Penile cancer is an uncommon malignancy. Patients typically present with low-stage lesions, with 3% to 4% presenting with metastatic disease.1,2 Because of the intimate nature of the disease, many men will delay diagnosis and as many as one third of cases manifest with locally or regionally advanced disease. Lesions rarely arise from the shaft of the penis and in 98% of cases originate from the glans, prepuce, or corona.³ From here they progress to local invasion of the cavernosa and metastasize early to the inguinal lymph nodes. The most important factor for long-term survival is disease stage at the time of diagnosis, followed by histologic grade of the tumor. Although penile cancer is a very treatable disease with good prognosis when detected early, advanced penile cancer is associated with poor survival and ineffective systemic treatment options.

Epidemiology

Penile cancer is exceedingly rare in North America and Scandinavia and is far more prevalent in South America, Asia, and Africa. In industrialized nations, penile cancer affects between 1 and 9 per 1,000,000 men. In less developed nations such as sub-Saharan Africa and parts of South America it represents as many as 10% of male malignancies.⁴ Incidence in Africa and Asia ranges between 10% and 20%.⁵ Possibly because of improving worldwide health conditions and increasing prevalence of circumcision, the incidence of penile cancer has been decreasing in recent years.⁶

Etiology and Biological Characteristics

There are many cited risk factors for penile cancer. Risk factors include phimosis, human papilloma virus (HPV) infection, genital warts, cigarette smoking, and trauma or balanitis.³ Twenty-five percent to 60% of penile cancer cases are associated with phimosis.^1,7 Phimosis is a known risk factor for invasive carcinoma (OR = 16), but not for carcinoma in situ (CIS).⁸ Circumcision performed in the first year of life virtually eliminates the risk of invasive penile carcinoma. Older studies have shown that the risk of penile cancer is the same in men who are uncircumcised as in those circumcised after the first year of life.⁹ Cigarette smoking is a risk factor (OR = 1.44), especially in long-term smokers or those who smoke more than 10 cigarettes daily (OR = 2.1). Chewing tobacco (OR = 3.1) is a greater risk than cigarette smoking.¹⁰ History of trauma is a risk factor for CIS and invasive cancer, as is balanitis. Likewise, men with a personal history of anal or genital warts are at elevated risk for the disease (OR = 3.7).^8,9

In recent years, infection with human papilloma virus (HPV) has been a subject of investigation as a major etiologic factor for penile cancer. HPV is highly prevalent worldwide in men, with up to 70% of all males infected. Only 10% of men are infected with known oncogenic strains of HPV, however. Men with invasive penile cancer have a 24% to 62% rate of infection with high-risk HPV, whereas controls have a 12% rate. As many as 95% of penile cancers are associated with HPV-16 infection.3,11

Evidence suggests that oncogenesis of penile cancer falls into two pathways—HPV associated and non–HPV associated. HPV associated tumors are much more likely to be of the basaloid or warty subtypes.¹² These tumors are similar in nature to tumors arising from the mucosa of the anal and oropharyngeal regions and most frequently occur on the glans.¹² Non–HPV-associated cancers tend to be keratinizing squamous cell carcinoma (SCC), similar to what is seen on nongenital skin and tends to be well differentiated. Up to 30% of these tumors may contain HPV DNA but it is uncertain if HPV plays an etiologic role in these tumors. Non–HPV-associated cancers tend to be associated with chronic inflammatory skin conditions such as lichen sclerosus.

Little is known about molecular alterations common in penile carcinoma owing to its rarity as well as its association with concomitant infection and inflammation. Observations have been made regarding certain DNA copy number gains (8q24, 16p11-12, 20q11-13, 22q, 19q13, 5p15) and deletions (13q21-22, q21-32).¹³ Increasing aneuploidy appears to be associated with a high risk of invasive cancer.¹⁴ E6, the oncogenic product of HPV, is known to bind to p53, causing suppression of its normal cell cycle inhibitory function. This results in increased cell proliferation, decreased apoptotic control, and loss of differentiation. As such, the relationship of p53 expression to penile cancer prognosis has been investigated with contradictory results. Alternately, a positive or negative relationship between p53 expression and HPV infections has been seen. It has been suggested that late alteration of p53 may be associated with disease progression and metastasis.¹⁵

Other HPV-associated pathways and genes that have been investigated include p16^INK4a/cyclin D/retinoblastoma, c-RAS, MYC, PIK3CA, PTEN, BRAF, HRAS, KRAS, and NRAS. The general observation is that larger and more advanced tumors are associated with mutations in more of these pathways. HPV18 has been found in metastatic tumor linked to p53 and c-ras mutation.¹⁵ DNA methylation has been evaluated in penile cancer and hypermethylation found in DAPK, HIT, MGMT, p14ARF, p16INK4a, RAR-B, RASSF1A, and RUNX3.¹⁶ In another study, methylation of TSP-1 was associated with poorly differentiated tumor and increased risk of vascular invasion.¹⁷

Prevention and Early Detection

Penile cancer is a disease with relatively low prevalence in the industrialized world, so formal preventive programs have not been enacted. Discussion regarding prevention of penile cancer centers around the role of neonatal circumcision and prevention of oncogenic HPV.

Circumcision is a divisive topic in the medical literature, with strong proponents both for and against routine circumcision. Many political authorities are withdrawing public funding for circumcision based on evaluation of cost-effectiveness in preventing disease. Also, opponents of circumcision argue that the procedure is primarily cosmetic and is performed without the assent of the patient.¹⁸ A recent meta-analysis suggests a significant decrease in the likelihood of developing invasive penile cancer in patients who underwent childhood or adolescent circumcision (OR = 0.33).¹⁹ Also, regardless of the direct goal of preventing penile cancer, circumcision reduces the transmission of high-risk HPV by up to 35% and of HIV by up to 60%.¹⁹

Although HPV appears to have a significant role in the development of penile malignancy, vaccination of men against HPV for penile cancer prevention is considered unreasonable because of the low incidence of penile cancer. Many other cancers in both men and women, however, are associated with high-risk HPV, and some groups have proposed increased efforts to vaccinate against HPV on the basis of herd immunity.²⁰ In 2011, the Advisory Committee on Immunization Practices recommended immunization of all males of age 11 or 12 with the HPV4 vaccine on the basis of risk reduction for anal, pharyngeal, and penile cancer and to prevent genital warts.²¹

Pathology and Pathways of Spread

There are many dermatologic processes that manifest on the penis, most of which are associated with benign disease. It is a particular challenge to healthcare providers to be vigilant for a low-incidence disease such as penile cancer in the background of a diverse range of visible dermatologic manifestations that may be benign. It should be recognized by providers that skin lesions of the penis can be quite disturbing to patients, but at the same time embarrassment often causes them to avoid seeking treatment. Therefore when a patient has a complaint about a penile skin lesion, a diligent effort should be made for diagnosis.

Leukoplakia

Leukoplakia is a disease seen primarily in diabetic men. Perimeatal blanched plaques and/or scaled areas are seen that extend into the urethral meatus. Microscopically the appearance is consistent with acanthosis, parakeratosis, and hyperkeratosis. Leukoplakia can be seen in proximity to malignant lesions and is a response to recurrent inflammation or irritation. It is not, in and of itself, proved to be a premalignant condition. Because of its association with comorbid malignancy, however, treatment is excision or biopsy followed by close follow-up. Up to 20% of men with leukoplakia have been shown to eventually develop penile cancer.²² Extensive lesions have been treated successfully with bleomycin.²³

Penile Lichen Sclerosus (et Atrophicus)

Widely known also as balanitis xerotica obliterans (BXO), lichen sclerosus et atrophicus (LSA) of the penis is a disorder primarily affecting the glans, prepuce, and urethra. This is seen almost exclusively in uncircumcised boys and men and circumcision is often curative. Although most often a complaint of middle-aged men, epidemiological data support diagnosis at any age in males from 2 to 90.²⁴ BXO manifests as ivory-colored sclerotic plaques on the glans and inner prepuce. These are often pruritic in nature. They are grossly and histologically distinct from leukoplakia. Microscopically there is marked fibrosis, epidermal atrophy, interface dermatitis, and dermal edema. Patients may experience painful erections—particularly a burning sensation when the phallus is engorged, phimosis, or dysuria. In advanced disease, sexual intercourse can cause fissuring and blistering.

Penile LSA may play a role in the development of SCC. Malignancy has been observed in 2.3% to 5.8% of patients.²⁵ Etiologic associations of BXO include HPV, particularly serotype 16, spirochetes, and atypical mycobacteria.²⁴ First-line treatments for BXO are topical steroids and/or circumcision, though it is not known whether treatment for BXO has a preventative role for the development of penile SCC.

Carcinoma In Situ

CIS of the genitalia is named differently depending on the location of the lesion. A sharply demarcated, shiny, raised erythematous plaque of the nonkeratinized glans or mucosal surface of the prepuce is called erythroplasia of Queyrat (EQ). Bowen disease (BD) describes the same histologic entity presenting as red scaling patches on the keratinized genital surfaces such as the penile shaft, scrotum, or perineum.26,27 Unlike BXO, these lesions are definitely considered premalignant or malignant because of a progression rate to SCC of 10% to 30%.²⁸ EQ and BD tend to be diseases of older men with the most common diagnosis in the fifth decade. Bowen disease typically involves the epithelial cell layers of hair follicles with a very similar histologic appearance to EQ. When found on the penis, this lesion often appears as a scaling plaque without notable erythema and signifies the presence of CIS. Only about 1 lesion in 10 will progress to invasive carcinoma, a rate that is comparable with EQ.

Histologically, these lesions demonstrate diffuse changes throughout the squamous epithelial cell layers including keratinocyte hyperplasia, nuclear atypia with many mitoses, proliferation of enlarged hyperchromatic cells, multinucleated cells, and loss of polarity within most cells. Presence of inflammatory cell infiltration and increased density of microvasculature is common. Similar to invasive penile carcinoma, links to HPV infection have been investigated and have shown association with many of the same viral strains.29,30 A small study of EQ identified DNA from HPV type 8 in every sample of penile CIS, whereas this viral DNA was not identified in any samples of BD lesions. In addition, HPV type 16 was found in more than 80% of BD samples.³⁰

Bowenoid Papulosis

Bowenoid papulosis (BP) is markedly different from EQ and BD in presentation, demographics, and clinical course. Men who have BP are much younger than EQ and BD patients, with a mean of about 30 years of age.³¹ These lesions are groups of scaling, erythematous papules typically seen on the keratinized skin of the penile shaft. Histologically, the cellular morphology mimics CIS, but the keratinocytes tend to be slightly more differentiated than those seen in CIS. In addition, histologic sections of bowenoid papules demonstrate that the more atypical-appearing cells tend to be found among the top epithelial cell layers and in the upper portion of the sweat glands. Because of histologic similarities, a physician must combine the clinical presentation and the histologic findings in order to confidently arrive at the diagnosis.²⁶

The etiology of BP is still unclear. Investigations into the viral etiology of BP have provided increasing evidence to support a link to HPV subtypes (6, 11, 18, 42, 43, 44).³² Progression of BP to SCC has been reported in lesions with high-risk HPV strains.³³ There have been other reports of malignant conversion as well.³⁴ Spontaneous regression has also been reported.³⁵

Recently, treatment for BP has consisted primarily of topical therapy including 5-FU, imiquimod cream, and cidofovir in immunocompromised patients.³⁶ Historically, these lesions have been surgically excised and results with laser and other forms of ablative therapy have been mixed.³⁷ Often, topical and extirpative therapy can be used in combination with good results.

Buschke-Lowenstein Tumor (Verrucous Carcinoma)

Commonly known as verrucous carcinoma or giant condyloma acuminatum, Buschke-Lowenstein (BL) tumors are very similar in appearance to benign condyloma venereatum. Unlike their benign counterparts, BL tumors tend to invade tissue and cause significant damage. The rete pegs of these lesions are often seen penetrating deeply into surrounding tissue. This aggressive behavior is in contrast to the well-differentiated cells that compose BL tumors; cellular anaplasia is very atypical in these specimens. A viral etiology appears to play a role in the development of BL tumors. Investigators have found associations with HPV strains 6 and 11.³⁸ Despite the local tissue destruction commonly found with these tumors, metastatic progression of the tumor does not occur. Therefore local control is the primary objective and may require partial or total penectomy. To date, no large-scale trials of topical or radiation therapies have shown efficacy. A report of BL tumor regression after treatment with intralesional injection of interferon-alpha suggests that local nonexcisional therapy directed at the viral etiology may hold promise for future nonexcisional treatment. Use of systemic chemotherapy with bleomycin, methotrexate, and cisplatin has been reported to achieve regression of BL lesions. However, given the toxicity of these agents, this approach is not routinely advocated for this disease.^39,40 CO₂ laser ablation has also been shown to have a role in local control of this disease.⁴¹

Nonsquamous Malignancy

Penile tumors not arising from squamous epithelium are rare, comprising fewer than 5% of tumors. The most common nonsquamous malignancy is sarcoma. Other known malignancies include melanoma, basal cell carcinoma, and lymphoma. With the increasing prevalence of HIV and AIDS, the incidence of Kaposi sarcoma has risen; nearly 20% of patients with AIDS-related Kaposi sarcoma have a lesion on the genitals.⁴² Most of these appear on the scrotum or perineum and only a small percentage of these patients present with a penile lesion. The gross appearance of Kaposi sarcoma is of erythematous nodules, with sharp margins found most often on the glans penis. Standard treatment includes local excision, laser ablation, or palliative radiation.⁴³

Basal cell carcinoma of the penis most often is found on the penile shaft, with only a small fraction of cases reported on the prepuce or glans.⁴⁴ Appearance of this tumor on the scrotum or perineum is less common. The typical appearance of basal cell carcinoma of the penis is a well-circumscribed lesion with clear borders and central pitting. Given the slow rate of growth and lack of metastasis, local excision is often curative.⁴⁴

In contrast, melanoma of the penis carries a very poor prognosis. Almost 40% of patients present with regional lymph node metastasis.⁴⁵ Two of every three lesions are found on the glans. Wide local excision with a 3- to 5-cm margin is the treatment of choice for lesions less than 1.5 mm Breslow depth.⁴⁵ Bilateral inguinal lymph node dissection has been the standard of care of lesions more than 1.5 mm thick.⁴⁵

Far more unusual tumors have been cited in sporadic case reports. These tumors include penile schwannoma, plexiform neurofibroma, vascular hemangioendothelioma, leiomyosarcoma, rhabdomyosarcoma, epithelioid sarcoma, Ewing sarcoma, mucoepidermoid carcinoma, and synovial sarcoma.46–52 Generally, the prognosis of these tumors is similar to the outcomes of these malignancies when identified elsewhere in the body.

Extramammary Paget disease is a very rare penoscrotal neoplasm, and distinguishing this lesion from EQ or BD is clinically impossible. Histologically, it is diagnosed by the presence of large, clear staining cells with hypochromatic nuclei within the epidermis called Paget cells. This disease is seen in older men and appears as a well-demarcated, erythematous, eczematous lesion. Metastasis to regional lymph nodes occurs very rarely. It is considered the etiology of adenocarcinoma in situ of the epidermis. This entity arises from pluripotent intraepidermal cells undergoing malignant transformation during apocrine differentiation.⁵³ Clinical suspicion for underlying genitourinary malignancies should be very high because 16% to 33% of patients with penoscrotal Paget disease have concurrent internal genitourinary carcinoma.^54,55 Historically, patients with extramammary Paget disease were evaluated extensively for occult pulmonary and gastrointestinal malignancy. However, retrospective analysis of patients with penoscrotal Paget disease reveals that 92% of those with associated malignancy have genitourinary pathology.⁵³ Treatment generally consists of wide local excision that typically requires coverage of the defect with skin grafting or tissue flaps.⁵³ Mohs micrographic surgery has been recommended as the therapy of choice because of the very high incidence of positive margins using standard surgical techniques.⁵⁶ Nonexcisional treatments have been described, but these isolated reports do not provide enough data to evaluate for efficacy.⁵⁷ Recurrence in these patients is very common and close follow-up is recommended.

Metastatic Tumors

Secondary tumors of the penis from metastatic nonurologic primary malignancies are rare, with less than 500 reported cases.⁵⁸ Metastatic tumors to the penis are most often found in the presence of advanced systemic carcinoma. The index of suspicion for penile metastasis should be high in patients who have a known malignancy and subsequently suffer from priapism or complain of a new penile lesion. The common presentation of a penile metastasis is multiple nodules along the penile skin with occasional ulceration that may have the appearance of a syphilitic chancre. These lesions typically are not painful. Almost 50% of patients will have extensive involvement of the corpora cavernosa, which accounts for the common presentation of priapism.⁵⁹

The primary tumors that frequently metastasize to the penis are prostate, bladder, renal cell, testis, and rectal carcinoma.58,59 The prognosis is dismal with less than 6 month survival for these patients. Treatment should be with systemic chemotherapy or local radiotherapy with surgical treatment reserved for palliation.⁶⁰

Primary Squamous Cell Carcinoma

Over 95% of primary penile tumors are SCC. Unfortunately, more than half of patients will have invasive disease at the time of diagnosis.³ This malignancy can arise anywhere on the penis, but fewer than 20% of tumors originate proximal to the foreskin and glans. Fifty percent of tumors arise on the glans itself, 20% on the foreskin, and 10% involve both the glans and foreskin.³

Metastasis of penile SCC occurs first in the superficial inguinal lymph nodes, with risk of lymphatic spread related directly to tumor size and grade.⁶¹ The lymphatic drainage is unpredictable, meaning that it cannot be accurately assessed based on tumor location which side lymph nodes might be involved, necessitating treatment of both inguinal lymph node beds when indicated. Small tumors of the glans and prepuce are very rarely metastatic at presentation; however, tumors involving 75% of the penile shaft or more are almost always metastatic.⁶²

Penile SCC is graded using the Broder scale to quantify the degree of tumor cell differentiation.^62a Half of all lesions are either grade I or II at diagnosis. Histologically, these tumors have a hyperkeratotic dermis with cords of carcinoma cells extending into deeper tissue layers. There are also intercellular bridges, keratin, and keratin pearls prominent throughout the specimen. More than 50% of tumors that arise on the penile shaft tend to be high grade, whereas only 10% of preputial SCC demonstrate poorly differentiated histology.³

Other grading systems have been developed to improve the reproducibility of the Broder classification. Factors that influence grading in these systems are the number of mitotic cells per high-power field, degree of keratinization and cellular atypia, and infiltration of inflammatory cells into the tumor. Each parameter is assigned a score and these are then summed to give a grade. Application of this system revealed 80% survival among patients with low-grade tumors.⁶³ Another technique for correlating histology and survival classifies tumors based on superficial spread, vertical growth, verrucous features, and multicentricity. These categories revealed metastatic disease in 42%, with superficial disease and 82% with vertical tumor growth.⁶⁴ Other features studied for prognostic significance include ulcerative versus exophytic appearance. Exophytic tumors have a high degree of keratinization on histologic examination with cells that appear more differentiated. Conversely, ulcerative penile malignancy is more often poorly differentiated with a higher incidence of lymph node involvement.⁵ Sarcomatoid differentiation is a very poor prognostic indicator, with up to 89% chance of lymph node involvement at presentation.⁶⁵

The disease ultimately progresses to invasion and local tissue destruction with eventual invasion of the corpora and urethra causing urinary obstruction. Metastasis occurs with invasion of the lymphatic bed of the prepuce and penile skin. These empty to the penile base and then to both inguinal node clusters. The anatomy of lymphatic drainage has complicated efforts to develop reliable sentinel node biopsy techniques. Once the superficial lymphatic system is entered, tumor spreads to the deep inguinal nodes under the fascia lata and medial to the femoral vein. The lymphatic system for the glans, urethra, and corpus spongiosum are variable and may seed the superficial or deep inguinal nodes. Drainage is very rarely to the external iliac node complex. Metastatic disease to the iliac lymph nodes portends a high probability of distant lymphatic and nonlymphatic spread. Distant metastasis to liver, lungs, and bones are signs of advanced disease and carry a very poor prognosis. Fortunately, fewer than 5% of patients have clinically evident distant metastasis at diagnosis.³