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Carcinoma of the penis: Epidemiology, risk factors, and pathology

Carcinoma of the penis: Epidemiology, risk factors, and pathology
Literature review current through: Jan 2024.
This topic last updated: Sep 13, 2023.

INTRODUCTION — Carcinoma of the penis typically presents as a painless lump or ulcer on the penis. The vast majority of cases are epithelial squamous cell carcinoma (SCC).

The epidemiology, risk factors, and pathology of carcinoma of the penis are reviewed here.

The clinical presentation, diagnosis, staging, and treatment of penile cancer are covered separately:

(See "Carcinoma of the penis: Clinical presentation, diagnosis, and staging".)

(See "Carcinoma of the penis: Surgical and medical treatment".)

EPIDEMIOLOGY — Carcinoma of the penis is rare in the United States, Europe, and other resource-abundant countries. As an example, penile carcinoma accounts for less than 1 percent of cancers in males in the United States, with over 2000 new cases and less than 500 deaths annually [1].

By contrast, cancers of the penis are more common in more resource-limited areas of the world, such as parts of Africa, Asia, and South America. In parts of these areas, penile cancer accounts for approximately 10 to 20 percent of all malignancies in males [2].

Penile cancer is typically a disease of older males, and rates increase with age [3]. The mean age at diagnosis is 60 years, although penile cancer can be seen in males less than 40 years [4,5].

The prevalence of penile cancer varies by race [3,6]. In a study in the United States, the incidence rate of squamous cell carcinoma (SCC) of the penis was similar in White and Black males (0.81 versus 0.82 per 100,000 males), but was significantly higher among Hispanic males (rate ratio 1.72) and lower in Asian-American males (rate ratio 0.45) [3].

RISK FACTORS — A number of factors are associated with an increased risk of developing squamous cell carcinoma (SCC) of the penis or a precursor lesion.

Epidemiologic factors — In one series, 137 males with penile cancer and 606 males without cancer were interviewed to ascertain risk factors for in situ and invasive penile cancer [7]. Males who developed penile cancer were more often single, never married, and circumcised at an older age (mean age, 38 versus 20 years).

Medical conditions of the penis — A number of medical conditions are significantly associated with an increased risk of penile cancer [7,8]. These include a history of:

Genital warts (odds ratio [OR] 7.6).

Urinary tract infection (OR 1.7).

Penile tear (OR 5.2). Among males circumcised in childhood, the risk was twofold greater (OR 2.1); among males never circumcised, however, it was over 12-fold higher (OR 12.5).

Chronic penile rash lasting one month or longer (OR 3.2).

Penile injury (OR 3.5).

Urethral stricture (OR 2.0).

Phimosis — Phimosis is a circumferential fibrosis of preputial tissue that leads to narrowing and an inability to retract the penile foreskin over the glans penis. The presence of phimosis is associated with a 7- to 10-fold higher risk of penile cancer [7,9].

Males not circumcised in childhood are at an increased risk of penile cancer, and at least one study suggests that this risk is mediated by the presence of phimosis [7]. In a study comparing 127 males with penile cancer with 671 males without penile cancer, a lack of circumcision was associated with a twofold increased risk of penile cancer (OR 2.3). The increased risk associated with a lack of circumcision appears to be due to a history of phimosis:

Among uncircumcised males, a history of phimosis increased the risk of penile cancer (OR 11.4, 95% CI 5.0-25.9).

The risk of penile cancer was not significantly elevated among uncircumcised males who did not report a history of phimosis (OR 0.5, 95% CI 0.1-2.5), although the study was underpowered to evaluate this association.

Obesity — Obesity is a risk factor for the development of invasive penile cancer. This is likely due to obesity-associated mechanisms, such as poor hygiene potentially related to buried penis, and the inability to fully examine and clean the penis. The latter leads to build-up of smegma and potentially repeated bouts of inflammation (ie, a functional phimosis). (See 'Other factors' below.)

In one population-based study, body mass index (BMI) was directly correlated with invasive penile cancer; with every five-unit increase in BMI, the risk of invasive penile cancer increased by 53 percent [10].

HPV — Human papillomavirus (HPV) DNA can be identified in 30 to 50 percent of all penile carcinomas [11-16].

In a systematic review including 71 studies of males with penile cancer or penile intraepithelial neoplasia (PeIN), the HPV DNA prevalence in penile cancer was 51 percent, with the predominant oncogenic type being HPV 16 (68 percent), followed by HPV 6 (8 percent) and HPV 18 (7 percent). The pooled HPV DNA prevalence in PeIN was 80 percent [16]. High-risk (ie, oncogenic type) HPV infection is more common in males with phimosis [17]. Of note, the incidence of HPV infection in the genital tissues of healthy males from the United States, Mexico, and Brazil ranged from 61 to 72 percent, with oncogenic types found in 23 to 36 percent of the populations [18].

The presence of high-risk HPV infection in association with SCC of the penis has been associated with a better prognosis in some series:

In an analysis of 212 males with penile cancer, 25 percent had an association with high-risk HPV (predominantly HPV 16) [19]. The five-year overall survival rate was higher in those with HPV-positive disease compared with those with HPV-negative disease (96 versus 82 percent). The difference remains statistically significant after adjusting for stage, tumor grade, and the presence or absence of lymphovascular invasion.

Immunohistochemical (IHC) assessment of p16 is a downstream marker of high-risk HPV infection. It is consistently associated with better a prognosis when present than when absent in penile cancer [20,21]. In an observational study of 143 patients with penile cancer, p16 positive tumors was associated with a higher five-year CSS compared with p16 negative tumors (88 versus 58 percent). Tumor p16 status was an independent prognostic factor for overall survival [21]. (See "Virology of human papillomavirus infections and the link to cancer".)

HIV infection — The incidence of penile cancer is approximately four- to eightfold higher in males living with HIV compared with males without HIV infection [22]. (See "HIV infection and malignancy: Management considerations".)

The reason for this association is uncertain. Although HIV infection may be directly responsible, the increased incidence of penile cancer in this population may be mediated by an increased incidence of HPV infection due to lifestyle risk factors for acquiring both viruses. Alternatively, it may be caused by the host responses to these viruses. (See "HIV infection and malignancy: Management considerations", section on 'Genitourinary malignancies'.)

Tobacco exposure — Tobacco exposure (ie, smoking or chewing tobacco) is associated with an increased risk of penile cancer in a dose-dependent fashion [7,8,23,24]. In population-based case control studies, smokers were 3 to 4.5 times more likely to have penile cancer compared with nonsmokers [7,8]. The association between smoking and penile cancer is independent of known confounding factors (such as sexual history) [23].

A subsequent study extended these observations by showing that all forms of tobacco products, including cigarettes, chewing tobacco, and snuff, were significantly and independently related to the incidence of penile cancer subsequent to multivariate regression analysis [24].

Cigarette smoke may increase the likelihood of penile cancer by inhibiting the function of antigen-presenting Langerhans cells, with a subsequent detrimental effect on immune system surveillance [25]. Alternatively, HPV infection, chronic penile irritation, or phimosis may act synergistically with cigarette smoking to promote malignant transformation [8].

Psoralen and ultraviolet A photochemotherapy — Patients with psoriasis treated with psoralen and ultraviolet A photochemotherapy (PUVA) have an increased incidence of genital tumors [23,26]. In a prospective study of 892 males treated with PUVA, 14 patients (2 percent) developed SCC of the skin of the penis or scrotum [26]. This was approximately 60 times higher than the expected incidence in the general population. Furthermore, the risk was increased in those exposed to higher levels of PUVA.

Other factors — Other factors that have been studied include:

Smegma – Smegma is a cheese-like substance produced by glands located within the inner surface of the foreskin [27]. Smegma begins to form in the first few days of life as the result of desquamation of epithelial cells in the preputial sac. In addition, secretions from preputial glands also contribute to smegma formation. Although smegma has been shown to be carcinogenic in animal models, it is not clear whether it is a carcinogen in humans or an independent risk factor for penile cancer [28].

Sexual orientation – There is no association between sexual orientation and risk of penile cancer [7].

Zoophilia – In one study from South America, 118 males with penile cancer were compared with 374 males without penile cancer seen in the same clinics [9]. In multivariate analysis, sex with animals was associated with a twofold higher risk for penile cancer (OR 2.07, 95% CI 1.21-3.52).

Lichen sclerosis (LS) – LS (also known as balanitis xerotica obliterans) is a risk factor for the development of penile cancer. Among males with LS with long-term follow-up, the incidence of subsequent penile cancer is estimated between 2.3 and 9 percent [29]. There is also a long latent period between the diagnosis of LS and the development of penile carcinoma (about 18 years) [30,31]. In one observational study, the presence of LS occurring in association with penile cancer was distinctly noted among the subset of tumors unrelated to HPV [32].

PATHOLOGY — Squamous cell carcinoma (SCC) and its variants account for approximately 95 percent of cases of penile cancer [33]. A wide range of other malignancies may involve the penis; these include melanoma, Kaposi sarcoma (KS), basal cell carcinoma (BCC), lymphoma, and various sarcomas.

Penile intraepithelial neoplasia — Penile intraepithelial neoplasia (PeIN) is characterized by a penile squamous epithelium with dysplastic changes and an intact basement membrane. Risk factors associated with the development of PeIN include inflammatory skin diseases like lichen planus, diseases of the prepuce and balanitis, immunosuppressive drugs, penile surgical procedures, genital warts, and organ transplantation. Such risk factors increased the odds of developing PeIN by 4- to 14-fold [34].

HPV associated PeIN is a precursor lesion of invasive penile SCC. The most common types are the basaloid and warty subtypes. HPV independent PeIN (also known as differentiated PeIN) is characterized by hyperplastic squamous epithelium, keratin pearl formation, prominent intercellular bridges and atypical basal cells. HPV independent PeIN can be difficult to distinguish from reactive conditions causing a hyperplastic epithelium such as squamous hyperplasia and pseudoepitheliomatous hyperplasia.

According to the 2022 WHO classification, all PeIN lesions are regarded as high grade regardless of the degree of cytoarchitectural features within the lesion [33]. From a pathologic perspective, terms that should no longer be used to describe these lesions include low- and high-grade dysplasia and squamous carcinoma in situ. The previous practice of classifying PeIN into mild (PeIN I), moderate (PeIN II), or severe (PeIN III) categories is also discouraged [35].

Certain clinical terminology is used to describe lesions based on location and/or appearance. Such terms include erythroplasia of Queyrat (on the penile glans) and Bowen disease and Bowenoid papulosis (on the penile shaft). While these terms are useful for describing the clinical entities and natural history from a clinical perspective, they are not used to describe pathologic entities of PeIN because they do not distinguish unique histopathologic features. Further details on these specific conditions are discussed separately. (See "Carcinoma of the penis: Clinical presentation, diagnosis, and staging", section on 'Premalignant lesions'.)

Squamous cell carcinoma — Penile SCC was initially classified by the presence or absence of HPV infection, using the two broad classifications of HPV related and non–HPV related disease [36]. The 2022 WHO classification system followed this paradigm but changed the terminology to classify penile SCC tumors into HPV associated and HPV independent types [33]. Based on the WHO classification, strong diffuse p16 immunohistochemical (IHC) staining is the most practical and reliable method for separating HPV associated and independent SCC (in addition to the histologic diagnosis). If the assay cannot be performed, it is acceptable to designate these penile tumors as SCC not otherwise specified (NOS).

Subtypes — Penile SCC can be characterized and subclassified by microscopic histologic features as well as relationship to HPV into several of the most common subtypes [33,37]:

Warty (condylomatous) tumors (7 to 10 percent; HPV associated) – These are cauliflower-like cancers associated with HPV infection. The tumor is composed of a prominent fibrovascular core that exhibits papillomatous formations that penetrate the corpus cavernosum or spongiosum. The border with underlying stroma is jagged and irregular. The typical presentation is a grade II bulky slow-growing malignancy. Vascular and perineural invasion are uncommon. Inguinal node metastases are present in 17 to 25 percent of cases.

Basaloid carcinoma (4 to 10 percent; HPV associated) – These cancers often present as an ulcerated irregular mass. They are comprised of uniform and small basaloid cells with central necrosis and are deeply invasive into the corpus cavernosum or spongiosum. Mitotic figures predominate, and evidence of apoptosis is also seen microscopically. These are high-grade tumors, with more than one-half of patients exhibiting inguinal metastases.

Usual type SCC including (45 to 65 percent; HPV independent) – The biologic behavior of these tumors is related to size, histologic grade, depth and structure invaded, and the presence of lymphovascular or perineural invasion (which is present in approximately one-third of cases). The typical case is grade II with respect to differentiation and invades into the corpus spongiosum. Inguinal lymph node metastases are present in 25 to 40 percent of cases.

Papillary carcinoma (2 to 15 percent; HPV independent) – These tumors are usually low grade (although grade II is found in some cases) but are superficially invasive into erectile tissue. Microscopically, they have evidence of both hyperkeratosis and papillomatosis. The lack of uniform papillae, absence of koilocytosis, and jagged stromal border distinguish it from either verrucous or warty carcinoma. Papillary tumors are not associated with human papillomavirus (HPV) infection. Vascular and perineural invasion, or nodal metastases are uncommon (up to 12 percent of cases).

Verrucous carcinoma (3 to 7 percent; HPV independent) – These tumors are low grade and are associated with a broad pushing border instead of infiltrative growth. They are characterized by straight papillae lined by extremely well-differentiated neoplastic cells. There is hyperkeratosis on the surface, with interpapillary keratin also present. Tumors that meet the criteria of "true verrucous carcinoma" are distinct in that there is no metastatic potential. However, recurrence is common among tumors that are inadequately excised.

Sarcomatoid (spindle cell) carcinoma (1 to 6 percent; HPV independent) – These are rare tumors of the penis that can be confused with malignant melanoma or sarcoma. They appear as deeply invasive, ulcerated or rounded polypoid masses. Microscopically, both SCC and spindle cell carcinoma components are seen. It may mimic features of heterologous sarcomas (eg, leiomyosarcoma, fibrosarcoma, and angiosarcoma). These tumors are the most aggressive variant of penile cancer, commonly presenting with vascular and perineural invasion in addition to inguinal and distant metastases.

Other rare variants (up to 0 to 1 percent) –Other rare variants include HPV independent pseudoglandular, adenosquamous subtypes along with the HPV associated clear cell and lymphoepithelioma-like SCC. These rare tumors have an aggressive phenotype and are associated with deeply invasive tumors into the corpora cavernosa, recurrence, and nodal metastases. Pseudoglandular and clear cell subtypes are associated with the highest mortality rates, but data are variable given the rarity of these tumors [33,37].

Patterns of tumor infiltration — The manner in which SCC infiltrates the normal tissue is thought to reflect the tumor-host relationship [38,39].

"Pushing type" infiltration – Blocks of tumor cells invade normal tissue but keep well-defined boundaries, separating it from normal tissue.

"Reticular" infiltration – Reticular infiltration is also known as "standard" infiltration. Smaller blocks of tumor cells broadly infiltrate the normal stroma.

The pattern of infiltration is associated with the risk of nodal involvement in penile cancer. As an example, in one series, the incidence of lymph node metastases was lower for the pushing versus standard infiltrative pattern (23 versus 64.5 percent).

Penile cancer grading — The recommended grading system for penile SCC is the three-tiered WHO/International Society of Urologic Pathology grading system [36].

Well-differentiated carcinomas (grade 1) have cytologic aspects of normal squamous tissue. The tumor cells grow in an irregular nesting pattern with little intervening stroma.

Poorly differentiated carcinomas (grade 3) have an irregular growth of small tumor cell nests, poor keratinization, polymorphic tumor cells with hyperchromatic nuclei, frequent mitoses, and marked stromal reaction.

The cases that do not qualify as grade 1 or 3 are grade 2.

Molecular alterations — The presence or absence of HPV infection is used to classify the molecular alterations associated with penile cancer.

HPV associated pathways — We have a clear understanding of how the human papillomavirus (HPV) pathway leads to the development of penile carcinoma. Tumor HPV/p16 status is useful for prognostic purposes and may also help in counseling partners of males with HPV associated penile cancers [19-21,40-42].

HPV infection of the squamous epithelium basal layer likely occurs via interactions with proteoglycan or integrin receptors, in addition to viral inoculation via the trauma of sexual intercourse [29,43-46]. Specific details on the molecular pathogenesis of HPV infection and their association with cancer are discussed separately. (See "Virology of human papillomavirus infections and the link to cancer", section on 'Molecular pathogenesis'.)

HPV independent pathways — The carcinogenic mechanisms of HPV independent penile carcinoma are not as well understood. However, the clinical conditions associated with the development of penile cancer are commonly correlated with penile inflammation and include lichen sclerosis (LS), phimosis, and resulting chronic balanitis. Under such inflammatory circumstances, malignant transformation can be driven by the over-production of reactive oxygen species and nitrogen intermediates, resulting in DNA damage and genomic instability. In addition, induction of cyclooxygenase 2 (COX-2) results in prostaglandin production and thromboxanes that can result in proliferation, angiogenesis, and invasion [29].

Other pathways involved in penile cancer progression include epithelial-mesenchymal transition with the molecular phenotype of increased expression of vimentin and loss of e-cadherin, increased expression of CD44, and the mechanistic target of rapamycin. However, routine evaluation of many of these molecular markers is not indicated.

Another mechanism of HPV independent carcinogenesis includes somatic pathogenic variants including amplifications, deletions, loss of heterozygosity, and even epigenetic changes [29]. Molecular pathways that are frequently altered in penile cancer include Notch, TP53, RAS, Wnt, PI-3 Kinase, Hippo, and cell cycle gene pathways [47]. Since some of these pathways can occur downstream of HPV infection, convergence of HPV and non-HPV pathways could lead to effective targeted therapy. In addition, molecular alterations involving DNA damage repair gene have been noted in some penile carcinomas. This finding could impact the sensitivity of such tumors to poly ADP-ribose polymerase inhibitors or platinum-based chemotherapy [47].

Immune-mediated pathways — Defining the tumor microenvironment and its various components using the conceptual framework of a "cancer immunogram" is a novel strategy in oncology [48]. In penile cancer, such components include tumor recognition by the immune system by virtue of tumor neoantigens (ie, high tumor mutational burden or viral oncoprotein expression); capacity of immune cell infiltration into the stroma around the tumor or surrounding stroma; inhibitory checkpoints such as tumor CTLA-4 and the programmed cell death receptor-1 (PD-1)/programmed cell death-ligand 1 (PD-L1) axis interactions between tumor cells and infiltrating T cells; general performance and immune status measures such as neutrophil to lymphocyte ratio, c-reactive protein, and Interleukin 6 (IL-6) levels; soluble immunosuppressive factors such as cyclooxygenase (COX) and prostaglandin E2; and the sensitivity of the tumor to killing by the hosts T lymphocytes (ie, heterogeneity of T cell receptors) [48,49]. Data has also shown that HPV viral oncoproteins on tumor cells can successfully be targeted utilizing antigen specific T cell therapy to induce tumor regression in other HPV associated squamous malignancies [50].

These components may play a role in treatment response and overall survival. As an example, penile carcinomas frequently express PD-L1 (approximately 48 to 62 percent of tumors) [51-53]. Data also suggest that high PD-L1 expression is more frequent among HPV independent penile carcinomas and may be associated with worse outcomes [52,53]. Therefore, the use of checkpoint inhibitor immunotherapy, including agents that target PD-1 and PD-L1, is being evaluated for penile carcinoma [54]. (See "Principles of cancer immunotherapy" and "Carcinoma of the penis: Surgical and medical treatment", section on 'Immune checkpoint inhibitors'.)

Other malignancies

Basal cell carcinoma — Basal cell carcinoma (BCC) is a common skin cancer arising from the basal layer of the epidermis and its appendages. Although these tumors have a low metastatic potential, they are locally invasive and can be destructive of skin and the surrounding structures.

Biopsy is required to differentiate BCC from penile carcinoma. On biopsy, BCC is characterized by nests of basaloid cells that can exhibit a variety of growth patterns (eg, nodular/ulcerative, diffuse, or superficial). Unlike SCC, they are negative for epithelial membrane antigen on immunohistochemistry (IHC), which can aid in the diagnosis [55]. (See "Basal cell carcinoma: Epidemiology, pathogenesis, clinical features, and diagnosis", section on 'Diagnosis'.)

Penile sarcomas

Kaposi sarcoma — Kaposi sarcoma (KS) is an angioproliferative disorder that requires infection with human herpesvirus-8 (HHV-8). Approximately 18 percent of patients with acquired immunodeficiency syndrome (AIDS)-related KS have penile lesions [56]. KS is characterized by the appearance of purplish, reddish blue, or dark brown/black macules, plaques, and nodules on the skin, which may ulcerate and bleed easily. The skin lesions range in size from very small to several centimeters in diameter, and they can remain unchanged for months to years, or grow rapidly within a few weeks and disseminate.

Molecular analysis of KS lesions reveals amplified HHV-8 DNA sequences by polymerase chain reaction or HHV-8 latency-associated nuclear antigen expression within spindle cells by IHC staining. (See "AIDS-related Kaposi sarcoma: Clinical manifestations and diagnosis" and "Classic Kaposi sarcoma: Clinical features, staging, diagnosis, and treatment".)

KS is now subcategorized as follows: classic KS, which occurs in patients without known immunodeficiency, and has an indolent and rarely fatal course; immunosuppressive treatment–related KS, which occurs in a patient receiving immunosuppressive therapy for organ transplantation or other indications and is often reversed with dosage modification of the immunosuppressive agents; African KS, which occurs in young males and may be indolent or aggressive in course; and epidemic or HIV-related KS, which occurs in the patient with AIDS [57].

Penile involvement is more common in gay males than in others with AIDS. In the first 1000 cases of AIDS reported by the Centers for Disease Control and Prevention, the incidence of penile KS was 44 percent in gay and bisexual patients, compared with 16 percent in intravenous drug abusers and 0 percent in hemophiliac patients [58,59].

Other penile sarcomas — A review of 46 penile sarcomas revealed an equal number of benign and malignant lesions [60]. The patients ranged in age from newborn to the eighth decade of life. The presenting signs and symptoms of subcutaneous mass, penile pain and enlargement, priapism, and urinary obstruction were the same for both benign and malignant lesions. A sarcoma has been reported to masquerade as a Peyronie plaque [61].

Malignant lesions were found more frequently on the proximal shaft; benign lesions were more often located distally. The most common malignant lesions were those of vascular origin (hemangioepithelioma), followed in frequency by those of neural, myogenic, and fibrous origin [62]. Single case reports of sarcomatous lesions have been published, for example, malignant fibrous histiocytoma [63], angiosarcoma [64], leiomyosarcoma [65], epithelioid sarcoma [66], hemangioendothelioma [67], and osteosarcoma [68]. (See "Pathogenetic factors in soft tissue and bone sarcomas".)

Melanoma — Melanomas are the most aggressive form of skin cancer and can occur anywhere on the body (picture 1). The following skin findings are suggestive of melanoma: a dark pigmented lesion with asymmetry, irregular borders, variegated color, or a diameter ≥6 mm, or a recent change in a lesion. Unlike penile carcinoma, these are typically flat lesions without associated tumor. However, ulceration can occur in both diseases. (See "Melanoma: Clinical features and diagnosis", section on 'Clinical diagnosis'.)

Biopsy serves to establish the diagnosis, with subsequent definitive excision based upon location and extent. Melanomas are characterized by neoplastic melanocytes found throughout the epidermal layers. IHC is useful in difficult cases or in nodal metastases. The most widely used markers to make a diagnosis of melanoma include S-100, MART-1, and HMB-45. (See "Melanoma: Clinical features and diagnosis", section on 'Diagnosis confirmation'.)

Extramammary Paget disease — Paget disease is an adenocarcinoma of apocrine gland-bearing skin that presents as a slowly expanding, well-defined patch (white or erythematous) that is often pruritic (picture 2) [69]. The onset is typically insidious, which helps to differentiate it from penile carcinoma.

Paget disease is characterized by Paget cells, which are mucin positive and stain for low molecular weight cytokeratins (eg, CK7 and CK20), periodic acid-Schiff, and carcinoembryonic antigen [70].

Urethral carcinoma — Primary urethral cancer is a rare malignancy in males that typically arises in the proximal segments of the urethra but can arise anywhere along the urethral length. SCCs represent the predominant histology, with approximately 75 percent of male urethral cancers being SCCs, while 15 to 20 percent are urothelial carcinomas, and 5 to 7 percent are adenocarcinomas. (See "Urethral cancer".)

The most common symptom is urinary tract obstruction, which is not common in penile carcinoma. Other symptoms include hematuria (sometimes with blood dripping from the meatus), dysuria, and/or a purulent urethral discharge. When hematuria is present, it is more often seen on initiation rather than termination of the urinary stream. A biopsy of an intra-urethral lesion serves to establish the diagnosis and differentiate this from penile cancer, which occurs on the penile surface.

Anatomic location may be the only factor that allows one to differentiate SCC histology as originating from the penis versus the urethra.

Metastases — Metastatic disease involving the penis is rare. Penile metastases are generally a manifestation of widespread disease from another primary tumor site. Penile metastases often occur within the corpora cavernosa and can be a cause of priapism. Biopsy of the lesion establishes the diagnosis.

Metastatic disease to the penis is associated with a poor prognosis, with a median time to death of six months [71]. The poor prognosis of patients presenting with penile metastases was demonstrated in one series of 219 patients with penile metastases, over half of whom had additional metastatic foci [72]. The primary cancer arose in the bladder (30 percent), prostate (30 percent), colon or rectum (16 percent), and kidney (11 percent).

SUMMARY AND RECOMMENDATIONS

Epidemiology

Cancers of the penis are rare in the United States, Europe, and other resource-abundant countries but occur at a much higher frequency in resource-limited countries. (See 'Epidemiology' above.)

Penile cancer is typically a disease of older males, and rates increase steadily with age. However, males of any age may be affected.

Risk factors – Risk factors associated with an increased risk of penile cancer include medical conditions of the penis, phimosis, obesity, and human papillomavirus (HPV) infection, among others. (See 'Risk factors' above.)

Pathology of penile cancers

Squamous cell carcinoma – SCC and its variants comprise approximately 95 percent of penile cancers and are now broadly into HPV associated and HPV independent subtypes. (See 'Pathology' above and 'Squamous cell carcinoma' above.)

-Immunohistochemistry for p16 expression is a practical and reliable method for assessing for HPV infection. (See 'HPV' above.)

-Penile intraepithelial neoplasia (PeIN) is a precursor lesion of invasive penile SCC and is also classified as HPV associated and HPV independent. All PeIN lesions are also regarded as high grade. (See 'Penile intraepithelial neoplasia' above.)

Other malignancies – Other malignancies that can present in the penis include basal cell carcinoma (BCC), Kaposi and other penile sarcomas, malignant melanoma, extramammary Paget disease, urethral carcinoma, and metastases. (See 'Other malignancies' above.)

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