Penile Cancer and Penile Intraepithelial Neoplasia

What is Penile Cancer and Penile Intraepithelial Neoplasia?

Penile cancer is a rare form of cancer that can be emotionally distressing for the patient and challenging for doctors to treat. Often, patients may not seek medical attention right away because they can feel embarrassed, guilty, or scared, or they might be in denial or neglect the issue. In the early stages, penile cancer lesions are usually painless and do not cause problems with erection or urination. Therefore, many patients might try to treat themselves with lotions or creams before eventually going to a doctor. Unfortunately, up to half of all penile cancer patients might wait up to a year before seeking medical attention. This delay can also be partly blamed on doctors, as 25% of penile cancer cases are initially wrongly diagnosed as benign, or non-cancerous, lesions.

Patients often get ointments, salves, and antibiotics from their doctors before they see a specialist, like a urologist or a dermatologist. The issue of delaying a proper diagnosis got worse during the COVID-19 pandemic as virtual visits make it harder to properly examine penile lesions. This delay in getting a diagnosis can be very serious. It can reduce the patient’s chances of survival, increase their suffering, and limit the effectiveness of surgery to preserve natural function of the penis.

The most common type of penile cancer is squamous cell carcinoma, but there are also other less common types. There are also precursor lesions (abnormal growths that can turn into cancer) in the penis, which used to be called by several different names, but are now collectively termed penile intraepithelial neoplasia. One such precursor, Bowenoid papulosis, is often thought of separately due to its benign or non-cancerous nature and similarity to genital warts. However, under a microscope, it looks more like squamous cell carcinoma.

Squamous cell carcinoma is the main focus of this review, including its causes, how common it is, how it works, what it looks like, how it is diagnosed, the different conditions that can be mistaken for it, and how it is treated. This review talks about how crucial the exact stage and microscopic features of the tumor, as well as the presence of cancer in the lymph nodes, are in predicting the patient’s chances and planning their treatment. Lastly, it covers treatment options and follow-up care in great detail.

What Causes Penile Cancer and Penile Intraepithelial Neoplasia?

The chances of getting penile cancer vary and are linked to several things. Risk factors doctors have found include having a history of certain conditions affecting the penis like phimosis (a tight foreskin that cannot be pulled back), balanitis (inflammation of the head of the penis), chronic inflammation, injuries to the penis, not being circumcised at birth, smoking, poor hygiene in the genital area, and history of sexually transmitted infections (STIs), especially HIV and HPV. It has been found, for example, that cigarette smokers are 3 to 4.5 times more likely to develop penile cancer than people who do not smoke.

Being circumcised at birth has been linked with much lower chances of getting penile cancer. This preventative measure is very effective and can almost completely prevent the chance of getting penile cancer later on. This is because circumcision removes the skin covering the head of the penis, preventing the development of conditions that can lead to penile cancer.

Circumcision also prevents the buildup of smegma, which can contribute to chronic inflammation, a risk factor for penile cancer (although smegma itself is not directly the cause of cancer). Circumcision also eliminates the chances of developing conditions such as a tight or trapped foreskin, inflammation of the head of the penis and the foreskin, which are all linked to penile cancer.

Studies support the fact that being circumcised at birth can be a good preventative measure against penile cancer. For example, the chances of getting penile cancer in Jewish men, where circumcision at birth is a standard practice, is extremely low. In contrast, the chances of getting penile cancer in places like India, where circumcision is not common, are much higher.

In countries where circumcision happens later in life, the chances of getting penile cancer is higher. Cultures in Africa and Asia that do not routinely circumcise have higher rates of penile cancer. For men in these groups, it makes up 10% to 20% of all cancers.

STIs, particularly HIV and HPV, also increase the risk for penile cancer. People with HIV are 8 times more likely to develop penile cancer, but this risk is lower with circumcision.

Around 60% of penile cancers are linked to HPV, with a particular association to certain types of HPV (6, 18, and especially 16). Men with a history of a tight foreskin are more commonly found to have high-risk HPV. If positive for HPV, these patients might be more responsive to radiation therapy and have a better overall prognosis.

Having sex increases the risk of penile cancer, probably because it increases the chance of getting HPV. Using the HPV vaccines more should hopefully help lower the rates of this cancer.

All in all, the biggest risk factors for penile cancer are infection with HPV (especially types 6, 16, and 18), having a tight foreskin, and smoking. Other risks include chronic rashes on the penis lasting for at least 1 month, having circumcision later in life or not at all, obesity, urinary tract infections, genital warts, poor personal hygiene, and a history of a narrow urethra. Regular failure to use condoms doubles the risk of penile cancer. The risk is also higher for those with a weakened immune system. For example, men who have had a kidney transplant are 17 times more likely to develop penile cancer than the general population.

Lastly, PUVA treatment, a therapy often used for a skin condition called psoriasis, is linked to a higher rate of a type of skin cancer, even in areas not exposed to the treatment, including the genitals. The long-term risk of penile cancer in patients treated with PUVA, even when the genitals are covered, is almost 100 times higher than in the general population and seems to be related to the dose of the treatment.

Risk Factors and Frequency for Penile Cancer and Penile Intraepithelial Neoplasia

Penile cancer is a type of cancer more commonly diagnosed in the lesser developed regions such as Africa, Asia, and South America, with the most cases reported in Northeast Brazil (the state of Maranhão). Other countries with high rates of penile cancer include Botswana, Bolivia, Colombia, Paraguay, Uganda, and Venezuela.

In 2020, the International Agency for Research on Cancer reported 36,068 new cases of penile cancer worldwide, with 95% of them being squamous cell carcinomas. This type of cancer can make up to 10% to 20% of all cancers in men in these regions. The increased risk in these areas is often linked to hygiene practices, HPV and HIV infections, and a large number of uncircumcised men.

However, penile cancer is less common in developed regions such as the United States, making up less than 1% of cancers in men. With a little over 2,000 new cases and 500 deaths reported per year, the US sees an average of 0.81 cases of penile cancer per 100,000 men per year, a number that tends to increase with age.

There are no observed differences based on race, although Black and Hispanic individuals are typically diagnosed at a younger age. However, the incidence is 72% higher in the Hispanic population compared to the non-Hispanic population, and twice as common in Asians and Pacific Islanders compared to the general population. Despite this, the overall prevalence of penile cancer has been decreasing in the US over the last three decades of the 20th century.

A recent examination of the National Cancer Database found that all stages of squamous penile cancer increased between 1998 and 2012, with more advanced cases over time. The average age of diagnosis is around 60 years old. The incidence rates are also higher in areas with lower socioeconomic status and states in the Southern United States.

Signs and Symptoms of Penile Cancer and Penile Intraepithelial Neoplasia

Penile cancer generally starts as a painless sore or a lump that can be felt on the penis. Some people might also notice a rash, bleeding, or an inflammation of the penis head. The most common spot for these lesions to pop up is either on the penis head, its edge, or foreskin. Interestingly, a study in the United States showed that around 34.5% of penile cancer patients had their primary lesion on the penis head, 13.2% on the foreskin, 5.3% on the penis shaft, 4.5% in multiple spots, while in 42.5% of the patients the exact area couldn’t be specified.

About 30% to 60% of the people are diagnosed with affected lymph nodes in the groin area initially. However, only half of these will show a spread of cancer into these lymph nodes. Late-stage cancer might spread into the blood vessels; this is relatively rare probably because the tissue layer covering the shaft of the penis acts as a protective barrier. Although rare, 1% to 10% of patients presenting with penile cancer can have cancer that has spread to bones, liver, lungs, or brain from the time of presentation, usually, these patients will also have affected groin lymph nodes.

Testing for Penile Cancer and Penile Intraepithelial Neoplasia

When a man has an abnormal growth or ulcer on his penis, the first step in determining the cause is to see if there are signs of an infection or cancer. If it looks like an infection, the usual treatment is a 4-week course of medicine to kill the fungus or bacteria. After the treatment, the doctor will check again to see if the abnormality is gone. If not, then a small sample, called a biopsy, will be taken for further testing.

When looking at the penis under a special type of microscope, certain features can suggest that the abnormal cells are precancerous. These can include areas of different colors, unusual blood vessels, scars, or marks that shouldn’t normally be there.

A doctor may suspect penile cancer in men who have a painless growth or ulcer on the penis, particularly in those who are not circumcised. To confirm this, a biopsy is needed. Once the biopsy results show cancer, a series of tests and scans will follow to find out how far the cancer has spread. Magnetic resonance imaging (MRI) can, for example, show how deeply the cancer has moved into the tissues of the penis.

If the biopsy is positive, the doctor will also check the lymph nodes in the groin area. Penile cancer often spreads to these nodes first before it moves to other areas in the body. It’s important to note, however, that testing lymph nodes just by feeling them isn’t always accurate. Some may miss the cancer while others may mistakenly suggest cancer even when it’s not present. Therefore, imaging scans like computed tomography (CT), MRI, or ultrasound are often used. In advanced cases, positron emission tomography (PET) scans can be helpful. But these techniques can also miss microscopic spread of cancer to the lymph nodes. Therefore, the doctor often has to get a sample of the lymph nodes for testing.

The doctor may also want to check for human papillomavirus (HPV), as this virus has been linked to penile cancer. The usage of different markers in diagnosing and treating penile cancer is still being studied.

If the cancer has spread to the lymph nodes or if the patient is at high risk of metastasis, pathological staging is necessary. This means looking at the size, location, and extent of the cancer. This is typically done through ultrasound-guided fine-needle aspiration (FNA), dynamic sentinel node biopsy (DSNB), or an inguinal lymph node dissection.

Patients at high risk should also have a chest x-ray and CT scan of the abdomen and pelvis, and blood tests, including serum calcium and liver function tests. A bone scan should be done if the patient complains of bone pain, has high calcium levels, or high levels of certain liver enzymes. PET and CT scans are sensitive tools for finding spread of cancer in selected cases.

Treatment Options for Penile Cancer and Penile Intraepithelial Neoplasia

Penile cancer treatment often uses a combination of surgery, radiation, and chemotherapy. The goal is to get rid of the cancer while maintaining as much of the penile function and appearance as possible.

Low-risk tumors can be treated using processes that spare as much of the penis and the head of the penis (the glans) as possible. Treatments like topical treatments (creams), radiation therapy, Mohs surgery, laser removal, and full glans resurfacing can help. While these approaches have a higher chance of cancer reappearing than partial penectomy (partial removal of the penis), they are typically less invasive and have a comparable neglection rate.

Premalignant lesions or cells that can turn into a cancer called penile intraepithelial neoplasia can be successfully treated with topical creams. Surgical methods, such as Mohs surgery, glans resurfacing, laser removal, photodynamic therapy, freezing therapy or cryotherapy, and surgical removal, are generally preferred for these lesions.

Radiation therapy can be effective in treating low-risk, early-stage penile cancers. However, radiation therapy does require high doses that can lead to complications such as narrow urethra, infections, inflammation of the urethra, localized swelling, pain, abnormal connections between the urethra and skin, meatal stenosis (narrowing of the urethra), and tissue damage.

Mohs surgery involves removing cancerous tissues slice by slice until there’s no more cancer visible under a microscope. This technique helps conserve the maximum amount of tissue and yields results that are comparable or even superior to other treatments.

Laser removal generally uses lasers to treat carcinoma-in-situ lesions or early-stage cancers of the penis. Though the likelihood of recurrence and complications is higher than with partial penectomy, the procedure is still effective in over 90% of patients. The recovery is swift and it often gets top scores in patient satisfaction.

Total glans resurfacing consists of surgically removing the skin and layer underneath the skin to the corpus spongiosum (spongy tissue around the urethra) and then covering the area with a skin graft. This procedure is effective and has low rates of recurrence.

Wide local surgical removal of the tumor, such as circumcision where appropriate, is the fastest and most definitive treatment. If the cancer cells reach the edge of the removed tissue, further resection may be required.

For high-grade primary cancers, or when cancer invades the corpora cavernosa (one of the chambers that fill with blood during an erection), which can’t be safely managed by wide local surgical excision or other less invasive techniques, total or partial penectomy is recommended. It’s important to get a tumor-free margin during surgery to ensure all the cancer has been removed. If possible, leaving 2 to 3 cm of penile length allows the patient to retain some degree of sexual function.

Finally, managing regional lymph nodes in penile cancer is critical. It is because the existence and extent of the regional inguinal lymph node (nodes in the groin area) impact the long-term survival of men with squamous cell carcinoma of the penis. Patients are grouped into low-risk and high-risk for nodal involvement.

Dynamic sentinel node biopsies may be suggested for patients with high-risk disease. Recurrence treatment often involves surgical removal by wide local excision with negative margins or no cancer cells at the edge of the removed tissue.

Sometimes, chemotherapy or radiation treatments may be combined with surgery. Information on clinical trials is available for patients with penile cancer to understand the latest treatments.

Remember, the ultimate goal of each treatment is to coach patients towards being cancer-free while maintaining as much of the normal function and appearance of the penis as possible.

What else can Penile Cancer and Penile Intraepithelial Neoplasia be?

Medical professionals need to consider different conditions when diagnosing penile cancer. These conditions can be innocent, potentially cancerous, or cancerous. The potential cancerous conditions are currently categorized as penile intraepithelial neoplasia.

Some of the benign or non-cancerous conditions to consider include:

• Angiokeratomas: Scaly raised spots that often occur on the tip of the penis (glans).
• Balanitis and balanoposthitis: Typically fungal infections on the glans or foreskin that cause redness, swelling, itchiness, and sometimes discharge.
• Genital warts (condyloma acuminatum): Non-painful wart-like growths caused by a sexually transmitted infection (STI).
• Lichen planus: An inflammatory skin condition that can cause purple plaques on the penis.
• Papillomas: Benign, small white or yellow raised spots that form on the corona of the glans and do not need treatment.
• Psoriasis: This skin condition results in red raised patches of skin with sharp borders and is often accompanied by similar lesions elsewhere on the body.
• Syphilis: This STI begins as a painless ulcer and may be associated with swollen lymph nodes. These ulcers typically heal even without treatment.

Conditions like penile intraepithelial neoplasia and similar penile cutaneous lesions need to be considered. These include:

• Bowen disease: Characterized by red, scaly patches or plaques on the penis. It’s a type of pre-cancerous condition (a carcinoma in situ).
• Bowenoid papulosis: It appears similar to small genital warts on the penis and is usually asymptomatic but can be itchy and is contagious.
• Buschke-Lowenstein tumor (giant condyloma): An exophytic cauliflower-like mass in the genital region or anorectal area, which can be invasive.
• Cutaneous penile horn: This rare condition often develops over another skin lesion and results in a significant amount of skin growth.
• Erythroplasia of Queyrat: This lesion typically appears as a red, velvety area on the glans or foreskin and is a type of carcinoma-in-situ (pre-cancerous condition).
• Leukoplakia: Appears as whitish, scaly patches, often involving the urethral opening and is frequently seen in people with diabetes.
• Lichen sclerosus: This presents as flat white patches on the glans and foreskin. It can result from chronic infection, trauma, or inflammation.
• Pseudoepitheliomatous keratotic and micaceous balanitis: This rare condition results in a thick, warty scale on the glans and is usually painless.

Malignant or cancerous conditions can include:

• Squamous cell carcinoma
• Basal cell carcinoma
• Melanoma
• Sarcoma
• Metastatic diseases
• Adenosquamous carcinoma

What to expect with Penile Cancer and Penile Intraepithelial Neoplasia

The spread of cancer to the inguinal lymph nodes (the nodes in the lower part of your body, near your groin) and the severity of the tumor play a big role in predicting the long-term survival of men suffering from a specific type of penis cancer called invasive penile squamous cell carcinoma. The outlook can vary based on factors like the number of cancerous lymph nodes, if the cancer has spread to just one side or both sides (unilateral or bilateral extension), and if it has spread to the pelvic lymph nodes.

For these reasons, it’s essential to thoroughly check the groin and pelvis when examining a patient with penile cancer. A physical exam provides critical information about the disease’s extent by checking the firmness, number, location, and mobility of the lymph nodes in the groin. The American Cancer Society estimates that the overall survival rate for patients with penile cancer in the US is 65% after five years.

However, if the cancer has already spread to the inguinal lymph nodes and is left untreated, survival beyond two years from diagnosis is unusually rare.

Survival predictions also depend on how advanced the cancer is. Stage I or II cancer, which is still confined within the penis at diagnosis, has up to an 85% chance of survival after five years if managed surgically. However, if the cancer is at stage III or IV, the survival rate decreases to around 59%. Furthermore, if the cancer has spread to distant parts of the body, the survival rate drops to a worrying 11%.

Several studies have shown that the extent of involvement of the inguinal lymph nodes is a significant indicator of survival. If no inguinal lymph node metastases (cancer spread) are found, the patients have a 5-year survival rate ranging from 85% to 100%. Patients with single lymph node involvement have a 79% to 89% chance of survival after five years. However, when cancer has spread to multiple nodes on both sides or to the pelvic nodes, the survival rates dramatically drop to 17%-60% and 0%-17% respectively.

Possible Complications When Diagnosed with Penile Cancer and Penile Intraepithelial Neoplasia

Complications from penile cancer can greatly affect a person’s quality of life and treatment results. It is crucial to have thorough plans in place to manage both the physical and emotional effects of the disease.

Surgery to Remove the Main Tumor

Any surgery can bring about general complications like infection, bleeding and risks related to general anesthesia. The frequent complication after penectomy, a surgery to remove the penis, is meatal stenosis, a narrowing of the urinary opening.

Surgery to Remove Lymph Nodes

Surgical removal of groin lymph nodes can have severe side effects, which is why there is often hesitation to recommend automatic groin lymphadenectomy, the surgical removal of lymph nodes. Expected complications soon after surgery include infections of the wound, tissue death in the flap, inflammation in a vein, seroma (a pocket of clear fluid), blood clot in the lung, and swelling of the scrotum and lower limbs due to lymph build-up. Wound infections and complications are more common in patients with serious obesity (a body mass index of 30 or above), those who also receive pelvic lymph node surgery, and those with longer surgical durations.

Radiation Therapy

The chances for complications increase with the size of the tumor being treated with radiation. Potential complications from this treatment may include urethral narrowing (strictures), local swelling (edema), openings between the urethra and skin (urethrocutaneous fistulas), penis tissue death, inability to retract the foreskin (phimosis), meatal stenosis, and pain.

List of possible complications:

• Infection
• Bleeding
• Risks from general anesthesia
• Meatal stenosis
• Wound infections
• Flap necrosis
• Phlebitis
• Seroma
• Pulmonary embolism
• Lymphedema of the scrotum and lower limbs
• Urethral strictures
• Local edema
• Urethrocutaneous fistulas
• Penile necrosis
• Phimosis
• Pain

Recovery from Penile Cancer and Penile Intraepithelial Neoplasia

After patients have gone through their main treatment, it’s extremely important for doctors to keep a close eye on their recovery. Usually, patients will see their doctor about two weeks after surgery to check that they’re healing properly and to start regular check-ups.

Here’s what these check-ups might look like:

* If a patient has had surgery that didn’t remove the entire organ (like part of the penis), the doctor might schedule appointments every three months for the first two years, every six months for the next three years, and then once a year for another five years. These appointments would include a physical examination of the penis and groin area.
* If a patient had surgery to remove the entire penis (penectomy) or part of it (partial penectomy), they might see the doctor every six months for the first two years, and then once a year for the next three years.
* If a patient is on a watchful waiting plan (active surveillance) with no evidence of cancer in the lymph nodes, they would likely visit their doctor every three months for the first two years and every six months for the next three years.
* If a patient had surgery to remove the lymph nodes in the groin area (inguinal lymph node dissections), and cancer was present but restricted (staged at N0 or N1), they might have appointments every six months for the first three years, and then once a year for the next two years.

Patients who had the same lymph node removal surgery, but where the cancer was more advanced (staged at N2 or N3), will most likely see their doctor every three to six months for the first two years, and then once a year for the next three years. They should also get x-rays or CT scans of the chest every six months for the first two years, and CT scans of the stomach and pelvic area every three months in the first year, and every six months in the second year.

Preventing Penile Cancer and Penile Intraepithelial Neoplasia

It’s important for patients to understand the significance of keeping the genital area clean, as a lack of hygiene has been linked to penile cancer. High-risk sexual behaviours that could potentially result in acquiring HPV or HIV need to be discontinued. This also includes quitting smoking. Importantly, any abnormal growth on the penis should be checked by a doctor as soon as possible. Getting a diagnosis early means that treatment can start sooner, which could lead to better chances of survival and fewer noticeable changes to the penis. Patients with advanced stages of the disease are especially encouraged to join clinical trials.

The topic of circumcision, particularly on newborns, can be confusing as you might find varying opinions on it. Currently, fewer newborns are being circumcised in the United States. However, statistics from the National Center for Health Statistics show that around two-thirds of newborn boys still undergo the procedure. Pediatricians may be hesitant to perform the procedure due to immediately visible negative effects and complications like bleeding, infection, and pain. On the other hand, urologists may recommend it as they see the long-term consequences in adults who weren’t circumcised (such as inflammation of the penis, a tight foreskin that cannot be pulled back, and penile cancer).

After thoroughly reviewing studies on male circumcision, the benefits and drawbacks of the procedure are found to be the following:

Benefits

Circumcision can help protect men against inflammation of the penis, yeast infections, skin conditions, a tight foreskin that cannot be pulled back, and certain sexually transmitted infections, including penile cancer. It also improves genital hygiene, reducing the risk of sexually transmitted infections and cervical cancer in female partners. Also, it can help to avoid a more complex surgical procedure in adulthood. Around 4% to 11% of all boys who are not circumcised get balanoposthitis, an inflammation of the penis. More than half of men who aren’t circumcised will experience some health problems related to the foreskin at some point in their lives. The reported complication rate of circumcision is about 1.5%.

The procedure doesn’t seem to affect sexual sensitivity, activity, or satisfaction in any provable way. Circumcision significantly improves genital hygiene and eliminates smegma, which can have a noticeable foul odor even when not infected. Any discomfort during the procedure can be reduced by using local anaesthetics. Circumcision done on newborns essentially eliminates the risk of developing penile cancer later in life, which can be lethal.

Drawbacks

Some possible negatives of circumcision include the potential side effects from the procedure, it is less acceptable socially, perceived as painful which might have emotional or psychological consequences, it’s viewed as “unnatural,” a belief that having an intact foreskin increases male sexual pleasure, and an argument that the health benefits of circumcision are exaggerated. The surgery might result in the removal of too much or too little skin which may require another surgery for correction.

It is estimated that at thousand or more circumcisions on newborns are needed to prevent one case of penile cancer. It is still uncertain whether increased use of HPV vaccines will reduce the incidence of penile cancer even without circumcision. Deaths among newborns due to circumcision have been quoted as a reason to avoid the procedure, but actual figures from any official government agency or medical professional society are not available because it’s such a rare occurrence. Studies have shown that the proven benefits of circumcision greatly outweigh the negatives. The American Academy of Pediatrics and the American Academy of Family Physicians agree with this conclusion.

However, circumcision is still a controversial topic. Often, the decision comes down to family traditions or religious practices.

The medical team’s role is to provide all the facts to the patients—both the pros and the cons. The parents’ wishes should be respected unless it’s medically inappropriate. Therefore, it’s recommended that factual, evidence-based information is provided to the family during pregnancy, if possible. This way, they have enough time to think about their decision related to circumcision. Baby boys who are circumcised can potentially avoid painful deaths due to penile cancer. Even though it’s a very rare disease, not many such incidences are needed to convince some medical professionals about the benefits of circumcision in newborns. This is because circumcision essentially eliminates even the small risk of penile cancer later in life.