Penile cancer is an uncommon malignancy, but when diagnosed is psychologically devastating to the patient and can pose a difficult challenge to the treating urologist. Patient’s with this condition tend to delay seeking medical attention. This delay is associated with embarrassment, guilt, fear, and denial of the patient. Patients often attempt to self-medicate with lotions or creams before seeing a doctor. The delays in treatment may also be attributable to physicians as well. Many patients receive salves and antibiotics from their primary care physicians before seeing a urologist. This delay in diagnosis is serious, as it can decrease the likelihood of survival and limits the ability to retain a functioning and satisfactory result after surgical intervention.
In the discussion of penile cancer, it is important to discuss benign, premalignant, and malignant conditions and to differentiate between them. The most common penile malignancy is squamous cell carcinoma (SCC), but nonsquamous penile malignant neoplasms also exist including basal cell carcinoma, melanoma, sarcomas, and adenosquamous carcinoma. This chapter will focus mainly on SCC, including the etiology, epidemiology, pathophysiology, histopathology, evaluation, and treatment of this tumor. The chapter will examine the importance of the pathologic stage and histologic features of the primary tumor, as well as any presence of lymph node (LN) metastasis in determining the prognosis and treatment planning for squamous carcinoma. The treatment options and follow up will be discussed in depth.
The incidence of cancer of the penis varies and is related to a number of factors. Clinicians have identified risk factors including the history of phimosis, balanitis, chronic inflammation, penile trauma, lack of neonatal circumcision, tobacco use, lichen sclerosus, poor hygiene and history of sexually transmitted diseases (STDs), especially HIV and human papillomavirus (HPV).
Neonatal circumcision has been correlated with lower rates of penile cancer and has been established as an excellent prophylactic measure that can eliminate the occurrence of penile carcinoma. The reasoning behind this is that it eliminates the closed preputial environment where penile carcinoma develops. This helps prevent chronic irritation effects of smegma which can lead to chronic inflammation, which is a known risk factor for penile cancer. It also eliminates the possibility of phimosis and balanitis. Patients with a history of phimosis have an increased risk for penile cancer of 25% to 60%. Male circumcision has also been shown to be effective against the HIV-1 infection. Population-based studies support the fact that neonatal circumcision can be an effective prophylactic measure against penile cancer. Studies have shown a very low incidence rate in the Jewish population where neonatal circumcision is a universal practice. African tribes and Asian cultures that do not routinely perform circumcision have much higher rates of penile cancer, and it, in fact, accounts for 10% to 20% of all male malignant neoplasms in these groups.
Sexually transmitted diseases are also noted to be a risk factor for the development of penile cancer, particularly HIV and HPV. Patients with HIV have an 8-fold increased risk for the development of penile cancer. Forty-five percent to 80% of penile cancers are related to HPV with a strong correlation to types 6, 16 and 18. High-risk HPV is more common in men with a history of phimosis. A final risk factor to consider is tobacco use. Cigarette smokers are 3 to 4.5 times more likely to develop penile cancer.
Penile cancer is a malignancy that is rare in Western civilization. It accounts for less than 1% of cancers in men in the United States, with approximately 2300 new cases and 400 deaths annually. It is more common in less developed areas of the world, such as Africa, Asia, and South America. In these areas, penile cancer can account for up to 10% to 20% of all malignancies in men. The increased risk in these areas may be due to differences in hygiene practices and increased numbers of uncircumcised males.
According to a study of incidence trends by Barnholtz-Sloan et al., the overall incidence of penile cancer has decreased in the United States over the last 3 decades of the 20th century. Interestingly, the National Cancer Database found that between 1998 to 2012, cases of all stages of squamous penile cancer increased with a greater proportion of advanced cases over time.
The disease is associated with older age, and rates are seen to increase with age. The mean age of diagnosis is approximately 60 years old.
Penile cancers traditionally begin as small lesions, most commonly on the glans or prepuce. The appearance can vary greatly. Some appear as white grey exophytic masses growing out of the penile skin and others can be flat, reddish-colored, and ulcerated masses. These lesions grow slowly laterally along the surface of the penile skin and often cover the entire glans or prepuce before invading into the corpora and shaft of the penis. Growth rates of ulcerative versus exophytic lesions are similar, although ulcerative lesions appear to metastasize to LNs earlier. Penile lymphatics drain both the glans penis and shaft and drainage proceeds first to superficial inguinal LNs to deep inguinal LNs and then to external iliac LNs in the pelvis.
Confirmation of the diagnosis of penile cancer and assessment of depth of invasion, the presence of vascular invasion, and histological grade of the lesion by microscopic examination of a biopsy specimen are mandatory before initiation of therapy. SCC accounts for 95% of penile cancer and can be characterized and subclassified by microscopic histologic features. Subtypes include usual type SCC (45% to 65%), papillary carcinoma (2% to 15%), warty condylomatous tumors (7% to 10%), basaloid carcinoma (4% to 10%), verrucous carcinoma (3% to 7%) and sarcomatoid (spindle cell) carcinoma (1% to 6%). Usual type SCC demonstrates keratinization, epithelial pearl formation and various degrees of mitotic activity. Invasive lesions infiltrate the basement membrane and surrounding structures. SCCs have been classically graded using Broders classification which defines the level of differentiation based on keratinization, nuclear pleomorphism, number of mitoses and other features. Low-grade lesions (grade 1 and 2) constitute 70% to 80% of reported cases at diagnosis. These are well-differentiated lesions that show cords of atypical squamous cells that project downward from a hyperkeratotic epidermis. The high-grade disease has been associated with regional nodal metastasis in numerous studies. Vascular invasion by tumor cells has significant prognostic importance, and it is essential that the pathologist comment on the presence or absence of vascular invasion in the surgical specimen. Perineural invasion is also a strong predictor of LN metastasis.
Penile cancer most often presents with a skin lesion or palpable nodule on the penis. Lesions are most commonly found to arise on the glans, in the coronal sulcus or on the prepuce as either a mass or ulceration. A review of penile SCC in the USA showed that 34.5% of patients had the primary lesion on the glans, 13.2% on the prepuce and 5.3% on the shaft, 4.5% overlapping and 42.5% unspecified. Inguinal lymphadenopathy is present in 30% to 60% of cases at diagnosis. Distant metastases are uncommon until late in the disease course, with only 1% to 10% of cases having distant metastases at presentation.
Initial evaluation of men with a penile mass or ulcer depends on whether the clinical presentation is consistent with an infectious etiology or malignancy. In men where an infection seems more likely, a four-week course of antifungals or antibiotics would be appropriate for repeat clinical exam at the end of the medical course. If the lesion does not resolve or progresses, a biopsy is indicated.
Suspicion for penile carcinoma should be high in men who present with a penile mass or ulcer, especially if they are uncircumcised. A tissue biopsy is required for pathologic diagnosis and necessary before initiation of any therapy. A biopsy can be performed by using a punch, incisional or excisional technique. An excisional biopsy would be appropriate if the lesion can be removed in its entirety with little or no alteration to the penile form or function.
If the biopsy is positive for cancer, an extensive physical examination of the regional LNs is indicated. Penile cancer initially spreads to the inguinal LNs and then to the pelvic and retroperitoneal nodes. The inguinal LNs should be examined with attention to the location, size, a number of palpable nodes, as well as whether they are fixed or mobile. The presence or absence of LN involvement is extremely important as it dictates treatment and also provides important prognostic information.
Unfortunately, the clinical assessment of inguinal LNs is not reliable. False-negative clinical evaluations of the inguinal region by palpation alone are common, reportedly between 9% to 60%. False-positive assessments are also frequent. For this reason, imaging is often obtained in conjunction with a clinical exam. CT, MRI or inguinal ultrasound can be used as well as CT/PET.
Pathological staging is necessary for men with palpable lymphadenopathy and for those that are high risk for metastases based on the pathological features of the primary tumor. The nodes can be evaluated by ultrasound-guided fine needle aspiration (FNA), dynamic sentinel node biopsy (DSNB) or superficial or modified inguinal lymph node dissection (ILND).
Patients at high risk for cancer in the regional LNs should undergo a chest x-ray, CT scan of abdomen and pelvis, blood tests including serum calcium and liver function tests and a bone scan if the patient complains of bone pain, has elevated calcium or elevated alkaline phosphatase.
Surgical Management of Primary Tumors
Management of penile carcinoma depends on the stage of the tumor at the time of diagnosis. Surgical removal of the primary tumor remains the gold standard for rapid definitive treatment of the primary penile tumor. Tumors with low risk of recurrence (Tis involving shaft skin and glans penis, Ta involving glans only, T1a and T1b lesions involving shaft skin and glans alone) are appropriate for organ-sparing and glans-sparing procedures. This includes topical treatments (5-fluorouracil or imiquimod cream for Tis), radiation therapy, Mohs surgery, limited excision and laser ablation. If a patient has T1 grade 1 or 2 lesions, it is recommended to consider them for penile-preserving techniques, but the patient must be reliable regarding compliance and close follow-up. Patients with T1 grade 3 or 4 lesions or T2 lesions or greater typically require more extensive surgical intervention with partial or total penectomy. Intraoperative frozen sections can be obtained to achieve negative surgical margins. Traditionally a 2-cm, tumor-free margin has been recommended, but a 5-mm, tumor-free margin is considered safe.
Lymph Node Management
Management of regional lymph nodes (LNs) is important, as the presence and extent of regional ILN metastases is the single most important prognostic indicator in determining long-term survival of men with SCC of the penis. Up to 25% of patients with non-palpable LNs harbor micrometastases. Several factors help predict the risk of microscopic inguinal LN metastases. Tis, Ta, and T1 tumors have a risk of metastases from 4% to 14%. T2 and greater tumors are associated with significantly higher risk of metastases to the inguinal LNs. Metastatic potential is also associated with higher tumor grade, the higher the grade, the greater risk for metastases. Presence of lymphovascular or perineural invasion is also associated with greater risk of metastases. Patients are stratified into groups of low risk or high risk for nodal involvement.
Low Risk: Tis, Ta and T1a tumors; no lymphovascular invasion or perineural invasion; grades 1 and 2
High Risk: Grade 3 tumors, lymphovascular or perineural invasion present (T1b) and T2 or higher stage
Men with low-risk disease and non-palpable inguinal LNs have a 0-16% chance of nodal metastases. The European Association of Urology (EAU) and National Comprehensive Cancer Network (NCCN) recommend offering these men surveillance rather than surgical staging. These men must be reliable, however, and comply with follow-up recommendations. If unreliable or unwilling to proceed with surveillance these men should undergo bilateral inguinal node staging, either with dynamic sentinel node biopsy (DSNB) or superficial or modified ILND. Men with non-palpable inguinal LNs but high-risk disease should either undergo DSNB or superficial or modified inguinal LND. If the nodes are negative, posttreatment surveillance is recommended. Patients with one involved inguinal LN and without extranodal extension require complete ipsilateral inguinal LND. If a patient has 2 more positive nodes or one positive node and evidence of extranodal extension, he should undergo therapeutic ipsilateral inguinal LND and unilateral or bilateral pelvic LND.
Men who present with a unilateral, solitary inguinal node that is less than 4 cm in size should undergo fine needle aspiration (FNA) of the palpable node. If the FNA is positive, a superficial and deep inguinal LND should be performed. If the FNA is negative, excisional biopsy, superficial inguinal LND or surveillance is appropriate. If 2 or more nodes are positive or there is evidence of extranodal extension on ILND, it is recommended to proceed with a pelvic LND. These patients are also candidates for adjuvant chemotherapy or radiation therapy as they are at higher risk for recurrence.
Men with multiple or bilateral palpable inguinal nodes should undergo an FNA of one of the nodes for initial staging examination. If the FNA is negative, the surgeon should proceed with an excisional biopsy or superficial inguinal LND with frozen sections obtained intraoperatively. It is important to take into account that 30% to 50% of patients with palpable disease will simply have inflammatory LN swelling instead of metastases. For this reason, it is more favorable to obtain a biopsy to prove metastases. It is becoming more common to obtain a dynamic sentinel node biopsy. If the patient’s biopsy is positive, they should undergo neoadjuvant chemotherapy and then ILND and pelvic LN dissection.
Management of Primary Lesion
Much of the surgical management has been discussed in the treatment/management section of this topic. Low-risk tumors can be managed with organ-sparing and glans-sparing procedures. Penile sparing techniques have a higher local recurrence rate than partial penectomy, but these two techniques have a comparable cancer-specific survival rate. Penile sparing techniques include circumcision, wedge resection, Mohs’ surgery, laser ablation and laser excision, topical therapy (5-FU or imiquimod) and radiation therapy.
Patient’s with T1 grade 3 and 4 lesions or T2 lesions or greater typically require more extensive surgical intervention with partial or total penectomy. A partial penectomy removes the distal penis, including the glans, distal corpora, and distal urethra. Traditionally a 2cm tumor-free margin has been recommended, but a 5mm tumor-free margin is considered safe. 2-3cm of penile length should be left if possible to allow the patient to have some degree of sexual function and void in the standing position. A total penectomy removes all of the penis distal to the pubic bone. The urethral stump is diverted into the perineum with a perineal urethrostomy, so the patient must void in the sitting position.
Management of Inguinal Lymph Nodes
Please see the above treatment/management section for a full description of when to perform the below-described procedures.
Dynamic Sentinal Node Biopsy
For patients with high-risk disease, it is becoming more common to perform dynamic sentinel node biopsy (DSNB). This technique uses lymphoscintigraphy and is performed with technetium-99m-labeled nanocolloid and patent blue dye isosulfan blue to identify the sentinel LN in the inguinal region to allow for excisional biopsy of this node to evaluate for metastasis. Palpble nodes should be biopsied, preferably with FNA.
Inguinal Lymph Node Dissection
ILND should be performed on patients with proven metastases. It is a highly morbid procedure. The boundaries of the standard, full template are: the inguinal ligament superiorly. The fossa ovalis inferiorly, the medial border of the Sartorius muscle laterally and the lateral edge of the adductor longus muscle medially. The fascia lata separates the superficial and deep inguinal LNs. The superficial nodes are divided into 5 zones. The deep inguinal LNs are deep to the fascial lata and are located medial to the femoral vein in the femoral triangle. The node of Cloquet is the most cephalad node in the deep inguinal region. During radical ILND, the saphenous vein is ligated where it arises from the femoral vein and where it passes through the fossa ovalis, and this vein segment is removed. A Sartorius muscle flap is used to cover the femoral vessels after ILND.
A modified ILND technique has also been described and can be recommended for patients with the normal inguinal exam but high-risk penile cancers. This technique uses a smaller skin incision and narrows the field of inguinal dissection by excluding the area lateral to the femoral artery and caudal to the fossa ovalis. It also preserves the saphenous vein and eliminates muscle flap transposition. This template allows for good oncologic control as it is targeting the most common site for metastases while decreasing morbidity by narrowing the incision and decreasing the amount of disruption of lymphatic drainage. Frozen sections should be obtained when using this template and if nodal involvement is identified the procedure should be converted to a full-template lymphadenectomy.
Pelvic Lymph Node Dissection
Ipsilateral pelvic LN dissection should be considered in men with 2 or greater inguinal ipsilateral nodal metastases, metastases in the node of Cloquet, tumor extension through the capsule of the inguinal LNs or presence of high-grade tumor in involved nodes.
Penile radiation therapy (RT) is appropriate for Tis, T1 and T2 lesions that are less than 4cm in size. This therapy can be administered as external beam radiation therapy or interstitial brachytherapy. Radiation has a higher local recurrence rate than partial or total penectomy. High doses of radiation are required to eradicate penile squamous cell carcinoma and complications are high. The 2 most common late side effects of RT are meatal stenosis and soft-tissue ulceration. Circumcision must be performed prior to radiation therapy to prevent radiation-induced phimosis.
Adjuvant RT to the inguinal or pelvic regions has not been thoroughly evaluated. It is currently not recommended as prophylaxis for high-risk patients and is less effective therapeutically than a LN dissection for clinically involved nodes. It may be useful for palliation in patients with inoperable nodes.
Neoadjuvant chemotherapy should be considered for patients with an unresectable primary tumor, bulky lymphadenopathy or bilateral inguinal adenopathy. These patients have a low probability of cure from surgery alone. The TIP regimen is the standard regimen used and consists of Paclitaxel, Ifosfamide and Cisplatin. This is given at 3 to 4 week intervals for 4 cycles. There is little evidence for the role of adjuvant therapy in men with penile carcinoma.
The TNM staging system is used for staging carcinoma of the penis. It is currently in its 8 edition, and is used to define prognostic stage groups and to develop an appropriate treatment plan.
Primary Tumor (T)
Regional Lymph Nodes (N)
Clinical N (cN)
Pathological N (pN)
Distant Metastasis (M)
M0: No distant metastasis
M1L Distant metastasis
Anatomic Stage/Prognostic Groups
Clinical exam is essential for the initial evaluation of a patient with suspected penile carcinoma. A thorough examination of the inguinal LNs is necessary, with attempts to evaluate and assess for palpability of nodes, number of inguinal masses, if the masses are unilateral or bilateral in location, dimension, mobility or fixation of nodes or masses, relationship to other structures, and edema of the patient’s penis, scrotum and/or legs. It is necessary to describe the diameter of nodes/masses, unilateral or bilateral location, number of nodes identified in each region and whether these nodes are mobile or fixed.
If a patient has a clinically negative inguinal exam, the extent of staging is based on the risk for occult nodal metastases. The European Association of Urology and NCCN guidelines have created the following guidelines to follow in this situation. Men with low-risk disease (PTis, Ta, or T1a, histologic grade1) should undergo surveillance rather than nodal assessment by dynamic sentinel lymph node biopsy (DSNB) or superficial ILND. Men with intermediate-risk disease (pT1a, histologic grade 2), should undergo either a DSNB or superficial ILND. Men with high-risk disease (>pT1b) should undergo superficial or modified ILND, or DSNB depending on surgical expertise. CT/MRI or inguinal ultrasound may be useful in preoperative planning.
In men with the clinically suspicious inguinal exam, it is suggested to obtain an FNA for pathologic assessment. In men with low-risk disease (pTis, pTa, pT1a) with clinically suspicious adenopathy but negative FNA, it is recommended to proceed with excisional biopsy for definitive evaluation. For men with high-risk disease (greater than pT1b) with clinically suspicious adenopathy but negative FNA, it is recommended to proceed with superficial or modified ILND.
Men with penile cancer who present with bulky, fixed inguinal nodes or pelvic LNs have relatively low survival rates when treated with surgery alone and are candidates for multimodal treatment strategies.
The presence and extent of regional inguinal LN metastases have been identified as the single most important prognostic indicator in determining long-term survival in men with invasive SCC. This prognosis varies depending on the number of positive LNs, the presence of unilateral or bilateral inguinal extension, and pelvic LN involvement. For this reason, evaluation of the groin and pelvis is essential in the metastatic workup of a penile cancer patient and the clinical exam can be crucial for assessing palpability, a number of inguinal masses, unilateral or bilateral localization and mobility or fixation of inguinal nodes or masses.
Patients with inguinal metastases who are untreated rarely survive two years. Patients with stage I or II cancers, still confined to the penis, at time of diagnosis have a 5-year survival rate of around 85% after surgical management. Stage III and IV cancers have a 5-year survival rate around 59%. If cancer has metastasized to distant parts of the body, the 5-year survival rate is 11%. Numerous studies have looked at the extent of inguinal LN involvement as an indicator of survival. Patients with no inguinal node metastases have an 85-100% five-year cancer-specific survival rate. Patients with a single inguinal LN metastasis have a 79% to 89% 5-year survival rate. Patients with bilateral or multiple inguinal node metastases have a 17% to 60% 5-year survival rate. Patients with pelvic node metastases have a zero to 17% 5-year survival rate.
Excision of the Primary Tumor
Lymph Node Dissection
Intensive follow-up should be conducted in patients after definitive therapy. Patients are generally seen approximately 2 weeks after the initial operative procedure to ensure a good recovery and then will follow the surveillance protocol outlined below.
Patients that underwent organ-sparing surgeries should be seen every three months for years 1 and 2, every 6 months for years 3 to 5, and annually for years 5 to 10. Follow up should include a physical examination of the penis and inguinal nodes. Patients that underwent penectomy or partial penectomy should be seen every 6 months for the first 2 years and yearly for years 3 to 5.
Patients on active surveillance with clinically negative nodes should be seen every three months for the first 2 years and every 6 months for years 3 to 5. Patients that underwent ILND and were N0 or N1 should be seen every six months for the first two years and yearly for years 3 to 5. Patients that underwent ILND and were N2 or N3 should be seen every 3 to 6 months for the first 2 years and yearly from years 3 to 5. They should have chest imaging (CT or chest x-ray) every 6 months for the first 2 years. They should have abdomen/pelvis CT performed every 3 months for the first year and every 6 months for the second year.
Medical oncology consultation is appropriate if the patient is appropriate for neoadjuvant chemotherapy. Radiation oncology consultation is appropriate for patients wishing to have radiation therapy for treatment of their primary tumor. A palliative care consult is appropriate for patients with indicators of poor prognosis. Indicators of poor prognosis include higher primary tumor stage, perineural invasion, basaloid or sarcomatoid histology, or more extensive LN involvement.
Patients should understand the importance of hygiene and the association of poor hygiene with penile cancers. Phimosis should be treated quickly as chronic inflammation can lead to the development of penile cancer. High-risk sexual behavior that makes the patient at risk for HPV and HIV should be discontinued, as well as tobacco use. Most importantly, patients need to understand that any lesions on the penis must be evaluated by a medical professional as soon as possible. Prompt diagnosis allows for intervention at an earlier stage and improved cosmetic and survival outcomes.
Penile cancer is a relatively uncommon malignancy in the United States. Unfortunately, its diagnosis is often delayed due to a number of factors including patient embarrassment, denial, and misdiagnosis by primary care practitioners. If there is any concern about a possible penile lesion, the patient should be seen by a urologist as early in the workup as possible. Management of penile cancer is primarily surgical, but there are indications for radiation therapy or neoadjuvant chemotherapy.