Current Concepts in Penile Cancer

This review highlights the significant advances made in the diagnosis and management of penile cancer. This often-aggressive tumor phenotype has been characterized by its poor prognosis, mostly attributable to its late presentation and heterogeneity of surgical care because of the paucity of cases treated at most centers. Recent advances in understanding of the risk factors predisposing to penile cancer, including its association with the human papilloma virus (HPV), have brought forth the socioepidemiologic concept of HPV vaccination in certain high-risk populations and countries, which remains highly debated. The management of penile cancer has evolved in recent years with the adoption of penile-sparing and minimally invasive surgical approaches to the inguinal lymph nodes, which are a frequent site of regional spread for this malignancy. Lastly, this review highlights the importance of adopting a multimodal approach consisting of neoadjuvant systemic chemotherapy followed by consolidative surgical resection in patients presenting with bulky/locally advanced nodal metastases from penile cancer.

Abstract

This review highlights the significant advances made in the diagnosis and management of penile cancer. This often-aggressive tumor phenotype has been characterized by its poor prognosis, mostly attributable to its late presentation and heterogeneity of surgical care because of the paucity of cases treated at most centers. Recent advances in understanding of the risk factors predisposing to penile cancer, including its association with the human papilloma virus (HPV), have brought forth the socioepidemiologic concept of HPV vaccination in certain high-risk populations and countries, which remains highly debated. The management of penile cancer has evolved in recent years with the adoption of penile-sparing and minimally invasive surgical approaches to the inguinal lymph nodes, which are a frequent site of regional spread for this malignancy. Lastly, this review highlights the importance of adopting a multimodal approach consisting of neoadjuvant systemic chemotherapy followed by consolidative surgical resection in patients presenting with bulky/locally advanced nodal metastases from penile cancer.

NCCN: Continuing Education

Accreditation Statement

This activity has been designated to meet the educational needs of physicians and nurses involved in the management of patients with cancer. There is no fee for this article. No commercial support was received for this article. The National Comprehensive Cancer Network (NCCN) is accredited by the ACCME to provide continuing medical education for physicians.

NCCN designates this journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

NCCN is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center‘s Commission on Accreditation.

This activity is approved for 1.0 contact hour. Approval as a provider refers to recognition of educational activities only; accredited status does not imply endorsement by NCCN or ANCC of any commercial products discussed/displayed in conjunction with the educational activity. Kristina M. Gregory, RN, MSN, OCN, is our nurse planner for this educational activity.

All clinicians completing this activity will be issued a certificate of participation. To participate in this journal CE activity: 1) review the learning objectives and author disclosures; 2) study the education content; 3) take the posttest with a 70% minimum passing score and complete the evaluation at http://education.nccn.org/node/19339; and 4) view/print certificate.

Release date: May 13, 2013; Expiration date: May 13, 2014.

Learning Objectives

Upon completion of this activity, participants will be able to:

  • Identify the risk factors associated with penile cancer.
  • Discuss the rationale for adopting a multimodal approach consisting of neoadjuvant systemic chemotherapy followed by consolidative surgical resection in patients presenting with bulky/locally advanced nodal metastases from penile cancer.

In 2013, an estimated 1570 new cases of penile cancer are expected within the United States, with 310 predicted cancer-specific deaths.1 Penile cancer represents 0.4% to 0.6% of all malignant neoplasms in the United States and Europe, but up to 10% of cancers in men in the developing countries of Asia, Africa, and South America.2 Early diagnosis is paramount in improving a patient’s prognosis. The 5-year survival rate ranges from 0% to 66%, depending on the extent of regional and distant lymph node metastatic dissemination.3 Complete clinical staging requires a thorough metastatic workup. The single most important prognosticator of cancer-specific survival is the presence and extent of regional inguinal lymph node (ILN) metastases.2,4 Because of the paucity of penile cancer cases treated at individual centers, a significant heterogeneity in management remains. This lack of consensus is the reason behind the collaborative effort by the NCCN to provide guidelines for the diagnosis and treatment of penile cancer (available in this issue; to view the most recent version of these guidelines, visit NCCN.org). This evidence-based approach hinges on a critical appraisal of peer-reviewed scientific literature and is consistent with guidelines developed by the European Association of Urology (EAU) and the International Consensus of the Société Internationale d’Urologie/International Consultation on Urological Diseases (SIU/ICUD).

Epidemiology and Risk Factors

Patients typically present with penile cancer between the ages of 50 and 70 years, with a median age at diagnosis in the United States of 68 years.5,6 As with any other disease entity, the assessment of a patient begins with a thorough history and physical examination, focusing on potential risk factors for penile squamous cell carcinoma (SCC). Risk factors include an uncircumcised phallus, especially in the presence of phimosis and/or poor hygiene, tobacco use, psoriasis treatment with ultraviolet light A to the genital area, and lichen sclerosis.7-10 Also at increased risk are patients with a history of sexually transmitted diseases, including human papillomavirus (HPV; types 16 and 18) and HIV.6,7,11 Patients with HIV have an 8-fold increased risk, which may be secondary to the higher incidence of HPV among men with HIV.12 On physical examination, it is essential to characterize the primary penile lesion and assess the presence and extent of ILN.

Clinical Staging and Risk Stratification

The AJCC updated its penile cancer TNM staging system in 2010, and recognizes 4 subtypes of SCC: verrucous, papillary squamous, warty, and basaloid (“see Staging Table, in the NCCN Clinical Practice Guidelines in Oncology for Penile Cancer, available online at NCCN.org [ST-1]”). Adenosquamous and sarcomatoid variants carry a worse prognosis.13,14 The degree of cellular differentiation is an important predictor of metastatic nodal cancer dissemination and is assigned a pathologic grade, with grade GX indicating that grade cannot be assessed; G1 indicating a well-differentiated tumor (no evidence of anaplasia); G2 a moderately differentiated tumor (<50% anaplasia); G3 a poorly differentiated tumor (>50% anaplastic cells); and G4 an undifferentiated tumor.13 Additional tumor characteristics of importance are: 1) the distinction between corpus spongiosum and corpus cavernosum involvement, 2) lymphovascular invasion, 3) the size of the largest lymph node metastasis and the number of involved lymph nodes, and 4) a history of HPV infection, if known.13

Physical examination should assess the diameters, number, and laterality of ILNs, and their relationship to adjacent structures, all of which assist in assessing the locoregional extent of penile SCC.4 If the physical examination is difficult to perform because of body habitus or prior surgery, imaging studies such as contrast-enhanced MRI or PET/CT can help determine the extent of disease.15

For clinically node-negative patients, the risk of occult metastasis can be estimated based on the characteristics of the primary lesion, with an average of 25% (range, 11%-62%) of patients harboring micrometastatic disease.16 The NCCN Penile Cancer Panel recommends a modified ILN dissection or dynamic sentinel lymph node biopsy (DSNB) in the absence of palpable nodes (≤pT1G2 disease with superficial growth pattern), and a standard ILND for high-risk patients with a primary lesion of pT1G3 or greater, or those whose primary tumor exhibits lymphovascular invasion or greater than 50% poorly differentiated cancer. Slaton et al16 reported that these patients are at significantly increased risk (42%-80%) of nodal metastases.

The EAU guidelines panel defined prognostic stratification groups for inguinal metastases among patients with nonpalpable disease, with the low-risk group defined as patients with pTis, pTaG1-2, or pT1G1 disease; intermediate-risk patients as those with pT1G2 disease; and high-risk patients as those with pT2 and higher or G3 disease.4 Similar risk groups have also been defined by the SIU guidelines panel.17

Management

Primary Penile Tumor

Tis or Ta: Management of patients with Tis or Ta disease who are at lower risk of metastasis encompasses penile-preserving techniques, namely: 1) topical imiquimod (5%) or 5-FU, 2) circumcision and local excision, and 3) laser ablative therapy with carbon dioxide (CO2) or neodynium:yttrium-aluminum-garnet (Table 1).4,18,19 Topical treatments are generally prescribed as first- and second-line treatments for Tis or Ta penile cancer lesions, particularly in patients not seeking surgical resection. In those deemed not suitable surgical candidates, lesions on the foreskin are readily excised, whereas lesions on the glans are more amenable to laser ablation.

T1G1-2: For patients with T1G1-2 disease, penile-preserving techniques are preferred but patient compliance with follow-up is essential. These techniques include local wide excision plus reconstructive surgery, laser therapy, radiotherapy (external-beam radiotherapy), or brachytherapy with interstitial implant.20-22 Notably, a circumcision should be performed before radiotherapy for full exposure of the lesion and to avoid radiation-related complications. The reason for close follow-up stems from the 2-year recurrence rate reaching up to 50%23 with some techniques. Historically, a 2-cm surgical margin was recommended with local resection; however, recent studies have shown that surgical margins of 5 to 10 mm provide favorable oncologic outcomes and low recurrence rates (4% and 3%, respectively) with short duration of follow-up. Nevertheless partial/total penectomy remains the gold standard if the lesion is not amenable to penile-preserving approaches, depending on the extent of disease.24

Table 1

Literature on the Management of Penile Squamous Cell Carcinoma Using Penile-Preservation Techniques or Partial or Total Penectomy

Table 1

T1G3-4, T≥2: Patients exhibiting these lesions should be carefully counseled, because the mainstay surgical option consists of partial or total penectomy, depending on the characteristics of the tumor and whether complete tumor eradication can be completed while leaving a functional penile stump to direct the urinary stream and potentially maintain sexual activity.25 A more conservative approach, such as brachytherapy or external-beam radiotherapy, may be considered if the patient agrees to undergo close observation. The patient should understand that he is at an increased risk of recurrence and/or metastatic progression, and should be aware of the importance of a commitment to stringent follow-up (year 1-2 every 2 months; year 3 every 3 months; year 4 every 6 months; and annually thereafter) should be emphasized, along with the potential requirement for a repeat surgical resection should a locoregional recurrence be detected.26

Role of Radiotherapy: Radiation is an effective treatment for penile SCC, with more than 5 decades of reported experience. Either external-beam radiotherapy or brachytherapy can be used, but when technically feasible, brachytherapy gives superior results, with 5-year penile preservation rates of 75% to 88% and 10-year rates of 67% to 70%. Series that span several decades often use a range of techniques, doses, and dose rates, making it difficult to develop guidelines for the modality (Table 2). Most patients included in published series had T1-T2 lesions, with occasional T3 tumors. Both local recurrences and complications, such as soft tissue ulceration increase, have been associated with larger tumor sizes and larger volume implants.27-29 However, Crook et al30 found no size effect up to 5 cm using a consistent interstitial technique and a narrow range of dose rates between 50 and 60 cGy/h, provided the tumor was limited to the glans. When the tumor is larger than 4 cm and extends beyond the coronal sulcus and onto the shaft, a surgical approach may be preferable.31 The most common side effects are soft tissue ulceration (6%-26%) and meatal stenosis (8%-45%). Soft tissue ulceration or necrosis can be minimized in larger tumors by using a moderate dose rate of 50 to 60 cGy/h.31 Nonhealing ulcerations will often respond well to hyperbaric oxygen treatments.32

All of the large reported brachytherapy series used classic low-dose-rate techniques, with the radiation dose delivered at between 30 and 100 cGy/h over approximately 3 to 6 days. One recent report from Petera et al33 used the much more widely available high-dose-rate (HDR) technology, delivering 54 Gy over 9 days, with 2 fractions per day of 3 Gy each. These excellent results require validation in other centers, but guidelines on HDR fractionation for penile cancer will make penile brachytherapy much more widely available, because HDR “after-loading” machines are present in most radiation departments.

Reports on external-beam radiation show an equally large range of total dose and fractionation schemes. Penile preservation rates at 5 years are 50% to 65% at best, and less if the total dose is less than 60 Gy, the fraction size is less than 2 Gy per fraction, or the total course is prolonged beyond 45 days.22,34

Radiation therapy for penile SCC, as for so many other squamous carcinomas (eg, cervix, head and neck, anal canal), is a highly effective treatment modality. The site presents certain technical challenges, which can be overcome in a center of excellence with sufficient case volumes.

Inguinal Lymph Nodes

Inguinal Lymph Node Dissection: Penile cancer typically metastasizes in a predictable fashion to the ILNs; therefore, early surgical management of non-bulky nodal metastasis (<4 cm) has been shown to have a favorable impact on survival.35 However, because not all palpable lymphadenopathy at diagnosis warrants an immediate ILN dissection (ILND), careful evaluation based on the primary penile lesion’s risk factors is warranted. Up to 70% of patients with palpable lymph nodes at diagnosis will not have metastatic disease. Fine-needle aspiration is the favored approach among many leading penile cancer experts in lieu of a course of antibiotics in low-risk men with a palpable node after primary tumor therapy.36

Cabanas et al37 used lymphangiograms and dissection targeting specific anatomic areas to define the sentinel node in an area superior and medial to the junction of the saphenous and femoral veins along the superficial epigastric vein. Because of high false-negative rates (9%-50%), this technique is no longer recommended as a diagnostic or therapeutic approach.4,38 To more accurately identify the sentinel node, researchers from the Netherlands Cancer Institute developed the concept of a DSNB using a patent blue dye and gamma emission, most recently reducing the false-negative rate from 18% to 4.9%.39 Because of the technical expertise necessary, DSNB is recommended only at high-volume centers.

In 1988, Catalona et al40 described a modified ILND approach using a shorter incision, limiting the field of ILND by excluding the area lateral to the femoral artery and caudal to the fossa ovalis, preserving the saphenous vein and eliminating the need to transpose the sartorius muscle while maintaining favorable oncologic outcomes. This technique reduces the morbidity associated with traditional ILND, and is an attractive alternative for clinically negative groins at increased risk of metastases based on primary penile tumor characteristics. Although the modified ILND has reduced surgical morbidity compared with the standard ILND, a standard ILND approach should be adopted if nodal metastases are detected on frozen section. Traditionally, a standard lymphadenectomy has been offered for resectable metastatic ILNs, although recent data would support neoadjuvant chemotherapy followed by surgical consolidation as the preferred treatment approach in patients with bulky disease.41,42

Table 2

Literature on Radiotherapy for Penile Cancer

Table 2

Pelvic Lymph Node Dissection: The presence of pelvic lymph node metastasis on imaging or pathologic staging is an ominous prognostic sign. Patients with 2 to 3 positive ILNs have a 23% probability of pelvic lymph node metastasis, and in those with more than 3 ILNs, this increases up to 56%.43 Lont et al44 determined that patients with 2 or more positive ILNs, extracapsular nodal extension, or poorly differentiated ILNs were at increased risk for pelvic metastasis and could benefit from a pelvic lymph node dissection.

Advances in Surgical Approach Minimally Invasive: Recent surgical series have found that minimally invasive techniques for ILND (such as video-assisted laparoscopic ILND) offer encouraging oncologic outcomes comparable to open surgical series with respect to lymph node counts,45,46 with only 20% of patients developing minor complications. These techniques, however, require validation in large, multicenter, preferably prospective studies with longer follow-up.

Locally Advanced or Bulky/Unresectable Disease

Multimodality Approach: Patients with locally advanced or bulky/unresectable disease require a multidisciplinary approach involving medical, radiation, and urologic oncologists. The preferred approach for patients with 4 cm or larger or fixed ILNs should be neoadjuvant cisplatin-based systemic chemotherapy.47 Based on a patient’s response to systemic chemotherapy (ie, stable disease, partial or complete response), surgical consolidation may be considered thereafter. Pagliaro et al42 recently reported that neoadjuvant chemotherapy with paclitaxel, ifosfamide, and cisplatin produced complete or partial responses in 50% of patients, with most (73.3%) subsequently undergoing surgery as planned. This finding compares favorably with historical response rates of only 30% to 35% for advanced metastatic disease. In this series, the median follow-up was 34 months, with 30% of the patients alive and with no evidence of disease at their last visit. This treatment approach may redefine the therapeutic paradigm of more advanced penile SCC.

Unresectable or Metastatic Disease: Paclitaxel, ifosfamide, and cisplatin chemotherapy was effective for patients with lymph node metastases (N2-3, M0), and is also a reasonable choice in first-line therapy for patients presenting with distant metastases (M1). Another acceptable first-line therapy is 5-FU and cisplatin, as recently described by Di Lorenzo et al.48 No standard second-line systemic therapy exists, and depending on the first-line therapy used, the patient may benefit from suitable single-agent treatment, such as capecitabine, carboplatin, docetaxel, 5-FU, irinotecan, methotrexate, or paclitaxel.49 Additional studies are needed, particularly with newer targeted therapeutics.

Conclusions

The onus is on both the patient and society-at-large for the prevention, education, and early detection of penile cancer. Once diagnosed, the impetus rests with the treating physician to determine the appropriate treatment approach for a given patient based on the primary tumor’s characteristics, regional ILNs, metastatic status, and patient compliance with stringent follow-up. The adoption of novel diagnostic and surgical techniques, and of a multidisciplinary approach to suitable cases, is redefining the therapeutic approach to penile SCC.

The authors have disclosed that they have no financial interests, arrangements, affiliations, or commercial interests with the manufacturers of any products discussed in this article or their competitors.
EDITORKerrin M. Green, MA, Assistant Managing Editor, JNCCN—Journal of the National Comprehensive Cancer NetworkMs. Green has disclosed that she has no relevant financial relationships.
CE AUTHORSNicole B. Harrold, BS, Manager, Continuing Education and GrantsMs. Harrold has disclosed that she has no relevant financial relationships.Kristina M. Gregory, RN, MSN, OCN, Vice President, Clinical Information OperationsMs. Gregory has disclosed that she has no relevant financial relationships.

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Correspondence: Philippe E. Spiess, MD, MS, FACS, Department of Genitourinary Oncology, Moffitt Cancer Center, 12902 Magnolia Drive, Office 12538, Tampa, FL 33612. E-mail: philippe.spiess@moffitt.org

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