Penile Carcinoma: Causes, Symptoms, and Treatments

Penile carcinoma is a rare but serious cancer, with roughly 36,000 new cases and 13,000 deaths worldwide each year, most of them squamous cell carcinomas originating in the skin of the penis.¹ Its rarity often works against patients: many men and even some clinicians fail to recognize it early, and the stigma surrounding genital disease can delay the first visit to a doctor by months. The causes range from viral infection to chronic inflammation, and the treatment landscape has shifted meaningfully in the past decade toward organ-sparing approaches and immunotherapy combinations that did not exist a generation ago.

How Common Is It, and Who Is at Risk?

Penile cancer accounts for fewer than one in every hundred thousand men globally each year, but the burden is not evenly distributed. South America reports the highest incidence rates, while many European countries have recently seen upward trends. Fifteen countries showed rising rates, thirteen of them in Europe and two in Asia.¹ The reasons behind these geographic patterns are complex, but they track with differences in circumcision practices, HPV vaccination rates, and access to early urological care. In higher-income countries, the disease tends to appear in men over 50, though it can occur at younger ages.

The Two Main Causal Pathways

One of the most important things to understand about penile cancer is that it arises through at least two biologically distinct routes. The first involves infection with human papillomavirus (HPV), the same virus linked to cervical cancer in women. About 40% of penile tumors carry HPV, with HPV-16 being the most frequently detected type.² In one study, high-risk HPV strains were confirmed in roughly 35% of penile cancer cases using direct tissue analysis.³ HPV-positive tumors tend to have a basaloid cell appearance under the microscope and often stain positive for the p16 protein, which pathologists use as a marker of viral involvement.⁴

The second route is HPV-independent. These tumors typically develop against a background of chronic irritation and inflammation. Lichen sclerosus, a long-term skin condition that causes whitish, scarring patches on the foreskin and glans, dramatically elevates the risk. In one case-control study, men with lichen sclerosus had an odds ratio for penile cancer around 81 compared to controls without the condition, and over half of those patients also had phimosis, a tightening of the foreskin that traps moisture and promotes chronic inflammation.⁵ Separate work looking at men who already had penile squamous cell carcinoma found that more than half had evidence of lichen sclerosus, sometimes diagnosed years before the cancer appeared.⁶

Beyond HPV and lichen sclerosus, a handful of other risk factors have been identified. Cigarette smoking carries roughly a four-and-a-half-fold increase in the risk of invasive disease.⁷ Lack of circumcision, obesity, immune-compromised states, and certain ultraviolet light treatments for psoriasis have also been linked to higher risk.⁸

Why This Distinction Between HPV-Positive and HPV-Negative Matters

Whether or not a tumor is HPV-driven affects more than just its origin story. Under the current classification system, penile squamous cell carcinomas are formally divided into HPV-associated and HPV-independent types. HPV-associated subtypes include basaloid, warty, and clear cell tumors, while HPV-independent carcinomas include the common “usual type,” verrucous, papillary, and sarcomatoid variants.⁹

Counterintuitively, HPV-independent tumors tend to be lower grade (more well-differentiated) while HPV-associated tumors are more often poorly differentiated. Yet the picture flips when you look at lymph node spread: HPV-independent and p16-negative tumors are significantly more likely to have spread to the inguinal lymph nodes.⁹ From the patient’s perspective, this matters because the specific subtype helps the surgical team decide how aggressively to investigate and treat the groin lymph nodes, a decision that carries real consequences for recovery and long-term outcomes. Researchers have grouped subtypes into low, intermediate, and high prognostic risk categories based on how likely they are to spread and how patients fare afterward.¹⁰

Symptoms and When to See a Doctor

Penile cancer usually starts as a visible change on the glans (the head of the penis) or the inner lining of the foreskin. Early signs include a lump, a persistent sore or ulcer that does not heal, unusual redness, a thickened area, or a change in skin color. Some men notice a foul-smelling discharge or bleeding from underneath the foreskin. The early stages can closely mimic harmless conditions like fungal infections, warts, or dermatitis, which is precisely why the disease is so easy to dismiss.

Experts stress that any penile lesion that does not respond to a short course of conservative treatment should be biopsied rather than watched and waited on. Survival correlates directly with stage at diagnosis, and there is frequently a mismatch between how a tumor looks on physical exam and what pathology reveals. Inflammatory changes around the tumor can mask how deeply it has invaded, and imaging does not always catch early lymph node spread.¹¹ MRI during an artificially induced erection, though not widely used, provides the best non-invasive view of how far the tumor extends into the deeper tissues.¹¹

The Problem of Delay

One of the cruelest features of this cancer is how often men wait before seeking help. In one large study, nearly 73% of patients waited more than a month after first noticing symptoms, roughly 46% waited more than three months, and about 24% waited longer than six months. The most common reasons were believing the symptom would go away on its own, feeling embarrassed to describe a genital problem to a doctor, or assuming it was not serious.¹² Each month of delay allows the cancer to invade deeper and potentially spread to the lymph nodes, turning a problem that might have been treated with a minor procedure into one requiring radical surgery.

How Staging Works

Penile cancer is staged using the TNM system, which evaluates the size and depth of the primary tumor (T), whether nearby lymph nodes are involved (N), and whether the cancer has spread to distant sites (M). In practice, accurately staging penile cancer is harder than it sounds. One study evaluating the TNM classification found no meaningful survival difference between the T2 and T3 categories or between the N1 and N2 categories, suggesting the staging system does not always cleanly separate patients by risk. A modified version of the classification did produce significant survival differences across all categories.¹³ This is an area of ongoing refinement, and clinicians typically weigh the formal stage alongside the histological subtype, tumor grade, and whether lymphovascular invasion is present.

Organ-Sparing Surgical Approaches

The treatment of penile cancer has evolved considerably. Decades ago, partial or total penectomy was the default, but accumulating evidence now supports organ-sparing surgery for appropriately selected patients. A systematic review found that while organ-sparing procedures carry a higher risk of local recurrence compared to amputation, overall survival is generally the same. The key is strict patient selection: when the cancer is caught early and confined to the glans, conservative surgery followed by close surveillance produces cancer-specific survival equivalent to more radical approaches, with the added benefit of preserved function and quality of life.¹⁴

Glansectomy, the removal of the glans with subsequent reconstruction using a skin graft, is one of the more common organ-sparing options for tumors confined to that area. In a systematic review, local recurrence after glansectomy ranged from about 3% to 17%, and disease-specific survival reached 89–97%.¹⁵ Another series found that over 90% of men retained glans sensation after glansectomy with split-thickness skin graft reconstruction, and nearly 90% reported satisfaction with the cosmetic result.¹⁶ Complications were not negligible: partial graft loss occurred in about 18% and narrowing of the urethral opening in about 6%, though these are manageable problems compared to the psychological toll of amputation.

For cancers that are too advanced or too proximally located for conservative surgery, partial or total penectomy remains necessary.¹⁷ Even among these patients, reconstructive techniques have improved, and urethral rerouting allows urination in a seated position when the entire shaft has been removed.

Managing the Lymph Nodes

Because penile cancer tends to spread first to the inguinal (groin) lymph nodes, managing this area is critical and often the most contentious part of treatment planning. The challenge is that even when the groin feels normal on examination, hidden cancer cells may already be present. Inguinal lymph node dissection, the traditional approach of surgically removing the groin nodes, is effective at catching disease but comes with meaningful side effects. The most common early complication is fluid collection at the surgical site, which occurs in roughly 44% of all dissections and up to 60% of radical dissections. Long-term leg swelling, or lymphedema, affects up to 36% of men who undergo radical dissection.¹⁸

To spare men with truly negative nodes from these complications, dynamic sentinel node biopsy has gained traction. This procedure uses a radioactive tracer and dye injected around the tumor to identify the first node or nodes that would receive drainage from the cancer. If those sentinel nodes come back clean, the full dissection can be skipped. One study reported that about 63% of groins were able to avoid full dissection through this approach.¹⁹ A larger analysis found that the technique has a high negative predictive value, meaning that when it says the nodes are clean, they almost always are, with sensitivity around 89% and specificity at 100%.²⁰ It also catches hidden cancer that standard imaging would miss.²¹

Radiation as an Alternative

Radiation therapy, particularly brachytherapy (where a radioactive source is placed directly against the tumor), offers another organ-preserving option for tumors limited to the glans and smaller than about four centimeters. Brachytherapy provides about 73% amputation-free survival at eight to ten years and 81% progression-free survival at five to ten years. External beam radiation can also control disease, though with somewhat higher relapse rates. Compared to total amputation, radiation does sacrifice some disease-free survival, but it preserves the organ, and salvage surgery remains possible if the cancer returns.²² The trade-off between maximum local control (surgery) and organ preservation (radiation) is one patients should discuss at length with a multidisciplinary team, ideally at a center experienced in treating this rare disease.

Chemotherapy and Immunotherapy for Advanced Disease

When penile cancer has spread to multiple lymph node stations or to distant organs, systemic treatment becomes the mainstay. Platinum-based chemotherapy regimens have historically been the standard, but outcomes in advanced disease remain poor, with median overall survival estimated at only about seven to eight months. Treatment decisions balance symptom control, side-effect tolerability, and patient preference, and early involvement of palliative care is considered essential.

Immunotherapy has begun to change this landscape. Because 40–60% of penile cancers express PD-L1, which signals susceptibility to immune checkpoint inhibitors, clinical trials have tested these drugs in combination with chemotherapy. A prospective trial of the checkpoint inhibitor tislelizumab combined with chemotherapy in locally advanced disease reported a 75% overall response rate, with a median progression-free survival of about 12.5 months and median overall survival of nearly 23 months.²³ A separate phase II trial using cemiplimab (a PD-1 inhibitor already approved for advanced skin squamous cell carcinoma) alongside cisplatin-based chemotherapy achieved a response rate above 50% at 12 weeks, with a median progression-free survival of about six months and overall survival estimated at roughly 15.5 months.²⁴ These numbers are modest by the standards of more common cancers, but they represent real progress for a disease that had few options beyond conventional chemotherapy.

Researchers are also exploring whether genomic profiling of tumors can identify men most likely to benefit from immunotherapy. Tumors with a high mutational burden may respond especially well to checkpoint inhibitors, and comprehensive genomic profiling can flag actionable mutations for targeted therapy or help match patients to clinical trials.²⁵ HPV-driven tumors also have emerging therapeutic avenues: vaccines targeting HPV cancer proteins and adoptive T-cell therapies are under investigation.²

Prevention

Several measures reduce the risk of penile cancer. Circumcision, particularly when performed in infancy or childhood, is the most well-established protective factor, largely because it eliminates phimosis and reduces the moist environment that fosters chronic irritation and HPV persistence. HPV vaccination, now widely recommended for boys and girls in many countries, targets the high-risk viral strains responsible for the majority of HPV-associated penile cancers. While no randomized trial has directly measured the vaccine’s effect on penile cancer rates (the disease is too rare for that to be practical), the vaccine’s proven ability to prevent the precursor HPV infections makes its benefit highly plausible. Smoking cessation matters too, given the roughly four-and-a-half-fold risk increase that cigarettes carry.⁷ Good genital hygiene and prompt treatment of conditions like lichen sclerosus round out the preventive picture.

The Psychological Toll

Even when treatment is successful from an oncological standpoint, penile cancer leaves a deep psychological mark. Studies using validated mental health screening tools have found impaired well-being in up to 40% of survivors, pathological anxiety in up to 31%, and diagnosable psychiatric illness in over half of patients in one study. About 40% of those screened showed symptoms consistent with post-traumatic stress disorder.²⁶ Men who undergo more disfiguring procedures are, unsurprisingly, hit hardest. Even after partial penectomy, where most men retain erectile function and the ability to ejaculate, sexual satisfaction tends to decline because of concerns about appearance and self-worth.²⁷

This emotional dimension is under-addressed in most clinical pathways. Fewer than half of treatment centers have formal psychosexual support services integrated into penile cancer care, and many men report feeling isolated because the disease is so rare that peer support groups are hard to find. If you or someone you know is facing this diagnosis, asking the clinical team about psychological referral early in the treatment process, rather than waiting until distress becomes severe, can make a meaningful difference.

Non-Squamous Penile Cancers

Though squamous cell carcinoma accounts for the vast majority of penile malignancies, other cell types occasionally arise. Melanoma, sarcoma, and extramammary Paget’s disease of the penis are all documented, though each is exceedingly rare. In one 15-year institutional series, just 12 non-squamous penile cancers were identified: five sarcomas, four melanomas, two cases of Paget’s disease, and one sebaceous carcinoma. Outcomes varied widely. Some melanoma patients were managed with penis-sparing surgery and remained disease-free, while those with deep or metastatic disease at diagnosis had much worse trajectories.²⁸ Because these cancers are so uncommon, there are no standardized treatment guidelines, and management decisions tend to be individualized.

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