Penile Cancer

Introduction

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, the most common penile malignancy, behaves similarly to squamous cell carcinoma in other parts of the skin. Metastasis, which is possible with this type of carcinoma, is often lethal.

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 receive various salves and antibiotics from their primary care physicians before they see a 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.

History of the Procedure

Surgery is the traditional therapy for penile cancer. Superficial penile carcinoma is typically managed with local resection, while invasive disease is treated with partial or total penectomy and bilateral lymphadenectomy. In recent years, the diagnostic techniques, surgical procedures, radiotherapy management, and local and systemic chemotherapy used to detect and treat penile cancer have been greatly improved. In addition, techniques of penile reconstruction have undergone major improvements, meaning that cancer eradication can be coupled with good cosmesis.

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 such cases, radiation therapy to the penile tumor is applicable. Palpable inguinal lymph nodes should prompt surgical evaluation of these nodes.

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 bilateral inguinal lymphadenectomy, which is associated with a high degree of morbidity.

In the past, it was thought that an excisional margin of 2 cm around the cancer was necessary, but, with improved histopathology techniques, a margin of 0.5-1 cm may be sufficient. In addition, although a 4- to 6-week waiting period was once believed to be necessary, tumor excision and lymph node assessment can be performed in the same setting.

Problem

Penile tumors can originate anywhere on the penis, but most are found on the glans (48%) and prepuce (21%). Tumors may initially form on the corona of the glans and spread superficially across the glans and into the prepuce. The etiology of these cancers may be related to chronic exposure to carcinogens contained in smegma that collects within the prepuce. Men who have been circumcised rarely develop penile cancer.

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, but, when it invades the deeper tissues, the cancer has ready access to lymphatics and blood vessels.

Frequency

Penile cancer is rare in Western countries and is reported in approximately 1000 men each year. 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 Brazil, the age-adjusted incidence of penile cancer is 8.3 cases per 100,000 population. In Uganda, this is one of the most commonly diagnosed cancers, with 1% of men developing the disease by age 75 years.

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 has been decreasing over the past 3 decades. 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).

Penile cancer is rare in circumcised men, particularly if they were circumcised as a neonate. 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.

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.

Etiology

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.3

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.



Pathophysiology

Penile cancers usually begin as small lesions on the glans or prepuce. 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.

Penile carcinoma follows a relentless and progressive course that proves to be fatal in most untreated patients within 2 years. Spontaneous remission has not been reported.

Presentation

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. Malignancy may appear as a shallow erosion or a deep ulceration with rolled edges. Because most of 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 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.

Lichen sclerosis, 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.

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

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.

Relevant Anatomy

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.

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