median follow-up of 36 months, only a single inguinal recurrence was noted [57].
●If the FNA is negative, we proceed with an ipsilateral SILND with frozen section pathology performed at the time of the procedure. In this setting, a minimally invasive (ie, RAIL or LAP) approach is also reasonable in the hands of experienced surgeons.
●All patients should also undergo a staging procedure on the contralateral clinically node-negative side, as bilateral inguinal drainage from the primary tumor is common [58]. Options for such staging procedures include SILND (using either an open or minimally invasive [ie, RAIL or LAP] approach) or DSNB.
Based on the results at inguinal LND, we suggest:
●No further treatment for patients with a single positive inguinal lymph node and no evidence of extranodal extension. (See 'Posttreatment surveillance' below.)
●A pelvic LND if two or more pathologically involved nodes are identified or if extranodal extension is seen on frozen section or final pathology. This information defines patients at higher risk for inguinal node recurrence and for pelvic lymph node metastases. Such patients are candidates for adjuvant therapy (either chemotherapy, radiation, or chemoradiation). (See 'Pelvic node dissection' below.)
Multiple or bilateral inguinal nodes present — For men with evidence of multiple or bilateral palpable inguinal nodes based upon clinical examination or imaging, we suggest FNA as the initial staging evaluation (algorithm 4). (See "Carcinoma of the penis: Clinical presentation, diagnosis, and staging", section on 'Fine needle aspiration'.)
●If the FNA is negative, we recommend a superficial inguinal LND with intraoperative frozen sections to determine the pathologic stage. If pathology from the inguinal LND is negative, surveillance is appropriate; if pathology identifies metastatic disease, complete inguinal LND is indicated, and potentially pelvic LND if multiple nodes are positive or extranodal extension is found. Alternatively, if intraoperative frozen sections cannot be performed or are felt to be unreliable, a fascial-sparing dissection is an alternative approach to SILND [57]. (See "Carcinoma of the penis: Clinical presentation, diagnosis, and staging", section on 'Superficial inguinal lymph node dissection (ILND)'.)
●If the FNA is positive, the patient likely has at least stage N2 metastatic penile cancer and is at risk for treatment failure with surgery alone [34,35]. We suggest neoadjuvant chemotherapy followed by complete inguinal and pelvic LND [59,60]. An alternative approach would consist of an upfront therapeutic inguinal and pelvic LND, provided the patient is a surgical candidate. (See 'Neoadjuvant chemotherapy for locally advanced or unresectable disease' below and 'Adjuvant therapy' below.)
Surgery — Most patients with proven inguinal metastases should undergo an open therapeutic inguinal LND. Patients with clinical or biopsy-proven N2 to N3 disease on inguinal LND are candidates for neoadjuvant chemotherapy followed by ipsilateral (or bilateral) pelvic LND. Patients with pelvic adenopathy on imaging should also be offered neoadjuvant chemotherapy. (See 'Neoadjuvant chemotherapy for locally advanced or unresectable disease' below.)
Therapeutic inguinal node dissection — A therapeutic inguinal LND is the most reliable means of establishing the presence or absence of nodal metastases and simultaneously treating any disease that is present [61,62]. For men with microscopically involved nodes, long-term cure may be achieved in as many as 90 percent using this approach [44,63,64]. In the largest series, 65 patients who were surgically treated for stage I to III penile cancer were followed for a minimum of five years [63]. More patients who underwent surgical treatment of the primary lesion followed by inguinal lymphadenectomy remained disease-free compared with those who underwent surgical treatment of the primary lesion alone for stage II (88 versus 38 percent) or stage III (66 versus 0 percent) disease.
As noted above, an inguinal LND can be performed as an open procedure or accomplished using a RAIL or LAP technique, if the expertise is available. RAIL or LAP techniques offer the potential of removing all inguinal nodes while minimizing complications such as wound infection or dehiscence. However, additional comparative studies with long-term follow-up comparing these minimally invasive techniques with a more traditional open approach are needed before they can be recommended as the standard of care, especially in the setting of cN2-cN3 penile carcinoma [50,52]. (See 'Clinically suspicious examination' above.)
Pelvic node dissection — The presence of multiple pathologically identified inguinal nodes or of extranodal extension increases the risk for pelvic lymph node involvement. Therefore, in the presence of multiple pathologically involved inguinal nodes or extranodal extension in a single lymph node, we proceed with a prophylactic pelvic LND. The pelvic LND can either be performed at the time of the open inguinal LND or in a delayed fashion using either open, laparoscopic, or robotic techniques.
While one series suggests that men with a single inguinal node involved and without evidence of extracapsular extension rarely have pelvic node involvement [65], another series reported that the risk of pelvic node involvement ranges from 22 percent, if one to three nodes are positive, to 57 percent, if more than three inguinal nodes are involved [66]. However, whether pelvic LND influences survival outcomes is not clear.
NEOADJUVANT CHEMOTHERAPY FOR LOCALLY ADVANCED OR UNRESECTABLE DISEASE
Indications — Men who present with an unresectable primary tumor, bulky inguinal adenopathy, bilateral inguinal node involvement, or pelvic adenopathy on imaging have a low probability of cure with surgery alone or may not be immediately resectable. In this setting, our approach is to use neoadjuvant chemotherapy [59,60,67].
TIP chemotherapy — The objective of neoadjuvant chemotherapy is to improve disease-free and overall survival following subsequent surgical therapy. We consider the TIP regimen to be the standard in the neoadjuvant setting. The TIP regimen consists of paclitaxel (T; 175 mg/m2 administered over three hours on day 1), ifosfamide (I; 1200 mg/m2 on days 1 to 3), and cisplatin (P; 25 mg/m2 on days 1 to 3) at three to four-week intervals for four cycles.
This treatment approach is based on a phase II study as well as an observational cohort study with extended follow-up of 61 men with advanced penile cancer receiving neoadjuvant chemotherapy [59,60]. Among patients who received neoadjuvant TIP, an objective response was noted in 39 of 60 patients evaluable for response (65 percent), with 10 patients achieving pN0 status at surgical resection [60]. The five-year overall survival rate was higher among patients achieving an objective response than among those with progressive disease during chemotherapy (50 versus 8 percent) [60].
All men who have a clinical response to treatment and those with stable disease should undergo surgical resection. Those with tumor progression or unresectable disease despite neoadjuvant chemotherapy should be offered palliative therapy. The approach to men in the latter situation is similar to that for men with metastatic disease. (See 'Distant metastatic disease' below.)
ADJUVANT THERAPY
Adjuvant chemotherapy — There is limited evidence regarding the role of adjuvant therapy in men with penile carcinoma. However, given the suggested benefit of neoadjuvant chemotherapy for men with locally advanced or unresectable disease, we suggest adjuvant chemotherapy for men who were not treated in the neoadjuvant setting if any of the following risk factors for disease relapse are present [68,69]:
●Pelvic lymph node involvement
●Extranodal extension
●Bilateral inguinal node involvement
●More than three positive nodes
For patients receiving adjuvant chemotherapy, we suggest four cycles of the TIP regimen (paclitaxel, ifosfamide, and cisplatin). We favor TIP through extrapolation from the neoadjuvant experience and because the prognosis for recurrent, metastatic disease is so poor. However, other cisplatin-based regimens have been utilized based on their activity in the metastatic setting. There is insufficient evidence to establish a standard adjuvant strategy, whether with radiotherapy, chemoradiation, or a cisplatin-based regimen. (See 'Neoadjuvant chemotherapy for locally advanced or unresectable disease' above and 'Distant metastatic disease' below.)
Adjuvant radiation — We suggest adjuvant RT, either as a single agent or concurrent chemoradiation, to the inguinal and pelvic regions for patients who have viable disease with extranodal extension and/or disease in bilateral lymph nodes on surgical staging, or for high-risk patients who refuse or are not candidates for adjuvant chemotherapy. For patients who receive chemoradiation, options for chemotherapy include cisplatin or fluorouracil plus mitomycin.
Adjuvant RT to the inguinal or pelvic regions (either as a single agent or concurrent chemoradiation) may be useful but has not been rigorously evaluated and is controversial [70]. Our treatment approach is generally consistent with the National Comprehensive Cancer Network guidelines, which recommend its use in the post-ILND setting with adverse pathologic findings, and based upon its potential efficacy in other squamous tumors. However, our approach differs from the European Association of Urology (EAU) guidelines panel. The EAU guidelines do not recommend its use in the absence of prospective data, the relatively sparse literature on its efficacy in penile cancer, and the potential for adverse side effects [71]. This strategy requires evaluation in a prospective clinical trial. (See 'Investigational options' below.)
Data supporting the use of adjuvant RT in penile cancer are as follows:
●In one study, women with pathologically node-positive vulvar cancer (a disease site with similar lymphatic drainage to penile cancer) were randomly assigned to postoperative pelvic and groin radiation (45 to 50 Gy, n = 59) or to ipsilateral pelvic node resection (n = 55) after radical vulvectomy and inguinal lymphadenectomy [72]. In this trial, adjuvant RT was found to be efficacious in terms of both local control and cancer-specific survival outcomes. Thus, to the extent that metastatic inguinal and pelvic nodes due to penile cancer behave in a similar fashion to those due to vulvar cancer, adjuvant RT to the inguinal and pelvic regions might be an alternative to pelvic lymph node dissection among those with pN2 to N3 disease on inguinal lymph node dissection.
●In another series of men with penile cancer from the Netherlands, adjuvant inguinal RT was routinely given when either extranodal extension or two or more inguinal metastases were present [73]. Among the patients with extranodal extension, five-year survival was 42 percent, which is greater than that in a separate series reporting extranodal extension without adjuvant RT [35].
The addition of chemotherapy to RT has been used effectively in patients with penile cancer and other squamous tumor sites such as anal, cervical, and vulvar cancers [74-76]. Although most studies demonstrated the efficacy of chemoradiation alone (ie, definitive chemoradiation) or before surgery (induction chemoradiation) [76,77], chemoradiation as a combined strategy could also further improve survival when administered in the adjuvant setting, extrapolating from these studies. Data supporting the use of chemoradiation in penile cancer are as follows:
●One observational study evaluated definitive chemoradiation in six patients with penile cancer who had both intact primary tumors and N2-3 nodal disease [77]. Patients received either weekly cisplatin or two cycles of fluorouracil plus mitomycin along with radiation to the primary tumor as well as involved and uninvolved inguinal and pelvic nodal basins. At a median follow-up of 7.2 years, four of six patients were recurrence free and two developed primary tumor recurrence. There were no nodal failures and none developed distant metastases [77].
●These initial data in penile cancer are consistent with prior observational data from the vulvar squamous carcinoma experience. In one study, 38 of 40 patients with vulvar carcinoma and nodal disease treated with induction chemoradiation were subsequently rendered resectable [76]. Among the 37 patients who received surgery, 15 (40 percent) had histologically negative disease in the lymph nodes on postoperative pathology.
INVESTIGATIONAL OPTIONS — There are limited prospective data studies for neoadjuvant or adjuvant therapeutic strategies in advanced penile cancer. An ongoing global clinical trial, the International Penile Advanced Cancer Trial (InPACT; NCT02305654) will prospectively determine the relative benefits and sequencing of surgery, chemotherapy, and chemoradiation in the management of patients with penile cancer who present with palpable or radiologically evident inguinal lymph node metastases [78]. InPACT will address the following questions:
●Is there a role for neoadjuvant therapy and, if so, which of two options (chemotherapy or chemoradiation) prior to surgery produces superior outcomes?
●Among patients whose inguinal node histology predicts high risk of recurrence, does prophylactic pelvic lymph node dissection plus chemoradiation to the inguinal and pelvic fields improve survival compared with chemoradiation alone?
POSTTREATMENT SURVEILLANCE — Historically, most invasive primary penile carcinomas were treated with radical surgery, and the frequency of local recurrences was low. With the increasing utilization of penile-sparing therapies, the incidence of local recurrence appears to have increased [10]. Many of those with a locoregional relapse may be treated with curative intent using aggressive locoregional therapy. (See 'Localized recurrence' below.)
All men treated for penile carcinoma require close follow-up. Although there are no high-quality data looking at outcomes to inform an optimal follow-up paradigm, posttreatment surveillance guidelines have been published by the European Association of Urology (EAU) and the National Comprehensive Cancer Network (NCCN) [41,42]. While both are suitable, our posttreatment surveillance is consistent with NCCN guidelines:
●For patients who underwent an organ-sparing procedure (eg, wide excision, glansectomy, Mohs micrographic surgery, or laser ablation), physical examination should be carried out every three months for the first two years, every six months during years 3 to 5, then yearly up to 10 years.
●For patients who underwent a partial or total penectomy, physical examination should be performed every six months for the first two years, then every 12 months during years 3 to 5.
●For patients who did not undergo inguinal lymphadenectomy (ie, opted for surveillance), physical examination should be carried out every two to three months for the first two years, every four months during year 3, then every six months in years 4 and 5.
●For patients with pN0 disease following a lymph node dissection (LND), physical examination should be performed every four months for the first two years, every six months during year 3, then yearly during years 4 and 5.
●Patients who underwent an LND with pathologically positive nodes (pN+) are at high risk for local and/or distant recurrence. These patients should undergo follow-up with physical examination every three months for the first two years, every four months during year 3, then every six months in years 4 and 5. We would recommend an abdominal and pelvic computed tomography (CT) scan during all visits during the first two years for node-positive patients. Imaging studies are optional after this period.
RECURRENT OR METASTATIC DISEASE — Men with a history of penile cancer are at risk for both localized recurrence and distant metastases, and up to 30 percent of all patients will subsequently recur [79].
The outcomes of men following recurrence were evaluated in one study that included 314 men treated for penile cancer between 1942 and 2012 [80]. The median time to recurrence was 10.5 months, and 35, 38, and 10 percent of these recurred locally, regionally, and distantly, respectively. Time from the initial surgery to recurrence was significantly associated with shorter overall survival. In addition, factors significantly associated with an increased risk of cancer-specific mortality included:
●Lymph node metastases at initial presentation
●Regional recurrence
●Distant recurrence
For men who recur, treatment can be stratified by the type of recurrence. This approach to treatment is discussed below.
Localized recurrence — Following treatment, men are at risk for a penile recurrence (if not treated with penile amputation) or an inguinal recurrence.
●For men who have a penile recurrence, we proceed with a penile amputation in most cases. However, whether a partial or total amputation is required depends on the location and extent of the tumor recurrence. Occasionally, carefully selected patients (ie, those with small and low-grade recurrences) may be treated with a second organ-preserving strategy. Overall, disease-specific survival is good when local recurrence is promptly recognized and appropriately treated [1,79].
●For men who experience an inguinal recurrence, the prognosis is poor. We suggest multimodality treatment using either chemotherapy plus surgery or chemoradiation (with or without surgery) [1,33,79,80].
Any patient undergoing resection of a recurrent penile tumor should also undergo nodal reevaluation. A prophylactic inguinal staging procedure (ie, superficial or modified dissection or dynamic sentinel node biopsy) is a reasonable treatment option in cases with an invasive recurrent tumor where a prior lymph node dissection was not performed.
For men with localized recurrence and fixed groin nodes or high local tumor burden not amenable to surgical resection, treatment is palliative. However, chemotherapy-naïve patients should be considered for neoadjuvant chemotherapy followed by surgery with curative intent. Radiation therapy (RT) can alleviate pressure associated with tumor compression and improve quality of life for men with incurable disease [81]. Otherwise, for men who wish to receive further treatment and are deemed good candidates for systemic treatment, we suggest palliative chemotherapy. (See 'Distant metastatic disease' below.)
Distant metastatic disease — For patients presenting with or who develop disseminated disease (M1), we individualize treatment based on the patient's performance status and symptoms [82]. For men with a good performance status (eg, Karnofsky performance status >80 (table 2)), we offer platinum-based chemotherapy or enrollment in a clinical trial whenever possible.
For all others, we prefer best supportive care; some of these patients may also qualify for palliative platinum-based chemotherapy such as paclitaxel and carboplatin.
The role of immunotherapy, including checkpoint inhibitors, is not established for advanced penile cancer except in cases with DNA mismatch repair deficiency or microsatellite instability. (See 'Immune checkpoint inhibitors' below and "Tissue-agnostic cancer therapy: DNA mismatch repair deficiency, tumor mutational burden, and response to immune checkpoint blockade in solid tumors".)
Chemotherapy
●Initial therapy – Chemotherapy results in overall response rates of up to 30 to 38 percent in patients with distant metastatic penile carcinoma [83-85]. A 2010 review of the literature concluded that cisplatin-containing regimens were most active [81]. Although bleomycin had a similar level of activity, it was associated with a high incidence of clinically significant pulmonary toxicity and should not be used [83].
Active combination regimens in penile carcinoma have been identified, but there are no randomized clinical trials to inform a preferred regimen. The choice of the regimen should be based upon patient and provider preference after an individualized consideration of their potential toxicities. Active regimens include:
•Paclitaxel, ifosfamide, and cisplatin (TIP). (See 'Neoadjuvant chemotherapy for locally advanced or unresectable disease' above.)
•Cisplatin (70 to 80 mg/m2 on day 1) plus fluorouracil (800 to 1000 mg/m2 per day continuous infusion on days 1 to 4 or 2 to 5) every three to four weeks [86].
•Paclitaxel (175 mg/m2 on day 1) plus carboplatin (area under curve = 6 on day 1) given every three to four weeks (for patients who are ineligible for cisplatin) [87].
●Subsequent therapy – For patients who progress after their initial chemotherapy, the prognosis is poor, with a median survival of less than six months [88]. Whenever possible, patients with chemotherapy-recurrent disease should be offered participation in clinical trials.
Other potentially active agents include panitumumab and cetuximab, which target the epidermal growth factor receptor (EGFR) [89,90]; responses have been noted with these agents either alone or in combination with chemotherapy.
Immune checkpoint inhibitors — The role of immune checkpoint inhibitors (ICIs) is not established in patients with metastatic penile carcinoma, and this approach remains experimental. In early phase clinical trials, limited responses have been seen with atezolizumab with or without radiation therapy [91], pembrolizumab [92], and cabozantinib plus nivolumab (with or without ipilimumab) [93].
SUMMARY AND RECOMMENDATIONS
●Treatment of the primary tumor – Management of the primary tumor is guided by tumor location, size, and AJCC eighth edition Tumor, Node, Metastasis (TNM) stage (table 1 and algorithm 1). (See 'Treatment of the primary tumor' above.)
•Tis, Ta, T1-T2 disease – For men with stage Tis, Ta, or T1 penile tumors (table 1), we recommend limited excision rather than penile amputation (Grade 1B), as these patients have a good prognosis with treatment and are at a low risk of recurrence. Some men with distal, T2, glanular penile lesions are also candidates for glans resection or removal alone, sparing the corporal bodies. (See 'Tumors with a low risk of recurrence' above.)
•Organ-preserving strategies approaches – Alternative organ-preserving strategies include topical therapy (Tis), partial excision of the glans penis (Ta, T1, some T2), Mohs micrographic surgery (Ta, T1, some T2), resection of the glans penis skin and subepithelial connective tissue (ie, glans resurfacing [Tis]), laser ablation (Tis), and radiation therapy (RT; T1 or distal T2, tumors <4 cm). (See 'Alternative organ-preserving strategies' above.)
•T2-T4 disease – Men with bulky stage T2 to T4 tumors (table 1) are at higher risk of recurrence with organ-preserving strategies. For these men, we suggest penile amputation to obtain a negative surgical margin rather than more limited excisional strategies (Grade 2B). (See 'Penile amputation' above.)
●Approach to the regional lymph nodes – Management of the regional lymph nodes is based upon clinical examination and the histology of the primary tumor. (See 'Approach to the regional nodes' above.)
●Clinically negative lymph nodes – For men with a clinically negative inguinal examination, we stratify our approach to the regional nodes based upon whether there is a low or high risk of nodal involvement (algorithm 2) (see 'Clinically negative examination' above and 'Risk stratification' above):
•Low risk of nodal involvement – For men with Tis, Ta, or T1a tumors, we suggest surveillance, provided they are able to comply with posttreatment surveillance (Grade 2B). (See 'Treatment of low-risk disease' above.)
For men who are unable or unwilling to proceed with surveillance, we suggest an inguinal node evaluation using dynamic sentinel node biopsy (DSNB), provided the expertise is available (Grade 2C). If DSNB cannot be performed, we proceed with a superficial inguinal lymph node dissection (SILND) using minimally invasive techniques such as laparoscopic (LAP) or robotic-assisted inguinal lymphadenectomy (RAIL).
•High risk of nodal involvement – For men with T1b or T2 to T4 tumors, a bilateral, superficial inguinal lymph node dissection (LND) or RAIL or LAP techniques, or DSNB are all acceptable staging techniques. (See 'Treatment of high-risk disease' above.)
-For men with up to one pathologically involved lymph node (based upon frozen section histology) without extranodal extension, we suggest a therapeutic inguinal LND performed either at the time of lymphadenectomy (if not already completed) or subsequent to DSNB (Grade 2B).
-For men with two or more pathologically involved nodes or with extranodal extension identified (based upon frozen section), we suggest a therapeutic inguinal LND plus pelvic LND (Grade 2C). Adjuvant therapy (ie, chemotherapy, radiation, or chemoradiation) should be offered.
•We suggest surveillance for men who have a negative DSNB or superficial inguinal LND (Grade 2B).
●Ipsilateral, clinically positive lymph node <4 cm – For men with an ipsilateral, clinically suspicious examination of the groin, we suggest a fine needle aspiration (FNA) (algorithm 3) (see 'Enlarged, unilateral inguinal node present' above):
•If the FNA is positive, we suggest an ipsilateral, therapeutic inguinal LND (Grade 2B).
•If the FNA is negative, we proceed with an ipsilateral SILND with intraoperative frozen sections or fascial-sparing dissection for further evaluation. LAP or RAIL procedures are suitable alternatives in experienced hands.
•All men should also undergo a contralateral inguinal staging procedure (ie, SILND or RAIL or LAP techniques, or DSNB; based upon experience).
•For men with two or more pathologically involved nodes (based upon biopsy) or if the presence of extranodal extension is proven, we suggest ipsilateral pelvic lymphadenectomy followed by adjuvant therapy (either chemotherapy, radiation, or chemoradiation) (Grade 2C). Clinical trial enrollment is encouraged, if available. (See 'Investigational options' above.)
●Multiple or bilateral clinically positive lymph nodes – For men with multiple or bilateral palpable inguinal nodes, we suggest an FNA (algorithm 4). (See 'Multiple or bilateral inguinal nodes present' above.)
•If the FNA is negative, we proceed with a unilateral or bilateral (as appropriate) superficial LND with intraoperative frozen sections for further evaluation. Other acceptable approaches on this setting include fascial sparing lymphadenectomy, LAP, or RAIL techniques.
•If the FNA is positive, we suggest neoadjuvant chemotherapy followed by surgery rather than an initial definitive surgical approach (Grade 2C). An alternative strategy includes surgical resection followed by adjuvant therapy or clinical trial enrollment. (See 'Neoadjuvant chemotherapy for locally advanced or unresectable disease' above.)
●Locally advanced or unresectable disease – For men with unresectable penile carcinoma, bulky adenopathy, or evidence of pelvic nodal involvement, neoadjuvant chemotherapy should be given for downstaging. Clinical trial enrollment is encouraged in this setting as well. (See 'Neoadjuvant chemotherapy for locally advanced or unresectable disease' above.)
•For patients who are candidates for neoadjuvant chemotherapy, we suggest four cycles of TIP (paclitaxel, ifosfamide, and cisplatin) (Grade 2C).
•Definitive surgery should be performed in men who have an objective response to treatment, and it may also be an option in men with stable/resectable disease. (See 'Neoadjuvant chemotherapy for locally advanced or unresectable disease' above.)
●Indications for adjuvant chemotherapy – We suggest adjuvant chemotherapy for men who did not previously receive neoadjuvant chemotherapy and with high-risk factors for relapse (Grade 2C). Extrapolating from the neoadjuvant experience, we suggest four cycles of TIP (Grade 2C). (See 'Adjuvant chemotherapy' above.)
●Indications for adjuvant radiation – For men at high risk of recurrence who are not candidates for adjuvant chemotherapy, we suggest adjuvant RT, either as a single agent or concurrent chemoradiation (Grade 2B). For patients who receive chemoradiation, options for chemotherapy include weekly cisplatin or fluorouracil plus mitomycin. (See 'Adjuvant radiation' above.)
●Locally recurrent disease – For men who experience a local recurrence, we suggest that a partial or total penile amputation be performed (Grade 2B). In addition, based on the grade and stage of the local recurrence, the inguinal region should be reevaluated and treated as appropriate. (See 'Localized recurrence' above.)
●Metastatic disease – For men with or who develop disseminated disease (M1), we individualize treatment based on the patient's performance status and symptoms. For those with a good performance status, we offer platinum-based chemotherapy or enrollment in a formal clinical trial, whenever possible. (See 'Distant metastatic disease' above.)
آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟
