Penile Cancer – Causes, Symptoms, Diagnosis, Treatment

Penile Cancer is an uncommon malignancy, but when diagnosed is psychologically devastating to the patient and can pose a difficult challenge to the treating urologist. Patient’s with this condition tend to delay seeking medical attention. This delay is associated with embarrassment, guilt, fear, and denial of the patient. Patients often attempt to self-medicate with lotions or creams before seeing a doctor. The delays in treatment may also be attributable to physicians as well. Many patients receive salves and antibiotics from their primary care physicians before seeing a urologist. This delay in diagnosis is serious, as it can decrease the likelihood of survival and limits the ability to retain a functioning and satisfactory result after surgical intervention.

In the discussion of penile cancer, it is important to review benign, premalignant, and malignant conditions and to differentiate between them. The most common penile malignancy is squamous cell carcinoma (SCC), but nonsquamous penile malignant neoplasms also exist including basal cell carcinoma, melanoma, sarcomas, and adenosquamous carcinoma. This chapter will focus mainly on squamous cell carcinoma, including the etiology, epidemiology, pathophysiology, histopathology, evaluation, and treatment of this tumor. The chapter will examine the importance of the pathologic stage and histologic features of the primary tumor, as well as any presence of lymph node (LN) metastasis in determining the prognosis and treatment planning for squamous carcinoma. The treatment options and follow-up will be discussed in depth.

Types of Penile Cancer

There are several types of penile cancer, depending on the type of cell the cancer developed from. The most common types include:

  • Squamous cell penile cancer – this accounts for more than 90% of cases and starts in the cells that cover the surface of the penis
  • Carcinoma in situ (CIS) – a particular type of squamous cell cancer where only the cells in the skin of the penis are affected and it hasn’t spread any deeper
  • Adenocarcinoma – cancer that starts in the glandular cells of the penis that produce sweat
  • Melanoma of the penis – this is where the cancer develops in the skin cells that give the skin its colour


Penile cancers traditionally begin as small lesions, most commonly on the glans or prepuce. The appearance can vary greatly. Some appear as white grey exophytic masses growing out of the penile skin and others can be flat, reddish-colored, and ulcerated masses. These lesions grow slowly laterally along the surface of the penile skin and often cover the entire glans or prepuce before invading into the corpora and shaft of the penis. Growth rates of ulcerative versus exophytic lesions are similar, although ulcerative lesions appear to metastasize to lymph nodes (LNs) earlier. Penile lymphatics drain both the glans penis and shaft and drainage proceeds first to superficial inguinal LNs to deep inguinal LNs and then to external iliac LNs in the pelvis.

Causes of Penile Cancer

The incidence of cancer of the penis varies and is related to a number of factors. Clinicians have identified risk factors including the history of phimosis, balanitis, chronic inflammation, penile trauma, lack of neonatal circumcision, tobacco use, lichen sclerosus, poor hygiene and history of sexually transmitted diseases (STDs), especially HIV and human papillomavirus (HPV).

Neonatal circumcision has been correlated with lower rates of penile cancer and has been established as an excellent prophylactic measure that can eliminate the occurrence of penile carcinoma. The reasoning behind this is that it eliminates the closed preputial environment where penile carcinoma develops. This helps prevent chronic irritation effects of smegma which can lead to chronic inflammation, which is a known risk factor for penile cancer. It also eliminates the possibility of phimosis and balanitis. Patients with a history of phimosis have an increased risk for penile cancer of 25% to 60%. Male circumcision has also been shown to be effective against the HIV-1 infection. Population-based studies support the fact that neonatal circumcision can be an effective prophylactic measure against penile cancer. Studies have shown a very low incidence rate in the Jewish population where neonatal circumcision is a universal practice. African tribes and Asian cultures that do not routinely perform circumcision have much higher rates of penile cancer, and it, in fact, accounts for 10% to 20% of all male malignant neoplasms in these groups.

Sexually transmitted diseases are also noted to be a risk factor for the development of penile cancer, particularly HIV and HPV. Patients with HIV have an 8-fold increased risk for the development of penile cancer. Forty-five percent to 80% of penile cancers are related to HPV with a strong correlation to types 6, 16 and 18. High-risk HPV is more common in men with a history of phimosis. A final risk factor to consider is tobacco use. Cigarette smokers are 3 to 4.5 times more likely to develop penile cancer.

  • HIV infection—HIV-positive men have eight-fold increased risk of developing penile cancer than HIV-negative men.[rx][rx]
  • Human papillomavirus—HPV is a risk factor in the development of penile cancer.[rx] According to the Center for Disease Control and Prevention (CDC), HPV is responsible for about 800 (about 40%) of 1,570 cases of penile cancer diagnosed annually in the United States.[rx][rx] There are more than 120 types of HPV.[rx]
  • Genital warts—Genital or perianal warts increase the risk of invasive penile cancer by about 3.7 times if they occurred more than two years before the reference date.[rx] About half of men with penile cancer also have genital warts, which are caused by HPV.[rx]
Hygiene and injury
  • Poor hygiene – Poor hygiene can increase a man’s risk of penile cancer.[rx]
  • Smegma – Smegma, a whitish substance that can accumulate beneath the foreskin, is associated with greater risk of penile cancer.[rx] The American Cancer Society suggests that smegma may not be carcinogenic, but may increase the risk by causing irritation and inflammation of the penis.[rx]
  • Balanitis and penile injury – Inflammation of the foreskin and/or the glans penis (balanitis) is associated with about 3.1 times increased risk of penile cancer.[rx] It is usually caused by poor hygiene, allergic reactions to certain soaps, or an underlying health condition such as reactive arthritis, infection, or diabetes.[rx] Small tears and abrasions of the penis are associated with about 3.9 times increased risk of cancer.
  • Phimosis – Phimosis is a medical condition where the foreskin cannot be fully retracted over the glans. It is considered a significant risk factor in the development of penile cancer (odds ratio of 38–65).[rx] Phimosis may also be a symptom of penile cancer.[rx]
  • Paraphimosis – Paraphimosis is a medical condition where the foreskin becomes trapped behind the glans. It is considered a risk factor for the development of penile cancer.[rx]
  • Circumcision – Some studies show that circumcision during infancy or in childhood may provide partial protection against penile cancer, but this is not the case when performed in adulthood.[rx] It has been suggested that the reduction in risk may be due to reduced risk of phimosis;[rx][rx] other possible mechanisms include reduction in risk of smegma and HPV infection.[rx]


  • Age – Penile cancer is rarely seen in men under the age of 50. About 4 out of 5 men diagnosed with penile cancer are over the age of 55.[rx]
  • Lichen sclerosus – Lichen sclerosus is a disease causing white patches on the skin. Lichen sclerosus increases the risk of penile cancer.[rx][rx] As the exact cause of lichen sclerosus is unknown, there is no known way to prevent it.[rx]
  • Tobacco—Chewing or smoking tobacco increases the risk of penile cancer by 1.5–6 times depending on the duration smoking and daily number of cigarettes.
  • Ultraviolet light—Men with psoriasis who have been treated using UV light and a drug known as psoralen have an increased risk of penile cancer.[rx][rx]

The cause of penile cancer isn’t known, but certain risk factors can increase your chances of getting it, including

  • carrying the human papilloma virus (HPV) – there are more than 100 types of HPV; some types cause genital warts
  • age – the condition rarely affects men under the age of 40 and is most common in men aged over 50
  • smoking – chemicals found in cigarettes can damage cells in the penis, which increases your risk of getting penile cancer
  • having phimosis – when the foreskin is difficult to retract, the chances of developing infections like balanitis increase; repeated infections are linked to a higher risk of developing some types of penile cancer as they can weaken your immune system

Symptoms of Penile Cancer

You should be aware of any abnormalities or signs of penile cancer, including:

  • A growth or sore on the penis that doesn’t heal within 4 weeks
  • Bleeding from the penis or from under the foreskin
  • Redness of the penis
  • Rash on the penis
  • Foul smelling discharge from the penis
  • Pain in the penis
  • Growth or sore on the penis that doesn’t heal within four weeks (may look like a wart, ulcer, or blister), may or may not be painful[rx]
  • Bleeding from the penis or from under the foreskin
  • Change in color of the penis
  • Phimosis[rx]
  • A foul-smelling discharge
  • Thickening of the skin of the penis or foreskin that makes it difficult to draw back the foreskin (phimosis)
  • A change in the colour of the skin of the penis or foreskin
  • A rash on the penis
  • An area of skin becoming thicker
  • Changes in the skin color
  • A lump
  • An ulcer (sore) that might bleed
  • A reddish, velvety rash under the foreskin
  • Small, crusty bumps
  • Flat, bluish-brown growths
  • Smelly discharge (fluid) or bleeding under the foreskin

Diagnosis of Penile Cancer

History and Physical

Penile cancer most often presents with a skin lesion or palpable nodule on the penis. Lesions are most commonly found to arise on the glans, in the coronal sulcus or on the prepuce as either a mass or ulceration. A review of penile SCC in the U.S. showed that 34.5% of patients had the primary lesion on the glans, 13.2% on the prepuce, and 5.3% on the shaft, 4.5% overlapping and 42.5% unspecified. Inguinal lymphadenopathy is present in 30% to 60% of cases at diagnosis. Distant metastases are uncommon until late in the disease course, with only 1% to 10% of cases having distant metastases at presentation.

Around 95% of penile cancers are squamous cell carcinomas. They are classified into the following types
  • basaloid (4%)
  • warty (6%)
  • mixed warty-basaloid (17%)
  • verrucous (8%)
  • papillary (7%)
  • other SCC mixed (7%)
  • sarcomatoid carcinomas (1%)
  • not otherwise specified (49%)

Other types of carcinomas are rare and may include small cell, Merkel cell, clear cell, sebaceous cell or basal cell tumors. Non-epithelial malignancies such as melanomas and sarcomas are even rarer.[rx]


Like many malignancies, penile cancer can spread to other parts of the body. It is usually a primary malignancy, the initial place from which cancer spreads in the body. Much less often it is a secondary malignancy, one in which cancer has spread to the penis from elsewhere. The staging of penile cancer is determined by the extent of tumor invasion, nodal metastasis, and distant metastasis.[rx]

The T portion of the AJCC TNM staging guidelines are for the primary tumor as follows
  • TX: Primary tumor cannot be assessed.
  • T0: No evidence of primary tumor.
  • Tis: Carcinoma in situ.
  • Ta: Noninvasive verrucous carcinoma.
  • T1a: Tumor invades subepithelial connective tissue without lymph vascular invasion and is not poorly differentiated (i.e., grade 3–4).
  • T1b: Tumor invades subepithelial connective tissue with lymph vascular invasion or is poorly differentiated.
  • T2: Tumor invades the corpus spongiosum or cavernosum.
  • T3: Tumor invades the urethra or prostate.
  • T4: Tumor invades other adjacent structures.
Anatomic Stage or Prognostic Groups of penile cancer are as follows
  • Stage 0—Carcinoma in situ.
  • Stage I—The cancer is moderately or well-differentiated and only affects the subepithelial connective tissue.
  • Stage II—The cancer is poorly differentiated, affects lymphatics, or invades the corpora or urethra.
  • Stage IIIa—There is a deep invasion into the penis and metastasis in one lymph node.
  • Stage IIIb—There is a deep invasion into the penis and metastasis into multiple inguinal lymph nodes.
  • Stage IV—Cancer has invaded into structures adjacent to the penis, metastasized to pelvic nodes, or distant metastasis is present.


The staging criteriaTrusted Source

National Cancer Institute

Stage 0

  • Cancer is only on the top layer of the skin.
  • Cancer hasn’t to spread any glands, lymph nodes, or other parts of the body.

Stage 1

  • Cancer has spread into the connective tissue just below the skin.
  • Cancer hasn’t spread to any glands, lymph nodes, or other parts of the body.

Stage 2

  • Cancer has spread to the connective tissue below the skin and to lymph vessels or blood vessels or cells look very different from normal cells, or cancer has spread to erectile tissues or the urethra.
  • Cancer hasn’t spread to any other parts of the body.

Stage 3A

  • Cancer has spread to the connective tissue below the skin and to lymph vessels or blood vessels or cells look very different from normal cells, or cancer has spread to erectile tissues or the urethra.
  • Cancer has spread to one or two lymph nodes in the groin.
  • Cancer hasn’t spread to any other parts of the body.

Stage 3B

  • Cancer has spread to the connective tissue below the skin and to lymph vessels or blood vessels or cells look very different from normal cells, or cancer has spread to erectile tissues or the urethra.
  • Cancer has spread to multiple lymph nodes in the groin.
  • Cancer hasn’t spread to any other parts of the body.

Stage 4

  • Cancer has spread to nearby areas, such as the pubic bone, prostrate, or scrotum, or cancer has spread to other areas and organs of the body.

HPV positive tumors

Human papillomavirus prevalence in penile cancers is high at about 40%. HPV16 is the predominant genotype accounting for approximately 63% of HPV-positive tumors. Among warty/basaloid cancers the HPV prevalence is 70–100% while in other types it is around 30%.[rx]

  • Initial evaluation – of men with a penile mass or ulcer depends on whether the clinical presentation is consistent with an infectious etiology or malignancy. In men where infection seems more likely, a four-week course of antifungals or antibiotics would be appropriate for repeat clinical exam at the end of the medical course. If the lesion does not resolve or progresses, a biopsy is indicated.
  • Suspicion for penile carcinoma –  should be high in men who present with a penile mass or ulcer, especially if they are uncircumcised. A tissue biopsy is required for pathologic diagnosis and necessary before initiation of any therapy. A biopsy can be performed by using a punch, incisional or excisional technique. An excisional biopsy would be appropriate if the lesion can be removed in its entirety with little or no alteration to the penile form or function.
  • If the biopsy – is positive for cancer, an extensive physical examination of the regional LNs is indicated. Penile cancer initially spreads to the inguinal LNs and then to the pelvic and retroperitoneal nodes. The inguinal LNs should be examined with attention to the location, size, a number of palpable nodes, as well as whether they are fixed or mobile. The presence or absence of LN involvement is extremely important as it dictates treatment and also provides important prognostic information. Unfortunately, the clinical assessment of inguinal LNs is not reliable. False-negative clinical evaluations of the inguinal region by palpation alone are common, reportedly between 9% to 60%. False-positive assessments are also frequent. For this reason, imaging is often obtained in conjunction with a clinical exam. CT, MRI, or inguinal ultrasound can be used as well as CT/PET.
  • Pathological staging – is necessary for men with palpable lymphadenopathy and for those that are high risk for metastases based on the pathological features of the primary tumor. The nodes can be evaluated by ultrasound-guided fine-needle aspiration (FNA), dynamic sentinel node biopsy (DSNB) or superficial or modified inguinal lymph node dissection (ILND).

Treatment of Penile Cancer

If your cancer is in the early stages, your treatment may include:

  • A medication – in the form of a cream for your skin
  • Cryotherapy – a procedure that uses an extremely cold liquid or a device to freeze and destroy cancerous tissue
  • Mohs surgery – in which doctors remove affected skin one layer at a time until they reach healthy tissue
  • Lasers – to cut and destroy areas that contain cancer
  • Circumcision – which is surgery to remove your foreskin. You would have this procedure if you had cancer only in your foreskin.
  • Radiation and/or chemotherapy – to rid your body of cancer cells
  • A penectomy, which is surgery to remove some or all of your penis

Most treatments for early-stage penile cancer don’t affect your ability to have sex, but chemotherapy and radiation might. Talk to your doctor about possible side effects.

Surgical Management of Primary Tumors

  • Wide local excision – the tumor and some surrounding healthy tissue are removed
  • Microsurgery – surgery performed with a microscope is used to remove the tumor and as little healthy tissue as possible
  • Laser surgery – laser light is used to burn or cut away cancerous cells
  • Circumcision – cancerous foreskin is removed
  • Amputation (penectomy) – a partial or total removal of the penis, and possibly the associated lymph nodes.

Management of penile carcinoma depends on the stage of the tumor at the time of diagnosis. Surgical removal of the primary tumor remains the gold standard for the rapid definitive treatment of the primary penile tumor. Tumors with low risk of recurrence (Tis involving shaft skin and glans penis, Ta involving glans only, T1a and T1b lesions involving shaft skin and glans alone) are appropriate for organ-sparing and glans-sparing procedures. This includes topical treatments (5-fluorouracil or imiquimod cream for Tis), radiation therapy, Mohs surgery, limited excision, and laser ablation. If a patient has T1 grade 1 or 2 lesions, it is recommended to consider them for penile-preserving techniques, but the patient must be reliable regarding compliance and close follow-up. Patients with T1 grade 3 or 4 lesions or T2 lesions or greater typically require more extensive surgical intervention with partial or total penectomy. Intraoperative frozen sections can be obtained to achieve negative surgical margins. Traditionally a 2-cm, tumor-free margin has been recommended, but a 5-mm, the tumor-free margin is considered safe.

Lymph Node Management

Management of regional lymph nodes (LNs) is important, as the presence and extent of regional ILN metastases is the single most important prognostic indicator in determining the long-term survival of men with SCC of the penis. Up to 25% of patients with non-palpable LNs harbor micrometastases. Several factors help predict the risk of microscopic inguinal LN metastases. T is, Ta, and T1 tumors have a risk of metastases from 4% to 14%. T2 and greater tumors are associated with a significantly higher risk of metastases to the inguinal LNs. Metastatic potential is also associated with higher tumor grade, the higher the grade, the greater the risk for metastases. The presence of lymphovascular or perineural invasion is also associated with a greater risk of metastases. Patients are stratified into groups of low risk or high risk for nodal involvement.

Low Risk: Tis, Ta and T1a tumors; no lymphovascular invasion or perineural invasion; grades 1 and 2

High Risk: Grade 3 tumors, lymphovascular or perineural invasion present (T1b) and T2 or higher stage

Men with low-risk disease and non-palpable inguinal LNs have a 0-16% chance of nodal metastases. The European Association of Urology (EAU) and the National Comprehensive Cancer Network (NCCN) recommend offering these men surveillance rather than surgical staging. These men must be reliable, however, and comply with follow-up recommendations. If unreliable or unwilling to proceed with surveillance these men should undergo bilateral inguinal node staging, either with dynamic sentinel node biopsy (DSNB) or superficial or modified ILND. Men with non-palpable inguinal LNs but the high-risk disease should either undergo DSNB or superficial or modified inguinal LND. If the nodes are negative, posttreatment surveillance is recommended. Patients with one involved inguinal LN and without extranodal extension require complete ipsilateral inguinal LND. If a patient has 2 more positive nodes or one positive node and evidence of extranodal extension, he should undergo therapeutic ipsilateral inguinal LND and unilateral or bilateral pelvic LND.

Men who present with a unilateral, solitary inguinal node that is less than 4 cm in size should undergo fine-needle aspiration (FNA) of the palpable node. If the FNA is positive, a superficial and deep inguinal LND should be performed. If the FNA is negative, excisional biopsy, superficial inguinal LND or surveillance is appropriate. If 2 or more nodes are positive or there is evidence of extranodal extension on ILND, it is recommended to proceed with a pelvic LND. These patients are also candidates for adjuvant chemotherapy or radiation therapy as they are at higher risk for recurrence.

Men with multiple or bilateral palpable inguinal nodes should undergo an FNA of one of the nodes for initial staging examination. If the FNA is negative, the surgeon should proceed with an excisional biopsy or superficial inguinal LND with frozen sections obtained intraoperatively. It is important to take into account that 30% to 50% of patients with the palpable disease will simply have inflammatory LN swelling instead of metastases. For this reason, it is more favorable to obtain a biopsy to prove metastases. It is becoming more common to obtain a dynamic sentinel node biopsy. If the patient’s biopsy is positive, they should undergo neoadjuvant chemotherapy and then internal LND and pelvic LN dissection.


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