Penile cancer is uncommon, but, when it is diagnosed, it is psychologically devastating to the patient and often presents a challenge to the urologist. Benign, premalignant, and malignant conditions must be differentiated. Penile squamous cell carcinoma (see image below), the most common penile malignancy, behaves similarly to squamous cell carcinoma in other parts of the skin. Metastasis, which occurs with this type of carcinoma when the diagnosis or treatment is delayed, is usually lethal. This is a slow-growing cancer in its early stages, and because it seldom interferes with voiding or erectile function, patients do not complain until pain or a discharge from the cancer occurs. By this time, the cancer has usually progressed from being superficial to invasive.
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Squamous cell carcinoma (Image courtesy of Hon Pak, MD).
Patients with carcinoma of the penis tend to delay seeking medical attention, with 15-50% delaying medical attention for more than 1 year from onset. This delay is attributed to embarrassment, guilt, fear, ignorance, and personal neglect. Patients often try to treat themselves with various skin creams and lotions. These may appear to be effective for a time, which further delays the diagnosis and worsens the prognosis.
Delays may also attributable to the physician. Some patients with penile cancer report that they received various salves and antibiotics from their primary care physicians before they saw an urologist. A delay in diagnosis and therapy not only affects the likelihood of survival but also limits the ability to retain a functioning and cosmetically satisfactory result. Nearly 25% of dysplastic or neoplastic penile lesions are misdiagnosed as being benign.
A biopsy should be considered in any uncircumcised male who presents with a penile lesion. These tend to originate on the glans penis and the undersurface of the prepuce. Many benign conditions may be found in this area, and only a biopsy can clarify the diagnosis.
Surgery has been the traditional therapy for penile cancer. Superficial penile carcinoma is typically managed with local resection, often with just a circumcision, whereas invasive disease is treated with partial or total penectomy and bilateral lymphadenectomy. Cancers on the glans or adjacent to the urethral meatus may be treated with Mohs surgery, in which a microscopic dissection can remove the cancer but obtain a good cosmetic result.
Comparing treatment strategies is difficult because this is a rare cancer and no institution is able to amass enough experience to conduct clinical trials. Most published reports cover a span of a decade or longer. The single greatest predictor of disease-free survival is the presence of inguinal nodal metastasis. The morbidity associated with inguinal lymphadenectomy has discouraged surgeons from aggressively pursuing this treatment unless palpable nodes are present. As many as 30% of patients without palpable inguinal nodes have micrometastatic disease. If these are removed, the surgery can be curative.
In recent years, improved diagnostic techniques have been developed to determine the presence of lymph node metastases. Surgical techniques have been refined to reduce the morbidity associated with penile and lymph node resection. Some surgeons are using laser treatment to remove small, superficial cancers.
Radiotherapy is an alternative to conservative surgical treatment for stage T1-T2 tumors of the glans that are less than 4 cm in size.
Local chemotherapy with 5% 5-fluorouracil cream or 5% imiquimod cream have reported success rates of 70% and 52%. Systemic chemotherapy is recommended in patients with inguinal lymph node metastases. The results are poor in men with extensive metastases.
Invasive penile cancer diagnosed in the absence of clinically evident nodal metastases (as determined by physical examination or imaging) can be treated with local resection and penile reconstruction. Inguinal lymph nodes need to be evaluated with bilateral lymphadenectomy or sentinel node biopsies. In some situations, radiation therapy to the penile tumor is applicable. Palpable inguinal lymph nodes should be assessed to determine the presence or absence of nodal metastasis. The 30% incidence of micrometastases in nonpalpable inguinal lymph nodes emphasizes the importance of nodal assessment.
The ability to identify a sentinel node has been a valuable adjunct in the refinement of surgical management. Various imaging techniques have shown increasing sensitivity for identifying these nodes, sparing the need for extensive, bilateral inguinal lymphadenectomy, which is associated with a high degree of morbidity.
In the past, an excisional margin of 2 cm around the cancer was thought to be necessary, but with improved histopathology techniques, a margin of 0.5-1 cm may be sufficient. In addition, although a 4-week to 6-week waiting period was once believed to be necessary to treat the patient with antibiotics prior to surgery. This would allow lymph nodes that were enlarged as a result of infection to return to their normal state. Currently, tumor excision and lymph node excision are performed at the same time.
The presence of palpable inguinal nodal metastasis is managed by a bilateral radical lymphadenectomy followed by an extensive pelvic lymphadenectomy. Postoperative chemotherapy and radiation therapy is used depending on the surgical outcome.
Penile tumors can originate anywhere on the penis, but most are found on the glans (48%) and prepuce (21%). The presentation can be a hyperemic area on the glans or near the urethral meatus. The cancers can range from an area of subtle induration to a small excrescence or papule. They can be exophytic or flat, or an ulcerated lesion may be present. A sensation of itching or burning under the foreskin or an ulceration of the glans are the most common presenting symptoms. Pain is rarely present.
A circumcised male rarely develops penile cancer; however, men with chronic lymphocytic leukemia are predisposed to the development of squamous cell carcinomas that can occur anywhere on the body, including the penis.
Tumors may initially form on the corona of the glans and spread superficially across the glans and into the prepuce. Phimosis may conceal the cancer, allowing it to progress. Eventually, as the cancer grows, erosion through the prepuce, a foul odor, and a discharge are evident. Buck fascia acts as a natural barrier to the corpora, but over time, the cancer invades the corpora. As these cancers spread over the glans, they may involve the urethral meatus and grow into the urethra.
The etiology of these cancers may be related to chronic exposure to carcinogens contained in smegma that collects within the prepuce, although no specific carcinogens have been identified.
Patients who are diagnosed with penile cancer have various treatment options. If the tumor is smaller than 2 cm (and particularly if it is confined to the prepuce), circumcision may be all that is necessary. Penile cancer tends to remain confined to the skin for long periods, often years, but when it invades the deeper tissues, the cancer has ready access to lymphatics and blood vessels and the growth rate is rapid.
Penile cancer is rare in Western countries. The American Cancer Society estimated that in 2018, 2320 penile cancers would be diagnosed in the United States, with 380 deaths.[1] This death rate of 17% underscores the seriousness of this cancer; for comparison, only 3% of men with prostate cancer die from this disease.
Barnholtz-Sloan et al studied the incidence trends of primary penile cancer in the United States using data from The National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) database of 1,817 men. They found that the overall incidence of primary malignant penile cancer decreased over the final 3 decades of the 20th century. The overall incidence was 0.84 per 100,000 from 1973-1982, 0.69 from 1982-1992, and 0.58 from 1993-2002. Most of the cancers were squamous cell and originated on the glans. From 1993-2002, the incidence was highest among Hispanics (1.01 per 100,000), followed by Alaskan Native Americans (0.77 per 100,000) and African Americans (0.62 per 100,000).[2]
In contrast, a review of the National Cancer Database found that from 1998 to 2012, cases of all stages of penile squamous cell carcinoma increased, with a greater proportion of advanced cases over time. Factors significantly associated with advanced presentation were age older than 55 years, the presence of comorbidities, and Medicaid or no insurance.[3]
Penile cancer accounts for 0.4-0.6% of all malignancies in the United States and Europe. In the rest of the world, the situation is different and represents an important health problem. Penile carcinoma represents 20-30% of all cancers diagnosed in men who live in Asia, Africa, and South America.
In urban India, the age-adjusted incidence of penile cancer ranges from 0.7-2.3 cases per 100,000 men. In rural India, the rate of penile cancer is 3 cases per 100,000 men, accounting for more than 6% of all malignancies in this population. In underdeveloped countries such as Uganda, the incidence is 2.8/100,000 and 1% of the men have developed this cancer by age 75. In Brazil, the age-adjusted incidence of penile cancer is 8.3 cases per 100,000 population.
Penile cancer is rare in circumcised men, particularly if they were circumcised as a neonate. Worldwide, the lowest incidence rates of penile cancer, 0.1 cases per 100,000 men, are found in countries that have robust medical systems and religious practices leading to high rates of neonatal circumcision, such as Israel.[4]
Seyam et al studied penile carcinoma in 22 men who had been circumcised. Eighteen of these patients came from the southwest part of Saudi Arabia and had undergone late ritual circumcision. This practice, known as “Tihamah” circumcision, involves removing an extensive amount of skin, including some of the pubic skin. This procedure results in extensive cicatrization, which is probably the underlying cause of the resulting squamous cell cancer. Radiation therapy was attempted in a few of the patients, with unsuccessful results, whereas the group treated with surgery had a median survival of 34 months.[5]
Penile cancer tends to be a disease of older men. The incidence of penile cancer increases abruptly in men aged 60 years or older and peaks in men aged 80 years. However, the tumor is not unusual in younger men. One study reported that 22% of patients with penile cancer were younger than 40 years, and 7% were younger than 30 years.
The frequency of penile carcinoma varies according to hygienic practices and cultural and religious beliefs. Phimosis is present in at least 25-75% of men with this disease. Information on presence of phimosis often goes unrecorded in underdeveloped countries, and epidemiologic data are lacking.
Circumcision has been well established as an effective prophylactic measure for penile cancer. Data from most large series have demonstrated that penile cancer is almost never observed in individuals who are circumcised in the neonatal period. The disease is found more frequently when circumcision is delayed until puberty. Adult circumcision offers little or no protection.
No firm evidence indicates that smegma acts as a carcinogen, although this belief is widely held. The role of viral infection continues to be studied. Both penile cancer in men and cervical cancer in women have been associated with human papillomavirus (HPV) infection. In women whose sexual partners had penile cancer, the prevalence of cervical cancer is increased 3- to 8-fold. HPV-16 and HPV-18 have been found in one third of men with penile cancer. Whether these viruses are involved with causation of the cancer or are found as saprophytes has not been determined. No data have indicated that herpes viral infections cause penile cancer.
Madsen et al studied a population that included 71 patients with invasive or in situ squamous cell carcinoma, 86 prostate cancer controls, and 103 men as population controls. PCR was used to examine for HPV in tissue samples of 37 patients with squamous cell carcinoma. The study found high-risk HPV in 65% of the 37 patients, of whom 22 of 24 (92%) were found to have HPV-16. Risk factors included early and high sexual activity, the lifetime number of sexual partners, the number of sexual partners prior to age 20 years, age at first occurrence of intercourse, penile-oral sex, a history of anogenital warts, and never having used condoms. A history of phimosis and priapism occurring more than 5 years prior to diagnosis were also significant risk factors.[6]
Cigarette smoking and chewing tobacco are also considered to be a risk factors. Harish and Ravi reported that the risk for those smoking more than 10 cigarettes a day was 2.14. The combination of chewing tobacco and cigarette smoking raised the risk to 3.39.[7] Maden et al found that the risk of penile cancer in men who were smoking at the time of diagnosis was 2.8 times that of men who never smoked.[8]
Penile trauma, usually consisting of small tears or abrasions involving the prepuce, and a history of chronic balanitis that occurred more than 2 years prior to diagnosis had an odds ratio of 23 for carcinoma in situ and 4.6 for invasive cancer. Hellberg et al reported that multiple episodes of balanitis had a relative risk of 9.49.[9] These observations support the theory correlating chronic inflammation to the development of cancer.
Abnormalities considered to be nonmalignant include cutaneous horns, pseudoepitheliomatous keratotic and micaceous balanitis, balanitis xerotica obliterans, giant condyloma, and bowenoid papulosis. Penile intraepithelial neoplasia is considered to be premalignant, but only 5-15% of these lesions evolve into invasive squamous cell carcinoma. When carcinoma in situ (CIS) occurs on the glans, it is termed erythroplasia of Queyrat; however, when it occurs on the follicle-bearing skin of the shaft, it is termed Bowen disease.
CIS can also develop in the tissue around the urethral meatus and spread down the urethra. These lesions have a red to red-brown appearance and generally have an irregular border. Suspicious lesions should prompt a biopsy to establish a diagnosis.
The National Cancer Institute’s SEER program was used to gather data on 1605 men diagnosed with squamous cell carcinoma of the penis. CIS was diagnosed in 37% of this population, localized disease was diagnosed in 39%, regional disease was present in 13%, distant disease was present in 2.3%, and unstaged disease remained in 7.9%.
According to SEER data, the proportion of men presenting annually with CIS has tended to increase, although the number of men with localized disease has decreased. Older age at diagnosis was associated with a higher stage of disease. The mean time until death from cancer was 66.6 months in those with CIS, 50.1 months in those with localized disease, 32.4 months in those with regional disease, and 7.4 months in those with distant metastases. Overall, 22.4% of the patients in this database died of this cancer.
Penile cancers usually begin as small lesions on the glans or prepuce. They range from white-grey, irregular exophytic to reddish flat and ulcerated endophytic masses. They gradually grow laterally along the surface and can cover the entire glans and prepuce before invading the corpora and shaft of the penis. The more extensive the lesion, the greater the possibility of local invasion and nodal metastasis. Penile cancers may be papillary and exophytic or flat and ulcerative. Untreated, penile autoamputation can occur.
The growth rates of the papillary and ulcerative lesions are similar, but the flat ulcerative lesions tend to metastasize to the lymph nodes earlier and are therefore associated with a lower 5-year survival rate. Cancers larger than 5 cm and those involving more than 75% of the shaft are associated with a high prevalence of nodal metastases and a lower survival rate, but a consistent relationship among the size of the cancer, the presence of inguinal node metastases, and survival has not been identified.
The Buck fascia, which surrounds the corpora, acts as a temporary barrier. Eventually, the cancer penetrates the Buck fascia and the tunica albuginea, where the cancer has access to the vasculature and from which systemic spread is possible.
Metastasis to the femoral and inguinal lymph nodes is the earliest path for tumor dissemination. The lymphatics of the prepuce join with those from the shaft. These drain into the superficial inguinal nodes. Because of lymphatic crossover, cancer cells have access to lymph nodes in both inguinal areas.
The lymphatics of the glans follow a different path and join those draining the corpora. A circular band of lymphatics that drains to the superficial nodes is located at the base of the penis and can extend to both the superficial and deep pelvic lymph nodes.
The superficial inguinal nodes drain to the deep inguinal nodes, which are beneath the fascia lata. From here, drainage is to the pelvic nodes. Multiple cross connections exist at all levels, permitting bilateral penile lymphatic drainage.
Untreated metastatic enlargement of the regional nodes leads to skin necrosis, chronic infection, and, eventually, death from sepsis or hemorrhage secondary to erosion into the femoral vessels. Clinically apparent distant metastases to the lung, liver, bone, or brain are unusual until late in the disease course, often after the primary disease has been treated. Distant metastases are usually associated with regional node involvement.
Microscopically, the tumors vary from well-differentiated keratinizing tumors to solid anaplastic carcinomas with scant keratinization. Most tumors are highly keratinized and are of moderate differentiation. Poorly differentiated carcinomas have variable amounts of spindle cell, giant cell, solid, acantholytic, clear cell, small cell, warty, basaloid, or glandular components.
Penile carcinoma follows a relentless and progressive course that proves to be fatal in most untreated patients within 2 years. The typical SCC has a recurrence rate of 28% and lymph node metastases are found in 28-39% depending upon the extent and grade of the tumor. The mortality rate is 20-38% with a 10-year survival rate of 78%. Spontaneous remission has not been reported.
Typical presentations of penile cancer include a lesion that has failed to heal, a subtle induration in the skin, a small excrescence, a papule, a pustule, a warty growth, a large exophytic growth, or a reddened area on the glans. The malignancy may appear as a shallow erosion or a deep ulceration with rolled edges. Because most patients with penile cancer are uncircumcised, they may have a phimosis that obscures the tumor and allows it to grow undetected. Many men do not seek medical attention until the cancer has eroded through the prepuce and has become malodorous because of infection and necrosis.
In rare cases, an inguinal mass ulcerates, suppurates, or hemorrhages.
Few symptoms are associated with the development of penile cancer. Even after significant local tissue destruction, pain is uncommon. Patients with advanced metastatic cancer may report weakness, weight loss, and fatigue; the penile lesion may bleed.
The presence of a nonhealing penile lesion usually prompts the patient to visit a physician. While carcinoma may manifest as a hyperemic patch on the glans that is characteristic of erythroplasia of Queyrat or as an ulcerated growth on the inner surface of the prepuce, the differential diagnoses include benign and premalignant lesions.
Penile lesions can be categorized as benign, premalignant, or malignant neoplasms. Benign lesions include pearly penile papules, hirsute papillomas, and coronal papillae. These lesions do not require treatment and are usually found on the glans in uncircumcised males. Rashes, ulcerations from irritation, and allergic reactions or infections must be considered. Some histologically benign lesions are potentially malignant (premalignant) or have been associated with the presence of squamous cell carcinoma. The most common is balanitis xerotica obliterans. This is a variation of lichen sclerosus et atrophicus and manifests as a white patch on the prepuce or glans, where it usually involves the urethral meatus. This can produce severe cicatrization, leading to obstruction of the urethra.
Leukoplakia manifests as solitary plaque or multiple whitish plaques, which often involve the meatus. Leukoplakia has been associated with squamous cell carcinoma.
Viral lesions include condyloma acuminata, which are soft papillomatous growths. They are also known as venereal warts and have a predilection for the genital and perineal regions. These lesions are usually sexually transmitted and are caused by HPV. Viral types 6, 11, 42, and 44 are associated with low-grade dysplasia. Types 16, 18, 31, 33, 35, and 39 are associated with neoplastic changes. De Paula et al studied the presence of koilocytosis, which is a feature of productive HPV infection and is characterized by large halos around cell nuclei. Koilocytosis is found in approximately 30%-60% of patients with penile cancer. They found that the presence of koilocytosis correlated with Jackson stage and grade but not with nodal disease or survival.[10]
Lichen sclerosus, also known as balanitis xerotica obliterans, is a chronic lymphocyte-mediated skin disease that can develop on any cutaneous surface and has been associated with squamous cell carcinoma of the penis. Biopsy of the lesion should be obtained prior to initiating therapy. A direct causative link between these entities has not been established, but the presence of a chronic inflammatory lesion is thought to promote the development of many types of cancers.
A study by Mannweiler et al revealed HPV-negative carcinomas were correlated with advanced lichen sclerosus and lichen planus, differentiated penile intraepithelial neoplasia, and accumulation of T lymphocytes with monoclonal rearrangement of the T-cell receptor γ locus.[11]
Kaposi sarcoma manifests as a cutaneous neovascular lesion that is raised, usually painful, and often ulcerated with a bluish discoloration. Patients with AIDS are predisposed to develop this condition.
Giant condyloma acuminata or a Buschke-Löwenstein tumor differs from the standard condyloma in that it displaces, invades, and destroys adjacent structures by compression, whereas the standard condyloma remains superficial and never invades. Despite their large size and invasive potential, Buschke-Löwenstein tumors show no signs of malignant change upon histologic examination.
Malignant carcinomas include variants of squamous cell carcinoma such as CIS, erythroplasia of Queyrat, or Bowen disease. The diagnosis depends on their appearance and the site of origin. Erythroplasia involves the glans, prepuce, or penile shaft, while similar lesions on the remainder of the genitalia and perineum are termed Bowen disease. Regardless of the terminology and clinical presentation, these are carcinomas with the same malignant potential; biopsies should be performed, and the carcinoma should be staged and treated.
Herpes viral infections have not been associated with the development of penile cancers.
Indications for therapy and therapeutic options depend on the histologic diagnosis of cancer established based on biopsy findings, the location and size of the tumor, and the presence or absence of palpable inguinal lymphadenopathy. All patients with penile cancer require therapy because spontaneous regression does not occur and, untreated, the cancer ultimately causes death.
Rippentrop et al studied the surgical therapy status among the 1605 men identified in the SEER database. Surgical therapy was recorded in 1422 patients, of whom 721 (50.7%) underwent some form of surgery. Excisional biopsy was performed in 19.7%, and topical therapy with laser or cryoablation was used in 0.3%. Of those undergoing surgery, 13.1% underwent partial penectomy without lymphadenectomy, 2.1% underwent a combined procedure, and only 0.5% required radical penectomy.[12]
The anatomy of the penis has important implications for the diagnosis and treatment of penile cancer. Embryologically, the 3 erectile bodies of the penis arise from the paired genital tubercles, which give rise to the corpora cavernosa, the caudal portion of the urogenital sinus that creates the corpora spongiosum, and the paired urethral folds, which join in the midline.
For purposes of description, the penis may be divided into the root, which is located within the superficial perineal pouch and is the primary fixation point; the body, which contains the 3 corpora and the overlying tissues; and the glans, which sits as a cap on the corpora cavernosa but is a part of the corpora spongiosa.
The superficial fascia is continuous with dartos fascia posteriorly and with the Scarpa and Camper fascia anteriorly. The superficial fascia consists of a single layer with loose connections to the overlying skin.
The corpora are covered by a layer of dense fibrous tissue called the tunica albuginea. The corpora cavernosa are incompletely separated by the septum penis, a thin layer of fibrous tissue continuous with the tunica albuginea. The fascia overlying the corpora cavernosa blends with the fascia of the urogenital diaphragm. The erectile tissue within the corpora is composed of a spongelike network of endothelium-lined sinusoidal spaces.
No specific laboratory studies or tumor markers are diagnostic for penile cancer.
A general evaluation, which includes a CBC count; a chemistry panel with liver function tests; and an assessment of cardiac, pulmonary, and renal status, is helpful as a baseline and in the detection of any unsuspected problems.
Patients with advanced penile cancer may be anemic, with leukocytosis and hypoalbuminemia.
Hypercalcemia has been found in some patients in the absence of metastases.
Magnetic resonance imaging (MRI) and ultrasonography are useful for local cancer staging and for assessing the inguinal lymph nodes. These studies may be helpful for detecting tumor invasion into the corpora. MRI produces sharp images of the penile structures, is accurate for demonstrating invasion of the corpora, and can help the physician determine the extent of the cancer along the surface of the penis in patients with tumors larger than 2 cm.[13]
Both MRI and computed tomography (CT) scanning can demonstrate enlarged pelvic and retroperitoneal lymph nodes. Positron emission tomography (PET) and CT scanning have not been studied extensively but may be helpful and should be obtained in patients with high-grade and extensive local disease and in those with evidence of inguinal node involvement.
CT images in men with proven unilateral or bilateral cancer with central node necrosis and/or irregular nodal borders of the regional nodes are very useful to identify high-risk patients. Graafland et al demonstrated an association between these unfavorable pathologic features and poor prognosis, with a sensitivity of 95%, a specificity of 82% and a diagnostic accuracy of 87%.[14]
Rarely, chest radiography can help detect metastases. However, CT is the preferred study to evaluate for metastases.
A technique to identify lymph node metastases using MRI following the intravenous injection of ferromagnetic particles has shown a high degree of sensitivity. Tabatabaei et al studied 7 patients with this imaging and found a sensitivity of 100%, a specificity of 97% and a positive predictive value of 81.2% in the ability to detect micrometastatic disease.[15] Further study are necessary to determine the tumor burden needed for this imaging modality to be effective, but current results indicate that it is more accurate than conventional CT scanning.
Positron emission tomography (PET)/CT imaging using 18F-fluorodeoxyglucose (18F-FDG) was used to study 42 patients with nonpalpable inguinal nodes. Five of these patients had micrometastatic disease but the PET/CT found tumor in only one patient. Another study using 18F-FDG-PET/CT scan imaging conducted by Schlenker et al on 35 patients with invasive penile carcinoma found that integrating PET/CT scanning into preoperative procedures could avoid surgical staging in selected patients.[16]
Naumann et al reported that in patients with penile cancer who do not have palpable inguinal nodes, preoperative sentinel lymph node (SLN) imaging with single photon emission computed tomography/CT (SPECT/CT) provided clear and precise anatomical localization of SLNs. These authors recommend SPECT/CT to enhance the safety and feasibility of SLN biopsy in such cases.[17]
The most important diagnostic test is a biopsy. This may be an excisional biopsy if the cancer is small or the lesion is confined to the prepuce and a circumcision is acceptable. The biopsy should contain tissue beneath the tumor, if this is feasible, in order to help stage the disease.
CT-guided or ultrasound-guided fine-needle aspiration of enlarged lymph nodes may aid the urologist in planning therapy. Aspiration biopsies of sentinel nodes using the identification techniques described below have also been reported. Kroon et al reported that only 9 of 23 patients (39%) were detected with fine-needle aspiration biopsy.[18]
Sentinel node biopsy may be of assistance in determining the need for extensive inguinal lymphadenectomy. Various methods have been used to identify the sentinel node. One method involves intradermal injection of 2 mL of patent blue dye around the tumor. Approximately 15 minutes later, the node can be identified and removed for histologic assessment.
Lymphoscintigraphy is another method used to identify the sentinel node. This technique, developed at The Netherlands Cancer Center Institute, involves injecting technetium-99m nanocolloid around the primary tumor. Following the injection, dynamic images are taken with a gamma camera to visualize lymphatic drainage. Static scintigrams are obtained 2 hours after the injection. A hot spot in the inguinal area is considered to be a sentinel node, and its position is marked on the skin. In some instances, both techniques are used to identify the sentinel node. Kroon et al found that that the size of the metastasis was predictive of nonsentinel node metastasis. They reported that, in groins with only micrometastases in the sentinel node, none of the other nodes were involved.[19]
Tabatabaei and McDougal reported on their results using lymphotrophic nanoparticle-enhanced MRI and found that this technique yielded 100% sensitivity and 97% specificity.[20]
The major limitation of these techniques is the need to perform the test in all patients regardless of the presence of clinically normal nodes and histologic features of the primary tumor. Another possible concern is thrombosis of the lymphatic vessels cause by inflammation. Finally, inexperience with these techniques is an obstacle. It has been estimated that experience with 25 patients is needed to achieve the 4.8% false-negative rate reached by the Netherlands group, and few centers see enough patients to become proficient.
Most penile cancers are squamous cell carcinomas that demonstrate keratinization, epithelial pearl formation, and various degrees of mitotic activity. The normal rete pegs are disrupted, and invasive lesions penetrate the basement membrane and surrounding structures.
Erythroplasia of Queyrat, a red, velvety, well-marginated lesion usually occurring on the glans, is characterized by atypical hyperplastic cells that appear disoriented and vacuolated and have hyperchromatic nuclei and multiple mitotic figures. The submucosa shows capillary proliferation and ectasia with a surrounding inflammatory infiltrate rich in plasma cells.
Campos et al studied E-cadherin (cell adhesion molecules involved in the metastatic process), matrix metalloproteinase (MMP)–2, and MMP-9 (part of a group of enzymes that degrade collagen type IV in the basement membrane). In the 125 available tumor specimens and clinical records, they found that low levels of E-cadherin and high expression of MMP-9 represented independent risk factors for nodal disease.[21]
Guimaraes et al examined the value of proliferating cell nuclear antigen (PCNA) and MIB-1/Ki-67 to determine if these might serve as prognostic factors in predicting nodal metastasis. PCNA was an independent factor in univariate and multivariate analysis (RR, 2.94; 95% confidence interval, 1.1-7.7). Unexpectedly, a high expression of MIB-1/Ki-67 reactivity correlated with a decreased incidence of nodal metastases.[22] Although these markers did have predictive value, they added little to the predictive value of tumor stage and grade and the presence of vascular invasion.
Stankiewicz et al found thatKi-67 was only a moderate surrogate marker for HPV infection in patients with penile squamous cell carcinoma. Ki-67 did not show prognostic value for cancer-specific survival or overall survival.[23]
No universal staging system has been established for penile cancer. A detailed and accurate assessment of the primary tumor, including identification of regional and distant metastatic disease, is important for selecting appropriate therapy and for assessing and communicating results.
The Jackson and TNM systems are used, although the TNM system is preferable. In the Jackson system, characteristics of the primary lesion, such as size and confinement to the epidermis (superficial or invasive), are not used. The presence and extent of nodal metastases is not addressed. Histologic criteria are not used, even though the grade and extent of invasion is important.
Solsona et al presented the European Association of Urology (EAU) guidelines on penile cancer. They proposed 3 risk groups for patients with clinically negative or occult nodal metastases: low risk, stage T1, grade 1; intermediate, stage T1, grade 2 or 3; and high, T2-T3, grade 2-3.[24] Most patients with positive sentinel node biopsy findings tend to fall into the high-risk category.
Most penile cancers are low grade, but correlation between grade and survival is lacking. High-grade disease is associated with regional lymph node metastases. The strongest predictor for survival is the presence or absence of nodal metastases.
The optimum surgical margin has been reduced from the classical 2 cm to 1 cm or, in some instances, to 0.5 cm, without any adverse consequences related to cancer recurrence or survival. The advantage of a smaller margin is important because nearly 80% of penile squamous cell carcinomas are distal, presenting on the prepuce, glans, or in the coronal sulcus. These lesions can be managed with local excision and reconstruction.
The Jackson classification is as follows:
Stage I (A): The tumor is confined to the glans, prepuce, or both.
Stage II (B): The tumor extends onto the shaft of the penis.
Stage III (C): The tumor has inguinal metastasis that is operable.
Stage IV (D): The tumor involves adjacent structures and is associated with inoperable inguinal metastasis or distant metastasis.
The TNM classification of the primary tumor (T) is below. Note that the following description is devoid of N (node) and M (metastasis) descriptions. These stages simply relate the presence or absence of nodal and distant metastases.
T2: Tumor invades corpora spongiosum or cavernosum.
T3: Tumor invades the urethra or prostate.
T4: Tumor invades other adjacent structures.
The WHO histopathological classification is as follows:
Grade 1 - Well differentiated, with 33% undifferentiated cells
Grade 2 - Moderately differentiated, with 33%-66% undifferentiated cells
Grade 3 - Poorly differentiated, with more than 66% undifferentiated cells
Novara and colleagues from the GUONE Penile Cancer Project compared the prognostic accuracy of the Solsona and European Association of Urology (EAU) risk groups in predicting lymph node metastases. They studied clinical and pathology data from 175 patients with squamous cell carcinoma from 1980-2002. Both groups used variations of the pathologic features and primary tumor stage. Although both risk groups could predict the probability of nodal metastases, their prognostic accuracy was poor when the data were analyzed according to the ROC curve analysis.[25]
The primary goal in the management of penile cancer is to eliminate the malignancy while preserving a cosmetically acceptable and functional penis. Achievement of this goal depends on early diagnosis and treatment, meaning that immediate biopsies of suspicious penile lesions are necessary.
Intraepithelial neoplasms such as Bowen disease or erythroplasia of Queyrat may be treated with topical 5-fluorouracil or imiquimod[26] ; treatment with cryotherapy followed by topical imiquimod has also been reported.[27] This causes denudation of the malignant areas while preserving the skin. The use of this therapy depends on whether adequate biopsy specimens were obtained to ascertain that no invasion has occurred beyond the basement membrane.
Radiation therapy
Radiation therapy can be used as an alternative to surgery in selected patients. The psychological trauma associated with partial or complete penectomy has encouraged radiation therapists to explore various techniques of treatment for penile cancer, but, unfortunately, few patients with penile cancer are candidates for radiation therapy. One of the advantages of radiation therapy is the potential to maintain potency.
Radiation therapy has disadvantages. Squamous cell carcinomas tend to be resistant, and the high tumor dose (ie, 0.6 Gy) necessary to treat the tumor may cause urethral fistulae, strictures, penile necrosis, pain, and edema. If the cancer is infected, the therapeutic effect of the radiation is diminished, while the risk of complications is increased.
Candidates for radiation therapy include young men with small (ie, < 3 cm), superficial, exophytic lesions or noninvasive cancers on the glans or coronal sulcus. Other candidates are patients who refuse surgery or who have metastatic disease and need some form of palliative therapy.
Circumcision is recommended prior to initiating radiation therapy for cancers involving the prepuce. This allows better evaluation of the tumor stage and minimizes the morbidity associated with therapy. Morbidity includes swelling, irritation, moist desquamation, phimosis, and infection.
External beam radiation therapy
Various dose-fractionated schedules have been reported, but the most widely accepted schedule for cancers smaller than 4 cm is 4,000 cGy in 20 fractions over 4 weeks to the entire shaft of the penis. Megavoltage beams with low-energy photons are delivered by opposed ports. The primary lesion and margins are boosted with an additional 0.02 Gy.
In carefully selected patients, the local control rate varies from 60-90%. Salvage surgery can be performed if local recurrence or significant adverse effects occur.
Brachytherapy
Two techniques have been described. In one, a radioactive mold is placed over the penis and is worn by the patient for 12 hours per day for 7 days. This delivers a 0.6-Gy dose to the tumor and a 0.5-Gy dose to the urethra. The other technique involves iridium Ir 192, which is placed into the penis and is removed when the predetermined dose has been delivered.
Circumcision is recommended prior to therapy, and the tumor should be smaller than 4 cm with less than 1 cm of corporal invasion. When these criteria are met, local control rates with penile preservation range from 58-89%.
Chemotherapy
A wide variety of agents and schedules have been used to treat patients with metastases beyond the pelvic and inguinal lymph nodes. The most commonly used drugs include cisplatin, bleomycin, methotrexate, and fluorouracil. Response rates for cisplatin monotherapy range from 15-23%, and these have been largely partial responses of short duration. Bleomycin alone or combined with radiation or vincristine and methotrexate has yielded a partial and/or complete response rate of 45% in patients with minimal metastatic disease.
Although chemotherapy has been generally ineffective in treating patients with large tumor burdens, Bermejo et al reported on 10 patients with pelvic and inguinal metastases who were managed with combination chemotherapy (ifosfamide, paclitaxel, cisplatin) followed by surgery. Four patients had a complete response, one a partial response, and 5 had stable disease. The median survival in this group was 26 months, although those with 3 or fewer nodal metastases had a median survival of 48 months.[28]
Pagliaro and colleagues reported on 30 men with stage N2 or N3 (stage III or IV) penile cancer who had regional but not distant metastatic disease. These patients received 4 courses of neoadjuvant chemotherapy consisting of paclitaxel, 175 mg/m2 over 3 hours on day 1; ifosfamide 1200 mg/m2 administered over 2 hours on days 1, 2, and 3; and cisplatin 25 mg/m2 IV over 2 hours on days 1, 2, and 3. The cycle was repeated every 22 days if the neutraphil count was ≥ 1400 uL and the platelet count was >100,000.
Surgery was performed in 22 of 23 patients who completed four courses of chemotherapy. A pathologic complete response occurred in three of 22 patients (13.6%) who completed the entire protocol. Overall response rate in the 30 patients was 50%. Twenty of the 30 patients died, with a median time to progression of 8.1 months and an overall survival of 17.1 months. Seventeen deaths were attributed to progressive, metastatic penile cancer. No deaths were related to chemotherapy toxicity.[29]
The largest prospective clinical trial of chemotherapy in metastatic disease was conducted by the Southwest Oncology Group. Patients were treated with bleomycin, methotrexate, and cisplatin. They reported an overall response rate of 32.5% and a median overall survival of 28 weeks, but this was offset by a 13.9% treatment-related mortality.[30] The Pagliaro protocol was safer and more effective.
European Association of Urology guidelines note that superficial lesions (Tis, Ta, and T1a disease) can be treated with the following penis-sparing techniques[13] :
Local excision with or without circumcision
Laser therapy
Mohs micrographic surgery (for verrucous carcinoma)
Photodynamic therapy (for superficial lesions)
The standard of therapy for the primary cancer is local excision and either partial or total penectomy. The low prevalence of distant metastases, the morbidity associated with untreated local disease, the success of long-term palliation, and the survival rates, even in patients with advanced local disease, support the use of aggressive local therapy.
In patients with small penile tumors confined to the prepuce, circumcision may be adequate. Attempts to treat cancers larger than 1.5 cm have led to a recurrence rate of 50%. Margins of 2 cm have traditionally been considered necessary to reduce local recurrences, but recent evidence has shown that such wide margins may not be needed, depending on the stage and grade of the cancer. Squamous cell cancers tend to require larger margins than Bowen disease. Frozen sections at the time of surgery are often helpful, and a careful review of the specimen and permanent sections with the pathologist helps determine if the resection has been adequate.
A partial amputation is appropriate when the cancer involves the glans and distal shaft. A 2-cm margin is necessary, and attempts to limit the resection can result in a repeated surgery to remove the recurrent tumor.
Local wedge resection is feasible in some situations, but this is associated with a recurrence rate of 50%. If surgical resection via either wedge or partial penectomy does not provide an adequate margin, a total penectomy should be considered. If the amount of residual penis and urethra is inadequate to allow the patient to urinate while standing, perineal urethrostomy can be performed.
Another surgical technique is Mohs micrographic surgery (MMS), which is applicable in some patients with noninvasive disease. This involves removing the skin cancer by excising thin layers of tissue and examining them microscopically. With a surgeon experienced in MMS, the ability to remove the cancerous tissue while preserving normal structures makes this an attractive technique because the results are similar to those obtained with more radical surgery; however, more procedures are often necessary.
Shindel et al reported on 33 patients who underwent a total of 41 Mohs procedures. An average of 2.6 ± 1.4 stages was necessary. Five procedures were terminated because of positive margins or the defect size. Follow-up data were available in 25 patients at a mean time of 58 ± 63 months. Eight patients (32%) had recurrences; 7 were treated with additional MMS and one with penectomy. Two patients had tumor progression, and one died of metastatic disease.[31]
In 2001, Brandes et al reported their experience using MMS in 20 patients who had 28 cancers and 28 procedures.[32] Eighteen of these cancers were on the penile shaft and 10 were on the glans. The average size of the MMS defect was 44.9 × 30.9 mm2. Five MMS procedures were terminated because of positive margins. Four patients had tumor invading the urethra, and one had a defect too extensive to continue the procedure.
Carcinoma in situ was present in 13 patients, squamous cell carcinoma occurred in 10, and verrucous carcinoma was found in 4. The tumors were staged as Tis in 5, T1 in 2, T2 in 8, and T3 in 2. No patients had clinical evidence of nodal or other metastatic disease. All patients with T2-3 disease or high-grade histologic findings were advised to undergo lymphadenectomy, but all refused.
Skin defects were treated with primary repair or granulation in 8 patients, skin grafts were used in 8 patients, and reconstructive surgery and urethroplasty were used in 5 patients.
The average follow-up time was 40 months (range, 3-109 mo). Nineteen of 20 patients were still alive, and 1 died from an unrelated cause without evidence of cancer. Local tumor recurrence developed in 6 (30%) of 20 patients. Three of these patients had Tis, one had stage T1, one had T2, and 1 had T2 verrucous disease. Tumor progression occurred in 1 of 6 patients with stages T1-T2 squamous cell carcinoma. No patient developed nodal or other metastatic disease. Two patients had more than one recurrence, and these were treated with MMS. The authors concluded that although the recurrence rate was high (30%), the survival rate was high and the rate of progression was low.
Gulino and associates have reported on a surgical technique that utilizes the distal urethra for glans reconstruction. They have demonstrated the ability to dissect and mobilize the entire penile urethra and use the redundant portion to cover the cavernous apexes. They have reported that their patients were able to maintain functional use of their penis.[33]
Laser surgery has been used for patients with superficial benign and malignant lesions.[34] This therapy has been applied in cases of local and limited invasive disease.The types of lasers that have been used include carbon dioxide, neodymium-yttrium-aluminium-garnet (Nd:YAG), thulium-yttrium-aluminium-garnet (Tm:YAG),[35] argon, and potassium-titanyl-phosphate (KTP) lasers.
The carbon dioxide laser vaporizes tissue but penetrates only to a depth of 0.01 mm and can coagulate blood vessels smaller than 0.5 mm. The Nd:YAG laser can penetrate 3-6 mm depending on the power and can coagulate vessels as large as 5 mm. The argon and KTP lasers have less tissue penetration than the carbon dioxide laser and are rarely used.
Ozsahin and colleagues conducted a retrospective study on men who received various therapies.[36] They reviewed the medical records of 60 men with nonmetastatic invasive squamous cell carcinoma. Partial or total penectomy was performed in 27 men, brachytherapy in 8, and primary external beam radiotherapy in 21. Four patients refused radiotherapy after excisional biopsy revealed margin-positive disease. Twenty-two of the 27 men who underwent penectomy patients and 7 of the 8 who underwent brachytherapy received external beam radiation to manage recurrent local disease.
Local failure was more common in those who underwent organ-sparing procedures (56% vs 13%; P =0.008). No survival difference was found between those who underwent penectomy and those who underwent radiation therapy. The authors did not have the data to assess functional status.
This information emphasizes the need for careful follow-up in patients with penile cancer.
Lymphadenectomy
Following the treatment of the primary penile tumor, management of the inguinal lymph nodes must be addressed. The decision to resect the inguinal nodes in patients with no evidence of adenopathy, either clinically or after imaging studies, is controversial. The incidence of occult metastases in patients who have no palpable adenopathy is 20%-25%.
A study by Djajadiningrat et al of prophylactic pelvic lymph node dissection in 79 penile cancer patients without preoperative evidence of pelvic disease found that inguinal extranodal extension or two or more inguinal tumor-positive lymph nodes are predictive for pelvic tumor positivity. Patients with pelvic node involvement treated with surgery only had a poor prognosis, with 5-year disease-specific survival of 17%.[37]
Kroon et al have reported that early resection confers a survival benefit over delayed resection.[38] Because of the morbidity associated with this surgery, some urologists have contended that observing these patients is safe. The cure rate among patients with cancer-positive inguinal nodes approaches 80%. The decision to perform an inguinal lymphadenectomy often depends on the grade of the cancer and its local extent. Cancers that have invaded through the basement membrane are much more likely to have nodal metastases than superficial tumors.
A modified approach, as suggested by Bouchot et al, diminished the rate of complications by nearly 8-fold, but most of the patients (95%) had negative nodes.[39] A modified inguinal lymphadenectomy has been advocated by D’Anacona et al. In this procedure, a 5-cm incision is made over the femoral canal. They advocate sparing the saphenous vein and using the adductor longus muscle as the median border, the femoral and saphenous veins as the lateral border, and the inguinal arcade as the superior border. Their complication rate decreased from 87.5% for the radical node dissection to 38.9% using the modified technique.[40]
Bilateral lymphadenectomy is necessary when the nodes are palpable or appear abnormal on CT scanning or MRI. The lymphatic drainage extends to both inguinal areas, and the typical radical lymphadenectomy is associated with high morbidity. The nodes may be palpable because of the cancer or because of the infection associated with the primary cancer. Even when cancer has spread to 1-2 lymph nodes, cure is possible in nearly 75% with only lymphadenectomy. Almost 20% of patients with limited pelvic lymph node involvement can be cured. Negative lymph nodes do not always mean that metastases has not occurred, since 20% of patients have occult inguinal metastases and 30% of those with positive nodal disease have pelvic node involvement.
The grade and stage of the primary tumor is predictive of lymph node status. Patients with high-grade and high-stage cancers are likely to have nodal disease. Tabatabaei and McDougal found that 80%-100% of these patients had positive nodes, compared with 24% of patients with well-differentiated cancer. They also found that 61%-75% of patients with T2 cancers had nodal metastases, compared with 5%-10% of those with T1 disease. This study also emphasizes that nodal metastases occur in a significant number of men, even those with low-stage, low-grade cancer.[20]
The various techniques that have been described to identify the sentinel lymph node have improved dramatically. This diagnostic tool has been shown to be predictive of nodal metastases in the other inguinal nodes but experience with at least 25 patients is necessary to achieve accurate results and few centers see this many patients. Combining the surgical technique advocated by D’Anacona with sentinel node biopsy should further reduce the morbidity associated with this procedure.
Sentinel node biopsy or limited inguinal node dissection superficial to the fascia lata has been advocated. Resection of the sentinel inguinal lymph node is more controversial because many investigators have reported that the predictive information obtained from this procedure is too limited and is often inaccurate in predicting the extent of the cancer. Others have reported that this procedure offers a high degree of accuracy in identifying the sentinel node and, in those with negative nodes, the morbidity associated with an inguinal lymphadenectomy can be avoided. Superficial dissection has been used for patients with no palpable nodes, but the procedure is extended to the deep fascia and femoral canal if any nodes are positive for cancer.
The value of sentinel node biopsy was evaluated by Horenblas et al in 2001 in 69 patients with clinical stage T2-3 squamous cell carcinoma.[41] These patients had a combination of lymphoscintigraphy and intradermal patent blue dye injected around the tumor. The sentinel nodes were identified and resected.
Images of 158 sentinel nodes were obtained in 118 inguinal areas. Lymphatic drainage was bilateral in 55 patients (80%), unilateral in 12 (17%), and absent in 2 (3%). The sentinel nodes were identified on images in 117 of the 118 inguinal regions. Discrepancies between the images and the surgical findings were encountered in 26 patients (38%). The sentinel nodes were blue and radioactive in 73% of patients and radioactive alone in 27%.
Two of 5 patients with unilateral pN1 disease had a contralateral cancer-positive sentinel node. Metastases were found in other lymph nodes in three patients who had a cancer-positive sentinel node. Unilateral lymph node metastases were identified in two patients who originally had cancer-negative sentinel nodes. In one of these patients, the pathologist found a micrometastasis upon review of the original specimen.
Also in 2001, Izawa et al conducted a similar study in 30 patients. They used isosulfan blue dye and lymphoscintigraphy to evaluate the sentinel nodes in patients with T1-3 squamous cell carcinoma. Preoperative and intraoperative lymphoscintigraphy were performed in 14 patients. They found that at least one lymph node was either blue or had detectable gamma activity in 28 patients. Eleven inguinal fields in nine patients had metastases, five of which were not palpable.[42]
By using preoperative lymphoscintigraphy and intraoperative use of the gamma ray probe (dynamic sentinel node biopsy) as developed by Horenblas et al[43] and confirmed by Perdona et al,[44] there is little reason not to evaluate the inguinal nodes. The results are similar to those provided by standard node dissection, but the morbidity is minimal. Still, Novara and associates caution that, because of the potentially high morbidity associated with inguinal lymphadenectomy, the routine use of this surgery cannot be supported in every patient.[25]
Lont et al reported that the extent of inguinal node involvement is predictive of the presence of pelvic node disease. Patients with 1-2 positive nodes who have no extracapsular growth and no poorly differentiated cancer do not require pelvic node dissection and have a 90% 5-year survival rate.[45]
Tobias-Machado et al used a minimally invasive endoscopic procedure called video endoscopic inguinal lymphadenectomy (VEIL) for removing inguinal nodes in 10 patients, all with nonpalpable nodes.[46] VEIL, a video endoscopic technology, was used to treat the nodes on one side, and standard open lymphadenectomy was performed on the other. The complication rate conferred by VEIL was much lower. This is another example of new surgical techniques that will be effective and will result in less morbidity.
Yuan et al used VEIL via a hypogastric subcutaneous approach (VEIL-H) in 37 patients with penile cancer, and found that VEIL-H was as effective and safe as VEIL using a leg subcutaneous approach, which was used in 35 patients. Moreover, use of VEIL-H in cases that require laparoscopic pelvic lymphadenectomy can spare the patient from operation on both the limb and abdomen.[47]
The indications for pelvic lymphadenectomy have not been clearly delineated in the absence of evidence for pelvic lymphadenopathy but imaging studies and sentinel node biopsy can help in identifying the 30% of patients with micrometastatic disease. When two or more inguinal nodes contain cancer, the probability of pelvic node involvement is increased and pelvic surgery is advocated even if the disease is micrometastatic. Patients with cancer-negative inguinal lymph nodes rarely have pelvic node involvement and pelvic lymphadenopathy is unnecessary.
The treatment and outcome of 161 patients with node-positive cancer was reported by Graafland et al.[48] They found that 26 of these patients had an inguinal recurrence. Most of these recurrences were identified in a median of 5.7 months from the initial inguinal lymphadenectomy, and these patients had a poor prognosis. Patients with three or more positive nodes had the worst prognosis.
After a short course of antibiotic therapy, surgery for the primary tumor can be completed. This allows for better staging and a chance for any lymph nodes enlarged secondary to infection to heal. No other specific study or preparation is necessary.
If biopsy is performed, adequate depth is important to allow the pathologist to stage the depth of the tumor and to determine if any invasion has occurred. Patients who undergo local excision or partial or total penectomy should have a 2-cm tumor-free margin. Serial frozen sections are used to achieve this goal. The local recurrence rate is significant, and attempts to salvage a portion of the penis often lead to a second surgery.
When only a short segment of penis is retained, urethral reconstruction can be attempted to allow the patient to stand and direct his stream during urination. If the penis is too short, the patient may be better served with a perineal urethrostomy.
Several weeks following removal of the primary tumor, the inguinal lymph nodes can be resected if the surgeon determines that this procedure is appropriate. Several techniques have been described for this procedure. An inguinal incision provides good exposure for the superficial lymph nodes, but exposure of the femoral canal is difficult. An incision extending across the inguinal crease allows good exposure for both areas, but the large flap is more prone to complications. Some surgeons stage these bilateral procedures, but most complete the surgery in a single sitting. Adequate wound drainage is important because a large amount of serous fluid usually collects.
Infection, undrained serous collections, ischemia and necrosis of the inguinal skin flaps, and peripheral edema are postoperative complications that should be prevented, if possible. Preservation of the dermis, Scarpa fascia, and saphenous vein help reduce the likelihood of these problems. Phlebitis and pulmonary embolism are additional concerns. Compression devices on the lower extremities and low-dose heparin therapy have been advocated.
Mortality associated with this procedure has led to attempts to perform penile surgery and lymphadenectomy at the same sitting. Sepsis has been the cause of death. The current mortality rate is less than 1% by separating these procedures. The healing process is slow, and patients can expect to have limited activities for 6-8 weeks. Peripheral edema may be a permanent condition.
Follow-up in patients with penile cancer is necessary to evaluate healing following the use of medicines applied to the tumor and following surgery, laser therapy, or radiation therapy. The frequency of follow-up visits depends on the therapy, but long-term observation is necessary to detect any areas of tumor recurrence.[49]
Tumors can recur locally or distally. Physical examination can be used to detect local recurrences or recurrence in the inguinal lymph nodes. Chest radiography and CT scanning of the abdomen and pelvis can help detect recurrences in the lungs or lymph nodes.
For patient education resources, see the Men's Health Center and Cancer and Tumors Center, as well as Cancer: What You Need to Know.
Few surgical complications are associated with excision of the primary tumor or partial or complete penectomy. They include infection, edema, or urethral stricture if a new urethral meatus must be constructed.
Complications associated with inguinal node dissections are more common and are generally associated with more extensive dissections. Early complications include wound infection, seroma, skin flap necrosis, phlebitis, and pulmonary embolus. Late complications include lymphedema of the scrotum and lower extremities. Mortality after node dissection has been reported only when the surgery was performed when the nodes were infected, resulting in sepsis.
Complications associated with radiation therapy are primarily observed when tumors larger than 4 cm are treated. Complications include urethral strictures, which are reported in up to 50% of the patients; urethral fistula; penile necrosis; edema; and penile pain. Surgery following radiation therapy has been necessary in 20-60% of the patients.
In an effort to predict cancer specific mortality, several nomogams have been developed. These were reviewed by Thuret et al.[50] They studied the Kattan nomogram and felt that it could not be used in routine clinical practice because of its emphasis on highly detailed pathological variables. Only 175 patients were used to construct the nomogram, and its accuracy was 74.7%. Zini et al developed a simpler tool by studying 856 patients.[51] Only 2 variables were used, including SEER stage and tumor grade. This gave an accuracy of 73.8%. Thuret et al used the staging system developed by the American Joint Committee on Cancer combined with tumor grade and found that this was the simplest and most accurate method (80.9%) to predict cancer specific mortality.
The prognosis of penile cancer is primarily related to the presence or absence of inguinal node metastasis. Untreated patients with inguinal metastases rarely survive 2 years. Of those with clinically palpable adenopathy and histologically proven metastases, 20-50% are alive at 5 years following inguinal lymphadenectomy. The results are even better when the extent of the nodal involvement is considered. An 82-88% 5-year survival rate has been reported when only 1-3 lymph nodes are involved. Lont et al reported that patients with 1-2 involved inguinal nodes that do not contain poorly differentiated cancer have a 90% 5-year survival rate. When the nodes are positive, the overall recurrence rate is 80%, and the 5-year survival rate is 10%-15%.[45]
Radiation therapy in a select group of patients with small superficial lesions has been successful in a large number of patients. Control rates of 90-100% have been reported. In a group of 10 patients treated at Memorial Sloan-Kettering Cancer Center by electron beam therapy, all were effectively treated as determined by negative findings on posttreatment biopsy specimens. The most common complication was urethral stricture, which occurred in 4 patients. Nine of the patients retained sexual function.
In 2001, Novak and Dvoaeek used interstitial brachytherapy with iridium wires to treat 28 patients with squamous cell carcinoma. Six patients had Tis, 11 had T1N0, and 4 had T2N0. The prescribed dose of 0.6-0.65 Gy was delivered in 2-7 days. Local tumor control was evident in all patients at a mean follow-up of 65 months. Cancer has not recurred.[52]
Hegarty et al reported on a prospective series of 100 patients treated at one institution according to EAU guidelines. Of men with palpable nodes, 72% had metastatic disease, but 18% of those who did not have palpable adenopathy also had metastases. The tumor grade was more predictive for nodal disease and survival than T stage. The 3-year disease-specific survival rates for N0, N1, and N2 disease were 100%, 100%, and 73%, respectively. The survival rate associated with N3 disease was 67%, and the overall survival rate was 92%. The median survival rate among those with metastases was 3 months. The EAU guidelines were deemed limited in their ability to predict micrometastatic disease. Although early lymphadenectomy was beneficial in those with nodal disease, 82% of patients underwent unnecessary prophylactic lymphadenectomy.[53]
Current techniques, such as intensity-modulated radiation therapy, will probably become more effective and produce fewer adverse effects.
The major controversy regarding penile cancer is the indication and extent of inguinal lymphadenectomy. Patients with clinically palpable or radiologically demonstrable lymph nodes after an adequate course of antibiotic therapy should undergo surgery. Depending on the size and extent of the apparent nodal involvement, a decision must be made regarding a superficial node dissection, which is associated with less morbidity, or a full inguinal node dissection, which includes the nodes in the femoral triangle.
In patients with clinically negative nodes, an argument can be made for observation. Because up to 80% of patients with inguinal node metastases can be cured with lymphadenectomy, monitoring patients and withholding surgery until metastases become evident may be possible with patient compliance. However, experience indicates that superficial dissections in patients with microscopic metastases result in few complications and limited morbidity.
In 2001, Slaton et al examined a group of 78 patients with squamous cell carcinoma in an effort to identify prognostic factors that would help predict extranodal metastases and select candidates for adjuvant therapy.[54] They identified 78 patients who had undergone inguinal lymphadenectomy, 42 of whom had nodal metastases. They found that the presence of bilateral nodal metastases, which occurred in 16 (38%) of 42 patients, and extranodal extension, which was found in 25 (60%) of 42 patients, were independent predictors for progression. They suggested that such patients be considered candidates for adjuvant therapy.
In the future, patients with superficial penile cancers can expect effective treatment with either surgery or radiation therapy and can expect to retain a functioning penis. Those requiring more extensive resections or penectomy can undergo penile reconstruction, which has produced acceptable results. The techniques available to identify and remove the sentinel nodes, as well as using a modified lymphadenectomy, should eliminate the need for observation, reduce the need for extensive inguinal lymph node dissection, and decrease the morbidity of this procedure.
The ability to effectively manage metastatic disease with chemotherapy has been disappointing, but the results of studies using molecular targeting agents in combination with chemotherapy offers hope.
The following organizations have published guidelines for the diagnosis and management of penile cancer:
2017 National Comprehensive Cancer Network (NCCN)[55]
2013 European Society of Medical Oncology (ESMO)[56]
2014 European Association of Urology (EAU)[13]
Risk Factors
The NCCN guidelines delineate the following risk factors for the development of penile cancer[55] :
Phimosis
Balanoposthitis
Chronic penile inflammation
Penile trauma
Lichen sclerosus
Smoking
HIV or HPV infection
Poor hygiene
Lack of neonatal circumcision
Diagnosis
All three guidelines concur that diagnosis begins with a complete physical exam that records the morphological and physical characteristics of the lesion, including the following:
Diameter of the lesion(s) or suspicious areas
Location(s) on the penis
Number of lesions
Whether the lesion(s) are papillary, nodular, ulcerous, or flat
Relationship with other structures, including submucosal, urethra, corpora spongiosa, and/or corpora cavernosa.
Accurate histological diagnosis with a punch, excisional, or incisional biopsy and staging of both the primary tumour and regional nodes are required before the appropriate therapy can be selected.[13, 55, 56]
Treatment
The treatment recommendations from all three guidelines are outlined in the table below.[13, 55, 56]
Table. Summary of Guideline Treatment Recommendations
The goals of pharmacotherapy are to reduce morbidity and prevent complications. Topical 5-fluorouracil can be used for penile intraepithelial neoplasia. Chemotherapy regimens are used to treat patients with metastases beyond the pelvic and inguinal lymph nodes.
Clinical Context:
Platinum coordination compound that inhibits DNA synthesis; cross-links and denatures strands of DNA; disrupts DNA function by covalently binding to DNA bases; can also produce DNA intrastrand cross-linking and breakage
Clinical Context:
Inhibits dihydrofolic acid reductase; inhibits purine and thymidylic acid synthesis, which in turn interferes with DNA synthesis, repair, and cellular replication; cell cycle specific for S phase of cycle
Stanley A Brosman, MD, Clinical Professor, Department of Urology, University of California, Los Angeles, David Geffen School of Medicine
Disclosure: Nothing to disclose.
Specialty Editors
Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Chief Editor
Bradley Fields Schwartz, DO, FACS, Professor of Urology, Director, Center for Laparoscopy and Endourology, Department of Surgery, Southern Illinois University School of Medicine
Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: AUA Journal of Urology<br/>Serve(d) as a speaker or a member of a speakers bureau for: Cook Medical; Olympus, .
Additional Contributors
Gamal Mostafa Ghoniem, MD, FACS, Professor and Vice Chair of Urology, Chief, Division of Female Urology, Pelvic Reconstructive Surgery, and Voiding Dysfunction, Department of Urology, University of California, Irvine, School of Medicine
Disclosure: Serve(d) as a speaker or a member of a speakers bureau for: Astellas<br/>Received research grant from: Uroplasty/Cogentix, Astellas, Allergen.
Acknowledgements
Dan Theodorescu, MD, PhD Paul A Bunn Professor of Cancer Research, Professor of Surgery and Pharmacology, Director, University of Colorado Comprehensive Cancer Center
Dan Theodorescu, MD, PhD is a member of the following medical societies: American Cancer Society, American College of Surgeons, American Urological Association, Medical Society of Virginia, Society for Basic Urologic Research, and Society of Urologic Oncology
Cancer Facts & Figures 2018. American Cancer Society. Available at https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2018/cancer-facts-and-figures-2018.pdf. Accessed: January 5, 2018.
Brandes SB, Sengelmann R, Hruza G. Mohs micrographic surgery for penile cancer: management and long term follow-up [abstract 708]. J Urol. 2001. 165:172.
Slaton JW, Huang SF, Levy DA. Lymph node-positive squamous penile carcinoma: Extent of nodal involvement predicts 3-year disease-free survival [abstract 712]. J Urol. 2001. 165:173.
[Guideline] NCCN Clinical Practice Guidelines in Oncology: Penile Cancer. National Comprehensive Cancer Network. Available at https://www.tri-kobe.org/nccn/guideline/urological/english/penile.pdf. Version 2.2017 — March 10, 2017; Accessed: January 3, 2018.
Leijte A, Graafland N, Valdes R. Prospective evaluation of hybrd 18F-fluorodeoxy-glucose positron emission tomography/computed tomography in staging clinically node-negative patients with penile carcinoma. BJU Int. January 2009. 104:640-5.
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