Risk Factors

Risk factors for penile cancer include [1] presence of an uncircumcised penis or phimosis, [2] human papillomavirus (HPV) infection, [3] lower socioeconomic status, [4] chronic inflammatory conditions, [5] smoking, and [6] poor genital hygiene [4]. A growing interest has been the impact of HPV and it thought to be causing nearly 4.5% of all cancer cases worldwide and 13,000 penile cancer cases/year [5]. HPV is found in the majority of basaloid and warty penile carcinomas, and found in about one-third of keratinizing and verrucous penile carcinomas [6].

Staging

It is important to note several changes in the most recent AJCC update for cancer staging with cT2 defined as invasion of corpus spongiosum and now invasion of the corpus cavernosum regarded as cT3 regardless of urethral involvement. Minor changes were made to three other primary tumor stages and two regional lymph node pathologic stages. Stage Ta is now non-invasive localized squamous cell carcinoma. T1a penile cancer is considered low risk, with an absence of lymphovascular or perineural invasion and no high grade pathology. The number and type of metastases in pN1 and pN2 have been modified with pN1 being ≤2 unilateral inguinal metastases without extra-nodal extension and pN2 including bilateral or ≥3 unilateral metastases.

Topical Chemotherapy

Topical chemotherapy with imiquimod or 5-fluorouracil (5-FU) is an effective first-line treatment for penile carcinoma in situ (CIS), with complete responses (CR) reported in up to 57% of cases [13]. Due to high persistence/recurrence rates with superficial non-invasive disease, treatment must be assessed by biopsy if suspicious lesions appear or persist and long-term surveillance is warranted with frequent physical examination. Topical chemotherapy can also be used in concurrence with laser ablation and/or circumcision to minimize recurrence rates with CR achieved in as high as 73.7% of patients [14, 15].

Laser Ablation

Laser treatment with a neodymium:yttrium-aluminium-garnet (Nd:YAG) or carbon dioxide (CO₂) laser is an effective treatment option for superficial non-invasive disease or CIS [8, 16–18]. Tang et al. reported 5-year local recurrence-free survival rates of 50% for pTa/Tis disease, 41% for pT1a disease, and 38% for pT1b disease in 161 patients treated with only laser ablation for squamous cell carcinoma (SCC) of the penis [8]. The 5-year inguinal/pelvic nodal recurrence rate was 2% for pTa/Tis disease, 5% for pT1a disease, and 18% for pT1b disease. Meijer et al. reported a pooled local recurrence rate of 48% in 44 consecutive patients treated with laser therapy for penile cancer although 17 patients had pT2 disease compared to 31 with pT1 and 6 with pTis [17]. For penile CIS, Chipollini et al. observed that the majority of recurrences occurred after laser ablation (58.3%) compared to circumcision, glansectomy, wide local excision, or total glans resurfacing [9]. Follow-up rebiopsy to ensure treatment control, therefore, is recommended after laser ablation for primary penile SCC [10].

Moh’s Micrographic Surgery

Moh’s micrographic surgery is a technique by which histological margins are taken in a geometrical fashion around a conus of excision with tissue is examined for cancer cells until negative surgical margins are obtained with maximum preservation of normal tissue. Shindel et al. reported on 33 patients who underwent a total of 41 Mohs procedures for penile SCC [19]. Of the tumors, 26 were stage pTis, 4 were pT1, 7 were pT2, and 4 were pT3 with five procedures terminated with positive surgical margins. Follow-up data on 25 patients at mean follow-up of 58 months revealed an overall recurrence rate of 32% (n = 8) of which repeat Mohs micrographic surgery was performed in 7. Machan et al., however, reported a cure rate as high at 94.7% in 42 patients with 44 penile SCCs treated with Mohs micrographic surgery as an alternative to partial or total penectomy [20] but one must remember this was within a highly selected patient population with the majority of these tumors being of low-grade and superficial.

Wide Local Excision

Penile-conserving surgery with wide local resection with negative surgical margins is an alternative approach to preserve functional and anatomic outcomes for primary penile SCC. Feldman et al. showed an overall recurrence rate of 21.4% in 60 patients with penile CIS or pT1 disease treated with wide local excision at mean follow-up of 5 years [21]. T1 tumors on the glans carried the highest risk of recurrence although no patient with pTis disease showed evidence of metastasis during follow-up. Philippou et al. also demonstrated an overall 5-year local recurrence-free rate of 86.3% in 179 patients with penile SCC treated with penile-sparing surgery with a surgical excision margin of less than 5 mm [22]. Tumor grade, stage, and lymphovascular invasion were identified as predictors of local recurrence on multivariate analysis.

Glans Resurfacing

Partial or total glans resurfacing involves excision of the glans epithelium and subepithelium of either the entire glans or the locally affected area with a macroscopic clear margin with reconstruction of the penis using a split-thickness skin graft. Shabbir et al. initially reported on 25 patients with biopsy-proven pTis of the glans penis treated with partial or total glans resurfacing [23]. At mean follow-up of 29 months, the overall local recurrence rate was 4% although 12 patients (48%) had positive surgical margins with 7 (28%) requiring further surgery. In a prospective study from 2013 to 2015, O’Kelly et al. followed 19 patients with penile cancer who underwent total glans resurfacing [24]. There was 1 local and no regional nodal recurrence at a mean follow-up of 23 months. One-year progression-free and OS rates were both 100%, and the 1-year recurrence-free survival rate was 95%. Of the patients, 81% reported an improved sex life postoperatively.

External Beam Radiation

External beam radiotherapy for localized penile cancer can provide local control and a reasonable chance of organ preservation. For pT1–T2 tumors, the 5-year local control rate has been reported at 62% with preservation of the penis approaching 40% [25]. For more advanced pT3–T4 penile tumors, local control has been observed to decrease to 40% with a 10-year probability of penile preservation of 38% [26]. Treatment of the primary tumor may be combined with concomitant treatment of the inguinal and/or pelvic nodal packets in regionally advanced cases but radio-sensitization with concurrent chemotherapy should be considered.

Partial or Radical Penectomy

Partial or radical penectomy remains the standard of care for high-risk (i.e. high-grade, pT2-T4) tumors of the penile shaft to minimize risk of local recurrence or metastatic spread. The decision for partial or radical penectomy depends on the proximal extent of tumor extension. The sensitivity and specificity of penile MRI in predicting corporal or urethral invasion was reported as 82.1% and 73.6%, and 62.5% and 82.1%, respectively [27]. Penile Doppler U/S, however, has been reported to have a higher staging accuracy than MRI in detecting corporal infiltration [28]. Patients do need to be counseled about the risk of possible placement of a perineal urethrostomy for urination with either surgical approach [10].

Clinical Evaluation

A clinical exam for LN involvement should assess for palpability, size and number of inguinal masses, laterality, mobility or any degree of fixation. Imaging with Computer Tomography (CT) or Magnetic Resonance Imaging is also an option for those with a challenging physical examination.

Consideration of the primary tumor is the main determinant for lymphatic staging. There are well established clinical predictors for harboring LNM, including: primary tumor stage, degree of differentiation, perineural invasion, and the presence of lymphovascular invasion [31, 32]. Given the low incidence of PeCa, which limits patient enrollment in prospective studies, controversies on the optimal management of the LNs continue to this day.

Prophylactic vs. Delayed ILND

For cN0 patients, early lymphadenectomy has been shown to have superior oncologic outcomes versus waiting for nodal disease to occur [33, 34]. Even a delay of up to 3 months can negatively impact recurrence in both LN negative and positive cases [35]. Thus both European Association of Urology (EAU) and National Comprehensive Cancer Network (NCCN) guidelines recommend invasive LN staging for any cN0 patient with high risk primary tumor features at risk of micrometastases, i.e.: pT1 with presence of lymphovascular invasion, perineural invasion and/or poor differentiation (pT1b) or any tumor pT2 and above [10] [36].

For patients with clinically positive groins (cN+), an ILND can still be beneficial while curing a subset of patients with nodal metastatic disease [37, 38]. For that reason, it is no longer recommended to await the traditional 4–6 weeks of antibiotic treatment for patients presenting with palpable disease. For atypical presentation or when in need for systemic therapy, a fine needle aspiration with cytology (FNAC) can be performed when in need of histologic confirmation of disease [39]. In select patients with symptomatic inguinal LNM, upfront ILND may be considered if deemed to be resectable with consideration for adjuvant therapy. Current guidelines recommend a multimodal approach for those with bulky disease consisting of neoadjuvant chemotherapy followed by surgical resection, although the timing of systemic therapies continues to be controversial.

To help answer some of these controversies, the International Penile Advanced Cancer Trial (InPACT) (NCT02305654) has recently opened. This is a large, multinational collaboration with plans to accrue 400 cN+ patients over a 5-year period to be randomized into three arms: upfront ILND, neoadjuvant chemotherapy, or neoadjuvant chemoradiotherapy; the latter two followed by surgery. The trial will undoubtedly provide valuable prospective data and answer some important questions in the optimal timing of surgery and its integration with systemic therapy.

Dynamic Sentinel Node Biopsy

An alternative approach to cN0 disease is to perform a dynamic sentinel node biopsy (DSNB). The method includes preoperative usage of lymphoscintigraphy to identify the sentinel nodes (SN), patent blue dye injection, and intraoperative guidance with a γ-probe to visualize lymphatic drainage, with a negative DSNB considered adequate staging of cN0 groins, and if positive proceeding with traditional ILND [40]. There are still however complications associated with this procedure including infection, seroma and wound edge necrosis as described in a large study with complication rate of 4.7% [41]. DSNB has acceptable sensitivity when performed at high volume centers using a standardized protocol [42]. Therefore, its utility and applicability should be limited to centers with experienced surgeons and nuclear medicine specialists.

Modified vs. Radical ILND

ILND has traditionally been known as a technically demanding procedure with high complication rates. In 1988, Catalona introduced the modified LND by reducing dissection lateral to the femoral vessels and caudal to the fossa ovalis while preserving the saphenous veins [43]. Over time, other modifications have added a shorter incision and avoidance of Sartorius muscle transposition [44]. Although this dissection is appealing for cN0 patients in whom the risks of surgery may outweigh the benefits, a radical ILND is still recommended in the presence of inguinal disease. Figure 36.1 displays the differences in extent of dissection between the two procedures.

Minimally-Invasive ILND

Another area of interest to minimize morbidity and complications is to utilize minimally invasive and robotic techniques. Several advantages are achieved with the robotic approach when compared to the standard laparoscopic approach including increased magnification, ergonomic platform, and three-dimensional vision that allows for greater precision and dexterity [45]. However, prospective studies comparing these techniques head-to-head are currently lacking and still require further validation with larger sample sizes and longer follow up.

Open Surgical Techniques

The most common types of incisions reported in the literature have been the horizontal versus “S” or “T”-type incisions, although the former has been the most commonly used by centers of excellence due to its lower risk of skin necrosis [37, 44]. There is little reported on the ideal number of LNs removed at the time of ILND although a registry study reported a LN yield >15 to be an independent predictor of survival [46].

Patients are placed in the frog-leg position and 10-cm parallel incision below the inguinal ligament is usually enough to gain exposure to the superficial inguinal nodes. The skin flaps should not be too thin and should keep a good amount of subcutaneous tissues above Camper’s fascia to keep vascularization of the flaps and minimize risks of wound ischemia and dehiscence; skin hooks can be used to minimize disturbance of subcutaneous tissues [47, 48].

Careful and meticulous ligation of lymphatic channels is necessary to decrease risk of leaks and seroma. All nodes above the fascia lata are considered the superficial inguinal LNs and are typically divided into five zones in relation to the femoral vessels (Fig. 36.2) [44, 49].

ILND should be carried to the level of the external oblique fascia and external ring, and proceed superiorly to the edge of the skin flaps as well as distally to the edge of the template. Intraoperative frozen section has been shown to have diagnostic value in determining the need to proceed to a radical dissection [50]. To harvest the deep nodes, the fascia lata is entered at the level of the fossa ovalis. The deep nodes are typically no more than 3–5 LNs contained within the femoral sheath. The node of Cloquet is the most proximal and considered the margin between the inguinal and pelvic LNs.

If a deep dissection is required, a Sartorius transposition maybe required for coverage of the femoral vessels. Postoperative closed suction drainage within the inguinal wound is also recommended and removed once outputs are less than 30–50 mL per 24 h period [48]. For larger defects, tissue flaps using gracilis, anterolateral thigh, internal oblique, tensor fascia lata and rectus abdominis have been described in small retrospective series although not without their own complications and should be done in centers with adequate experience with these reconstructive techniques [44, 51].

Prevention and Management of Complications

Identification of Micrometastatic Disease

Accurate identification of disease in pelvic lymph nodes is therefore important in determining candidates for PLND. For micro-metastatic disease, Leijte et al. evaluated the use of 18F-fluorodeoxyglucose positron emission tomography (PET-CT) to detect disease in patients with unilateral or bilateral LN positive disease and found specificity of 92% [57]. In another study of 18 patients with proven inguinal metastases, PET CT showed a sensitivity of 91%, specificity of 100%, with a negative predictive value 94% and positive predictive value of 100% [58]. More studies are needed, but NCCN guidelines currently incorporate PET-CT when pelvic lymph nodes are enlarged and a biopsy is not feasible or in selected cases, such as an equivocal CT or MRI [58].

Others have investigated risk factors for the presence of pelvic lymph node disease. Lughezzani et al. looked at 142 high-risk penile patients with inguinal lymph node involvement. They found patients with ≥3 inguinal lymph node metastases, and inguinal nodal diameter ≥3 cm were at increased risk of having pelvic nodal metastatic spread (p < 0.05) [59].

Technique

Pelvic lymph node dissection can be performed typically through a midline, suprapubic, infraumbilical, or extraperitoneal incision [60]. Boundaries of dissection are the bifurcation of the common iliac arteries superiorly, the ilionguinal nerve laterally, and the obturator nerve medially. PLND can be performed at the same time as ILND or in a delayed fashion. Per NCCN guidelines, a PLND is indicated in the following settings. A) in patients with unilateral lymph nodes ≥4 cm which are mobile and found to have ≥2 positive lymph nodes or with extranodal extension at time of inguinal lymph node dissection. B) unilateral lymph nodes which are fixed or bilateral lymph nodes c) Clinically enlarged pelvic lymph nodes [61].

Unilateral vs. Bilateral PLND

There is a lack of clarity and robust clinical data as to whether a PLND needs to be performed unilateral vs. bilateral in the setting of unilateral positive inguinal lymph node disease as crossover disease in pelvic nodes has not been demonstrated. One study by Zargar-Shostari et al. evaluated risk factors for bilateral pelvic metastatic disease and positive unilateral LN and found that detecting four or more positive inguinal LN had 95% sensitivity in predicting bilateral pelvic nodal metastasis on final pathology. Furthermore, variables associated on multivariable analysis for OS included ≥4 positive inguinal LN, use of adjuvant chemotherapy, inguinal ENE, and bilateral LND and authors recommend that bilateral PLND should be considered for patients with four or more positive inguinal LN [62].

Local Recurrence

Penile sparing treatments (PST) have emerged as an attractive alternative to radical surgery with improved outcomes in terms of orgasm, cosmetic appearance, urinary function and quality of life [67], at the expense of increased local recurrence (27% vs. 5%) [60]. Nevertheless, local recurrences did not appear to have an impact on cancer-specific survival; and local control can be achieved in 90–100% of recurrent cases [68].

Recent studies indicate that repeat penile-sparing treatment of local recurrent tumors can be a safe and acceptable option in patients who are motivated to comply with surveillance [68, 69]. In a multi-institutional retrospective cohort of 1188 patients with ≤pT2 tumors, 58% of the local recurrences could be managed with repeat organ sparing procedures such as wide local excision, laser therapy with or without local excision, glans resurfacing and glansectomy [70]. Of note, secondary penectomy (partial or total) rate for this cohort was only 19% and positive resection margin was only significant risk factor for local recurrence. Nevertheless, in a retrospective analysis, recurrent squamous cell carcinoma of penis was associated with high-risk features, and 52% of recurrent tumors had invasion of the corpus cavernosum and penile skin [71]. Compared to non-recurrent tumors, vertical growth pattern (52% vs. 34%) and aggressive histologic subtypes such as sarcomatoid and basaloid types (36% vs. 14%) were more common in these recurrent tumors. Radical surgery (partial or total penectomy) is currently recommended by NCCN and EAU guidelines for treatment of local recurrences invading corpora cavernosa and/or large high-stage recurrent tumors [10, 36].

Regional Recurrence

Optimal management of nodal recurrence in penile cancer remains elusive. The majority of lymph node occurs within 2 years following primary treatment [60, 72]. Nodal recurrence rate following treatment for primary tumor was 9% in a large retrospective cohort of 700 patients, and overall 5-year disease-specific survival was 32.7% in these patients. In a retrospective cohort of 161 patients with pathological node positive PeCa, 26 patients (16%) had inguinal recurrence after therapeutic lymphadenectomy [72]. As salvage treatment, 1 patient was treated with surgery, 5 with external radiotherapy, 13 with chemotherapy, 2 with chemoradiation and 5 with no treatment. Twenty-four patients (94%) died of disease within 14 months after inguinal recurrence. In a multi-institutional retrospective cohort of 20 patients with inguinal recurrence treated with salvage inguinal lymph node dissection, 11 patients were alive and 9 patients had no evidence of disease after a median follow-up of 12 months [73]. However the rate of pre-operative wound infection was around 30% and salvage ILDN was associated with high perioperative complication rate due to decreased vascularity, impaired lymphatic drainage and redo surgery.

Neoadjuvant chemotherapy and subsequent radical surgery is another alternative to salvage ILND alone in patients who responds to chemotherapy. In a retrospective cohort of 19 patients with unresectable locally advanced disease, eight out of nine neoadjuvant chemotherapy responders subsequently treated with consolidation surgery remained long-term survivors without evidence of disease [74]. Moreover, in patients without previous history of radiotherapy, inguinal radiotherapy can be another option for management of nodal recurrence. In a retrospective cohort of patients presenting with metastatic nodes larger than 4.0 cm, perioperative radiotherapy and subsequent ILND was associated with fewer perinodal infiltration and less post-operative inguinal recurrence [75]. The NCCN currently recommends ILND, chemotherapy followed by subsequent ILND and chemoradiotherapy for management of patients who has nodal recurrence after primary treatment of N+ disease [36].

Systemic Disease

About 4% of all penile cancer cases presents with metastatic disease [76], however, 5-year cancer-specific survival rate at the metastatic stage disappointingly approaches close to 0% [77]. Currently the mainstay treatment for metastatic penile cancer is platinum-based multi-agent systemic chemotherapy, but with limited efficacy and high toxicity. Several clinical trials of immunotherapy for management of metastatic penile cancer are currently being tested. Moreover personalized cancer treatment and targeted therapy might cause a paradigm shift in management of metastatic disease in the near future.

Systemic Chemotherapy

Although systemic chemotherapy has been the most commonly utilized treatment for metastatic penile cancer, there exists no curative first- or second-line systemic chemotherapy regimen. Visceral metastasis, along with poor performance status, is significant unfavorable prognostic factor for men treated with systemic chemotherapy [78]. There are no randomized clinical trials for PeCa and metastatic disease, and NCCN guidelines currently recommends cisplatin based combination chemotherapy for management of metastatic cancer [36].

In some historical cohorts, methotrexate, bleomycin and cisplatin as single chemotherapeutic agents were shown to have activity against advanced penile cancer [79]. However, unfavorable toxicity profile and limited efficacy of single agent chemotherapy agents led to exploration of combined chemotherapy regimens.

The Southwest Oncology Group evaluated combination chemotherapy in a large scale multi-institutional phase II trial that included 40 evaluable patients with locally advanced and metastatic penile cancer (Table 36.3) [80]. Chemotherapy regimen consisted of 75 mg/m² cisplatin on day 1 IV, 25 mg/m² methotrexate on days 1 & 8 IV and 10 Units/m² bleomycin on days 1 & 8 IV. Complete response and partial response was noted in five and eight patients, respectively. Objective response rate of 32% was obtained at the expense of high toxicity: Four treatment-related deaths occurred due to pulmonary complications and one death due to infection. Its high toxicity necessitated elimination of bleomycin from combination chemotherapy regimens.

Table 36.3

Outcomes of chemotherapy for metastatic penile squamous carcinoma

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