Penile and urethral cancer

• Penile cancer is rare, rises with age and is concentrated where human papillomavirus (HPV) is common; roughly one-third to half of cases are HPV-associated.
• Phimosis is a strong risk factor; neonatal circumcision lowers incidence, while lichen sclerosus, smoking, ultraviolet A photochemotherapy and low socioeconomic status add risk.
• Squamous cell carcinoma makes up more than 95% of penile malignancies; penile intraepithelial neoplasia (PeIN) is the precursor.
• Early disease is often curable by organ-sparing excision with minimal margins; survival falls sharply once nodes or distant sites are involved.
• Regional nodes decide prognosis: cN0 high-risk tumours need dynamic sentinel node biopsy (DSNB); cN1-cN3 disease needs inguinal lymph node dissection (ILND), often with cisplatin-based chemotherapy.
• Primary urethral carcinoma is even rarer, mostly urothelial in men and adenocarcinoma in women, and is managed along similar surgical and multimodal lines.

By the end of this page you should be able to:

1. List the premalignant penile lesions and explain the HPV and phimosis links.
2. Use the UICC/AJCC TNM stages and stage groups for penile cancer and for urethral cancer.
3. Plan (organ-sparing) surgery of the primary tumour, including when partial or total penectomy is required.
4. Stage the groins and choose between DSNB, ILND and pelvic lymph node dissection.
5. Outline cisplatin-based systemic therapy and radiotherapy roles, plus low-resource practice.
6. Outline the distinct epidemiology and management of primary urethral carcinoma in men and women.

Penile cancer is a squamous malignancy of the penile epithelium and mucosal surfaces. It is rare in most high-income countries but varies markedly by region and by the prevalence of HPV infection, neonatal circumcision and inflammatory penile disease.^[1] Primary urethral carcinoma (PUC) is a separate, even rarer malignancy arising from the urethral mucosa; its histology, staging and treatment overlap with penile cancer in men but differ in women.^[5]

Two guidelines anchor modern practice. The European Association of Urology (EAU) publishes an online guideline on penile cancer (2026 edition) and a separate online guideline on primary urethral carcinoma.^[1][5] The National Comprehensive Cancer Network (NCCN) lists a penile cancer guideline at Version 1.2027.^[2] Where guidance differs on details such as eligibility for neoadjuvant chemotherapy or breadth of inguinal dissection, this page notes the difference rather than choosing one rule.^[3]

Penile intraepithelial neoplasia (PeIN) is the precursor lesion of invasive penile squamous cell carcinoma. PeIN includes differentiated (HPV-independent, often lichen sclerosus-associated), basaloid, warty and mixed subtypes, and corresponds clinically to carcinoma in situ (Tis).^[1] Penile cancer itself is a squamous cell carcinoma (SCC) in more than 95% of cases, graded by depth of invasion and differentiation; other lines (basal cell, melanocytic, mesenchymal, metastatic) are exceptional.^[1]

A useful clinical split is between HPV-associated disease (warty, basaloid and some mixed lesions, often p16 positive) and HPV-independent disease (usual SCC, pseudohyperplastic, verrucous, carcinomas arising on lichen sclerosus).^[1] Premalignant lesions include PeIN, erythroplasia of Queyrat, Bowen disease of the penile shaft, bowenoid papulosis, giant condyloma of Buschke-Lowenstein, lichen sclerosus (often preceding differentiated PeIN) and condyloma acuminata. Most premalignant lesions remain indolent: isolated PeIN is highly recurrent after excision (about 30 to 48%) yet progresses to invasive carcinoma only in about 2%.^[1]

Penile cancer is rare. Incidence rises to a peak in the sixth decade, is highest in men with phimosis, and clusters regionally with low neonatal circumcision rates and high HPV prevalence.^[1] In the United States, SEER 2000-2016 data showed an estimated annual percent change of +3.5% from 2004 to 2016, following earlier declines.^[1] Regional examples include Saxony (Germany), where incidence (age-standardised) rose from 0.86 to 2.67 per 100,000 men between 2000 and 2018, and the Netherlands, where incidence rose from 0.92 to 1.83 per 100,000 between 1990 and 2020; by contrast, French rates (about 0.59 per 100,000) have been stable since 1989.^[1]

About one-third to one-half of penile cancers are attributed to HPV, and the proportion of HPV-related cases appears to be increasing in some registries.^[1] No report links penile cancer to HIV or AIDS.^[1]

Outcome depends on stage: SEER data from 18 cancer registries indicate an overall five-year relative survival of about 67%, up to 81% with localised disease and only 16% with distant metastases.^[1]

Phimosis is the dominant risk factor: inability to retract the foreskin keeps the glans in a chronic inflammatory, HPV-exposed environment. Chronic penile inflammation, lichen sclerosus, smoking, ultraviolet A phototherapy and low socioeconomic status are also implicated.^[1] Neonatal circumcision reduces penile cancer incidence but appears not to reduce PeIN risk; incidence is lowest in populations with near-universal neonatal circumcision.^[1]

The HPV link is mechanistic as well as epidemiological: HPV DNA is found in PeIN and invasive tissue, and viral oncoproteins interact with p16, p53 and Rb. HPV-driven lesions tend to be warty or basaloid; HPV-independent disease tends to be usual SCC on a background of lichen sclerosus.^[1]

HPV-independent cancer follows the sequence lichen sclerosus or chronic inflammation to differentiated PeIN to invasive SCC, with late nodal spread. HPV-associated cancer follows HPV infection to basaloid or warty PeIN to invasive SCC, with a different molecular pattern and often better response to radiotherapy. In both pathways the glans, foreskin and coronal sulcus are the common sites, and spread is first to the superficial and deep inguinal nodes, then the ipsilateral pelvic nodes; retroperitoneal disease is classified as distant metastasis.

Grossly, penile SCC is a papillary, ulcerative or flat lesion; microscopic grading runs from well to poorly differentiated. The current WHO approach separates HPV-associated from HPV-independent SCC and recognises subtypes (verrucous, pseudohyperplastic, basaloid, warty, sarcomatoid). p16 and p53 staining help classify but do not change stage.

History. Patients often present late because of embarrassment, phimosis or tolerable symptoms. Complaints include a non-healing ulcer or warty growth, bleeding, discharge, pain (often late), phimosis or urinary obstruction, and inguinal lumps. Constitutional symptoms appear with nodal or distant disease.

Examination. Inspect the whole penis including under the foreskin, document size, position and apparent invasion, and estimate stretched length. Palpate both groins and note number, mobility and fixation of nodes. A hidden lesion under a phimotic foreskin is a classic source of delay, so every phimosis in an adult deserves inspection.^[1]

Primary tumour. Detailed examination and measurement; biopsy for any non-obvious lesion or before non-surgical treatment. MRI helps when corporal invasion (cT3) is uncertain or when organ-sparing surgery is being planned: pooled sensitivity 80% and specificity 96% for predicting corporal invasion. MRI with and without artificial erection performed similarly. If MRI is unavailable, penile ultrasound is an alternative.^[1]

Nodes and staging. Physical examination of both groins; inguinal US with fine-needle aspiration cytology of sonographically abnormal nodes. CT, MRI and PET/CT cannot detect micrometastases and are of limited value in clinically node-negative (cN0) men. In cN+ men, image-guided biopsy confirms nodal metastasis, and CT of chest/abdomen or PET/CT stages the pelvis and excludes distant disease; PET/CT showed 91% sensitivity and 100% specificity for pelvic metastases in men with US plus FNAC-confirmed positive inguinal nodes.^[1]

Penile cancer is staged with the 8th/9th edition UICC/AJCC TNM. The 9th edition (2025) does not differ from the 8th. T1a are tumours without lymphovascular or perineural invasion that are not poorly differentiated; T1b have lymphovascular or perineural invasion or are poorly differentiated. T2 invades corpus spongiosum (with or without urethra), T3 invades corpus cavernosum, T4 invades other adjacent structures. For nodes, pN1 is one or two inguinal metastases, pN2 three or more unilateral or any bilateral, pN3 pelvic nodes or extranodal extension. Stage II subdivides into IIA (T1b-T2 N0 M0) and IIB (T3 N0 M0).

Risk stratification matters as much as stage: SCC grade and lymphovascular invasion are the main predictors of nodal metastasis, and T1a grade 2 lesions can be offered surveillance instead of surgical staging if the patient is frail and follow-up reliability is high.

Circumcision is the first surgical step because most PeIN sits on glans and prepuce mucosa and keratinisation of the glans after circumcision (three to six months) can resolve residual disease.^[1] Topical therapy with 5-fluorouracil or imiquimod is an effective non-invasive first-line option for biopsy-confirmed PeIN; laser ablation (carbon dioxide or Nd:YAG) is an option for biopsy-confirmed PeIN, Ta or T1 lesions.^[1] Glans resurfacing is used for superficially invasive lesions; response rates 40-100% for topical agents and 52-100% for laser ablation have been reported, with small glans resurfacing series showing low recurrence.^[1]

When feasible, small localised invasive lesions should receive organ-sparing treatment; excision gives both treatment and definitive pathological staging, while punch biopsy risks understaging or missing intratumour heterogeneity. Foreskin tumours are treated by (radical) circumcision. For glandular and coronal lesions the surgical options are wide local excision, partial glansectomy or total glansectomy with reconstruction; additional circumcision is advised in glandular tumours. Radiotherapy (external beam or brachytherapy) is an organ-preserving alternative. Laser monotherapy shows high local recurrence in reported series and is best limited to T1 disease, with careful pre-treatment biopsy for risk stratification.^[1]

Organ-sparing surgery is now standard, based on retrospective evidence that local recurrence has limited impact on long-term survival in lower-risk tumours, although residual predisposed epithelium carries a risk of metachronous recurrence. In one multi-institutional series enriched for lower-risk tumours (80% T1, 20% grade 3), local recurrence reached 30% but did not adversely affect survival; in a higher-risk cohort treated with glansectomy or partial penectomy, fewer local recurrences occurred but survival was worse. These contrasts likely reflect tumour biology rather than surgical completeness. Five-year recurrence-free rates for organ-sparing surgery were 82% in case series and 76.7% in non-randomised studies, versus 83.9% and 93.3% for (partial) amputation; laser therapy five-year recurrence-free rate averaged 69.4%.^[1]

Surgical margins. Most lesions do not spread more than 5 mm beyond the macroscopic margin, and an excision margin of 5-10 mm gives acceptably low recurrence rates. In lower-risk tumours, recurrence does not affect survival and margins greater than 1 mm do not raise local recurrence risk; margins can therefore be minimal in smaller, less aggressive lesions, with a rim of clinically normal skin around the tumour and surrounding erythema. For bulky or higher-grade lesions, a wider margin or partial penectomy is prudent. PeIN at a surgical margin is a difficult situation: re-excision may harm function and quality of life, and active surveillance with or without topical therapy is reasonable after discussion.^[1] Frozen-section assessment is helpful when radicality is in doubt but is not recommended for routine use.^[1]

Radiotherapy is an organ-preserving option for selected biopsy-confirmed T1 or T2 lesions, given as external beam radiotherapy at a minimum dose of 60 Gy EQD2 (with brachytherapy boost) or brachytherapy alone; brachytherapy has only been studied for lesions under 4 cm. Local control rates range from 70 to 90% with brachytherapy; cumulative mean five-year recurrence-free rates were 78.6% after brachytherapy and 55.2% after external beam radiotherapy. Complications include urethral stenosis (20 to 35%), glans necrosis (10 to 20%) and, rarely, penile amputation for necrosis. Sexual function is usually preserved. Radiotherapy can salvage local recurrence after surgery.^[1]

Corpora cavernosum invasion (T3) calls for partial penectomy, with or without reconstruction; large invasive tumours not amenable to partial amputation need total penectomy and perineal urethrostomy. Advanced fixed or non-resectable primary lesions may receive induction chemotherapy followed by surgery in responders, or chemoradiotherapy, or primary chemoradiotherapy where surgery is refused; in locally advanced urethral squamous disease, chemoradiotherapy with 5-fluorouracil and mitomycin plus radiotherapy achieved a clinical complete response of about 80% in a series of 25, whereas in penile squamous disease an observational chemoradiotherapy cohort had a 73% response rate and 39% complete response. Partial and total penectomy are also used for large local recurrences or corpora cavernosum involvement.^[1]

This is the decisive part of treatment.

cN0 (clinically negative groins). Surgical nodal staging is offered to all with high risk of micrometastatic disease (T1b or higher, and T1a grade 3 with risk features). T1a grade 2 disease can be surveyed in frail patients willing to comply with strict follow-up. When staging is indicated, dynamic sentinel node biopsy (DSNB) is the gold standard: sensitivity 92 to 96%, false-negative rate 4 to 8%, complication rate 6 to 14%; a meta-analysis reported a higher pooled false-negative rate of about 12%, with lower rates in high-volume centres. Performed with radioactive tracer and blue dye, increasingly with SPECT/CT and hybrid tracer, DSNB can be preceded by inguinal ultrasound with FNAC (positive FNAC moves the patient straight to ILND). If DSNB is unavailable or declined, ILND (open or videoendoscopic) is performed. Delay in nodal management of more than three to six months may affect disease-free survival, and early ILND in cN0 men improved three-year cancer-specific survival compared with delayed ILND (84% vs 35% and 71% vs 50% in two series).^[1]

cN1-N2 (mobile inguinal disease). Metastases are present in about 45 to 80% of palpable nodes, confirmed by image-guided biopsy. Radical ILND remains standard of care. Its classical template (Daseler) runs from the external ring to the anterior superior iliac spine, down 20 cm laterally and 15 cm from the pubic tubercle medially, to the apex of the femoral triangle; fascia-sparing variations aim to reduce morbidity with comparable three-year disease-free survival of 80 to 92% in small series. ILND labels are not quality surrogates: lymph-node yield varies from greater than 8 to greater than 15-16 and lymph-node density thresholds from under 6.7% to under 22% without consistency, and they cannot be recommended as standards. Radical ILND carries meaningful morbidity (21 to 55% in contemporary series), dominated by wound infection and necrosis, lymphoedema and lymphocele. ^[1]

cN3 (fixed or bulky disease, or pelvic adenopathy). These need multimodal treatment: induction cisplatin-based chemotherapy followed, in responders, by radical ILND and pelvic lymph node dissection (prophylactic ipsilateral dissection even without clinically evident pelvic metastases, because microscopic pelvic metastases occur in 44-100% with extracapsular disease). Surgery for fixed inguinal masses without prior chemotherapy has poor outcomes (median disease-specific and disease-free survival of six and three months in one series) and is discouraged. Surgical consolidation occurs 5 to 8 weeks after completing chemotherapy. ^[1]

Systemic therapy. Cisplatin-based combination chemotherapy achieves objective response around 40 to 50% with TIP (paclitaxel-ifosfamide-cisplatin) or TPF (docetaxel-cisplatin-5-fluorouracil). Neoadjuvant response rates average about 50% (median 50%, range 29 to 90% in a systematic review; pooled 53%, 95% CI 42-64% in EAU 2026), with pathological complete or ypN0 responses reported as 10 to 25% in the systematic review and 4 to 10% in EAU 2026 pooled prospective data; prospective trials report complete response in 10% with TIP and 4% with TPF (EAU 2026), while systematic reviews describe pCR of about 10 to 13%. EAU and NCCN favour cisplatin-based multi-agent regimens; ESMO-EURACAN is more conservative in neoadjuvant and adjuvant use. For cisplatin-unfit patients, carboplatin-taxane doublets or cisplatin plus 5-fluorouracil are alternatives; bleomycin-containing regimens should be avoided because of pulmonary toxicity. Adjuvant chemotherapy may be offered for pathologic N3 disease. Single-agent taxanes or vinflunine give modest second-line benefit.^[1][3][4]

• Local recurrence after organ-sparing surgery in 4 to 30% depending on risk and method; usually salvageable.
• Nodal recurrence in the first two years; under-staging and delayed treatment are the avoidable causes.
• Treatment morbidity: meatal stenosis after glansectomy, urethral stenosis, glans necrosis, lymphoedema and wound problems after ILND.
• Metastatic disease: liver, lung, bone, skin; second only to nodal burden in prognosis.

Nodal status is the dominant predictor. Survival is good for disease confined to the penis, worsens with the number of positive nodes and extranodal extension, and is poor with pelvic node involvement or distant metastasis. HPV-positive status and younger age tend toward better outcomes; lichen sclerosus-associated HPV-independent tumours can be more locally aggressive. Long-term follow-up with clinical examination and imaging is needed because late inguinal recurrence and metachronous primary lesions occur, particularly after organ-sparing surgery.

There is no population screening. Prevention includes:

• Neonatal or early childhood circumcision in high-incidence settings (evidence for prevention, not for PeIN reduction).
• HPV vaccination before sexual debut (HPV is responsible for about one-third to one-half of cases; the same types drive cervical and oropharyngeal cancer).
• Treatment of phimosis and lichen sclerosus, with biopsy of any indurated or changing lesion.
• Patient education about non-healing penile lesions and the need to seek care promptly, since embarrassment is a common cause of delay.

• Children. Penile cancer and high-grade PeIN are extremely rare in children; suspicious lesions need biopsy rather than reassurance.
• Older adults. Frailty shapes the extent of surgery and the use of radiotherapy instead of amputation; shared decision-making is essential.
• Immunocompromised patients. HPV-related disease may be more extensive and multifocal; margins and follow-up are tightened.

• Circumcision and topical treatment handle most PeIN where pathology and radiotherapy are unavailable.
• Biopsy confirms diagnosis before surgery whenever possible; fixed or buried lesions must be fully inspected.
• Inguinal palpation and ultrasound with FNAC replace DSNB for many patients.
• Cisplatin-based chemotherapy requires renal monitoring; carboplatin-based or 5-fluorouracil doublets are the fallback when cisplatin fitness is limited.
• Early referral for nodal disease saves lives: ILND and (chemo)radiotherapy are curative for limited nodal disease.

PUC is a rare malignancy (under 1% of genitourinary cancers), with 2013 European prevalence about 3,986 cases and about 1,504 new cases yearly, and a male to female prevalence of about 2.9 to 1.^[5] Incidence rises with age (peak over 75 years; 7.6 per million), with male age-standardised rate 4.3 per million and female rate 1.5 per million; rates are negligible under 55 years.^[5] Histology differs by sex: in men, RARECARE reports urothelial 54 to 65%, squamous 16 to 22%, adenocarcinoma 10 to 16%, a SEER analysis reports urothelial 78%, squamous 12%, adenocarcinoma 5%, and a further SEER series reports urothelial 53.6 to 78%, squamous 12 to 34.8%, adenocarcinoma 5 to 11.6%; in women, adenocarcinoma 38 to 47%, squamous 25 to 28%, urothelial 25 to 28%.^[5] Risk factors include urethral stricture, chronic irritation after catheterization or urethroplasty, prior radiotherapy, chronic infection with HPV 16, lichen sclerosus in men, and urethral diverticulum or recurrent urinary tract infection in women.^[5]

PUC is staged with the 8th edition TNM (distinct prostatic urethral carcinoma table). T1 invades subepithelial connective tissue; T2 invades corpus spongiosum, prostate or periurethral muscle (T2 not applicable in urethral diverticulum, which lacks periurethral muscle); T3 invades corpus cavernosum, beyond prostatic capsule, anterior vagina or bladder neck; T4 invades other adjacent organs. Nodes: N1 single node, N2 multiple; M as usual.

• Men with distal (penile) urethral disease: penile-preserving distal urethrectomy is an alternative to penile amputation if negative margins can be achieved, including with less than 5 mm margins; complete circumferential assessment of the proximal margin is required. Recurrence is significantly higher with positive proximal margins or lymphovascular or perineural invasion.^[5]
• Women with localised disease: radical urethrectomy with removal of periurethral tissue and soft tissue up to the pubic symphysis and bladder neck gives the highest chance of local cure. Urethra-sparing surgery or radiotherapy is an alternative for distal disease, but recurrence and local toxicity are substantial (median 65 Gy, range 40 to 106 Gy; five-year local control 64%, seven-year cancer-specific survival 49%; severe complications in 30%).^[5]
• Locally advanced disease: multimodal therapy (surgery plus cisplatin-based chemotherapy plus or minus radiotherapy) outperforms monotherapy. Neoadjuvant chemotherapy may improve survival in locally advanced or node-positive disease; nodes in urethral squamous cell carcinoma are managed by inguinal dissection when resectable.^[5]
• Chemoradiotherapy is an established organ-preserving approach in locally advanced squamous urethral cancer: in the largest series 25 patients treated with 5-fluorouracil and mitomycin plus radiotherapy achieved clinical complete response in about 80%, with five-year overall and disease-specific survival of 52% and 68%.^[5]
• Urothelial carcinoma of the prostate: BCG after transurethral resection has high disease-free survival; stromal invasion warrants consideration of radical cystoprostatectomy.^[5]
• For advanced urothelial urethral carcinoma, perioperative systemic therapy follows the EAU muscle-invasive bladder cancer guidelines.^[5]

• HPV and phimosis define risk; circumcision and HPV vaccination prevent most disease.
• Premalignant PeIN is very common but rarely invasive.
• Organ-sparing surgery with minimal margins is the standard early approach.
• Nodes decide survival; DSNB, then radical ILND, then multimodal therapy for cN3.
• Follow guidelines (EAU, NCCN) and record the edition used.