🎗️

Prof. Giacomo Novara — Urology, University of Padua

Penile Carcinoma

Epidemiology, staging, organ-sparing treatment, and lymph node management

Penile carcinoma is a rare malignancy in Western countries but carries a devastating impact on quality of life and body image. In the vast majority of cases it is a squamous cell carcinoma (SCC). Optimal management requires a multidisciplinary approach at high-volume centres, with absolute priority given to organ-sparing treatment when oncologically safe and to accurate lymph node staging — the most relevant prognostic variable.

📊 Epidemiology and Risk Factors

Incidence is 0.1–1/100,000 in Europe and North America, with peaks up to 4/100,000 in Brazil, sub-Saharan Africa, and Asia. In Italy, approximately 400–500 new cases per year are estimated. Median age at diagnosis is ~60 years, with a second peak after age 75.

Main risk factors

🦠
HPV infection

Present in ~50% of cases; HPV 16 and 18 are the predominant genotypes. Strongly associated with the basaloid and warty histotypes (HPV-related). Vaccination reduces the incidence of these aggressive variants.

🔵
Phimosis

OR ~10 for penile carcinoma. Promotes smegma retention, chronic infections, and HPV infection. Neonatal circumcision is protective (RR reduced ~3-fold).

🔴
Lichen sclerosus

HPV-independent carcinogenic pathway. Associated with the differentiated histotype (dPeIN). Cumulative risk of malignant transformation ~5–10% in untreated cases.

🚬
Cigarette smoking

OR ~4.5; independent effect, synergistic with HPV. Smoking cessation reduces but does not eliminate the risk.

🛡️
Immunosuppression

HIV infection, organ transplantation, biological therapies: increase the risk of HPV persistence and malignant transformation.

☢️
PUVA therapy

Cumulative UVA exposure (psoriasis, vitiligo) increases the risk of genital SCC. Dose-dependent.

🔬 Histology — WHO 2022

Over 95% of penile tumours are squamous cell carcinomas (SCC). The WHO 2022 classification distinguishes histotypes with different biological behaviour and HPV profiles.

Precancerous lesions — PeIN (Penile Intraepithelial Neoplasia)

🟡
Differentiated PeIN (dPeIN)

HPV-unrelated. Associated with lichen sclerosus and chronic phimosis. Includes erythroplasia of Queyrat and Bowen's disease. Risk of progression to invasive SCC: ~30%. Worse prognosis because often diagnosed late.

🟢
Undifferentiated PeIN (uPeIN)

HPV-related (HPV 16/18). Encompasses the warty, basaloid, and warty-basaloid subtypes. Moderate progression risk; responds well to topical therapies and local ablation in early stages.

Invasive histotypes — clinical behaviour

⬜
Usual SCC (>60%)

The most frequent histotype. Partially HPV-related. Intermediate prognosis, strongly dependent on grade and LVI.

🔴
Basaloid SCC (~5–10%)

HPV-related (>80%). Aggressive: high rate of lymph node metastases even in T1. Worst prognosis among HPV-positive histotypes.

🟥
Sarcomatoid SCC (<5%)

HPV-unrelated. The most aggressive histotype overall. Early haematogenous metastases. Poor prognosis; systemic chemotherapy often required upfront.

🟩
Verrucous SCC (~5%)

HPV-unrelated. Exophytic growth, locally invasive but rarely metastasises. Good prognosis after complete excision.

🟨
Warty / warty-basaloid SCC (~10%)

HPV-related. Condylomatous appearance; intermediate prognosis (warty) or unfavourable (warty-basaloid). LN positivity more frequent than in the verrucous type.

⬛
Papillary SCC NOS (~5%)

HPV-unrelated. Exophytic growth, low malignancy. Rarely metastasises if G1.

📌 Clinical relevance of histotype: the HPV-related vs HPV-unrelated distinction influences prognosis and, in the future, may influence response to immunotherapy (PD-L1, TMB). In advanced disease, request an extended molecular profile (NGS).

📋 Staging — TNM 2017 (AJCC/UICC 8th Edition)

T — Primary tumour

CategoryDefinition
TisCarcinoma in situ (PeIN)
TaNon-invasive verrucous carcinoma
T1aInvasion of lamina propria without LVI, G1–2
T1bInvasion of lamina propria with LVI or G3/sarcomatoid
T2Invasion of corpus spongiosum (with or without urethral invasion)
T3Invasion of corpus cavernosum (with or without urethral invasion)
T4Invasion of adjacent structures (scrotum, prostate, pubic bone)

N — Regional lymph nodes (inguinal and pelvic)

CategoryDefinition
cN0No palpable or visibly enlarged inguinal lymph nodes
cN1Palpable mobile unilateral inguinal lymph node
cN2Palpable multiple or bilateral mobile inguinal lymph nodes
cN3Fixed inguinal mass or pelvic lymph nodes (uni- or bilateral)
pN0No metastasis in regional lymph nodes
pN1≤2 unilateral inguinal lymph node metastases, no ENE
pN2≥3 inguinal lymph nodes, bilateral, or with ENE (extranodal extension)
pN3Metastasis to pelvic lymph nodes (uni- or bilateral)

M — Distant metastasis

CategoryDefinition
M0No distant metastasis
M1Distant metastasis (lung, liver, bone — rare but with poor prognosis)
📌 Key prognostic variables: lymph node status (pN) is the most powerful survival predictor. At the level of the primary tumour: lymphovascular invasion (LVI), grade, and sarcomatoid histotype are independent predictors of occult lymph node upstaging.

🔍 Diagnosis and Clinical Staging

Primary tumour

1
Clinical examination

Location (glans, foreskin, shaft), size, extension to the urethral meatus, depth of infiltration, foreskin status (phimosis). Photographic documentation recommended.

2
Mandatory pre-treatment biopsy

Punch biopsy or incisional biopsy. No treatment should be initiated without histological confirmation: grade, LVI, and histotype guide surgical and lymph node decisions. Preemptive circumcision if phimosis prevents access to the lesion.

3
Penile MRI with artificial erection

Gold standard for local staging. Sensitivity 82–88% for distinguishing T1 (lamina propria) from T2 (corpus spongiosum) and T3 (corpus cavernosum). Essential before planning organ-sparing surgery.

4
Peniscopy

Useful for flat, multifocal, or indeterminate lesions at the glans margin. Guides targeted biopsy in forms not macroscopically evident.

Lymph node and distant staging

5
Bilateral inguinal ultrasound + ultrasound-guided FNA

First-line option in cN0 with suspicious nodes on imaging. Sensitivity ~80%. Histological positivity bypasses the DSNB pathway and directs the patient straight to radical LND.

6
CT chest/abdomen/pelvis with contrast

Indicated in all patients with cN+ or pT ≥ T2. Evaluates pelvic lymph nodes, retroperitoneal stations, and distant metastases (lung, liver, bone).

7
18F-FDG PET/CT

Not standard. To be considered in cN+ to assess pelvic nodes and potential systemic disease. Higher sensitivity than CT for nodes >10 mm; false negatives possible in microdeposits.

8
DSNB (Dynamic Sentinel Node Biopsy)

Indicated in cN0 with pT1b–T4 (see § Lymph Node Management). Requires nanocolloid 99mTc + blue dye ± preoperative SPECT/CT. Sensitivity 88–90%; false-negative rate ~5–7%. Only at high-volume centres with certified expertise.

🔧 Treatment of the Primary Tumour

The guiding principle of the EAU 2024 Guidelines is organ-sparing: preserve penile function and aesthetics whenever oncologically safe. A negative margin of 5 mm is considered adequate for conservative procedures.

Tis / Ta Non-invasive disease and carcinoma in situ
✅ First choice for Tis
Topical therapy (5-FU 5% or imiquimod 5%)

Local application for 4–16 weeks. Effective for PeIN and superficial lesions ≤Tis. Response rate ~50–70%. Requires close follow-up to detect progression or recurrence.

✅ Alternative for Tis–Ta
CO₂ / Nd:YAG laser

Laser ablation of superficial lesions. Does not provide a histological specimen for margin assessment → intensive follow-up is mandatory. Excellent cosmetic outcome.

🔵 Surgical alternative
Glans resurfacing / WLE

Surgical excision with margins. Glans resurfacing removes the glans epithelium and covers it with a skin graft: assessable margins, low morbidity, acceptable cosmetic result.

T1a (G1–2, no LVI) Low-risk lamina propria invasion
✅ First choice
Partial or total glansectomy ± reconstruction

Excision of the glans with clear margins. Reconstruction using split-thickness skin graft (thigh or groin). Allows histological margin assessment. Excellent oncological control; good cosmetic result.

🔵 Selected alternative
Interstitial brachytherapy

Indicated for lesions ≤4 cm on the glans, cN0, without corpus cavernosum involvement. LDR 60–65 Gy or PDR 42 Gy. Oncological outcomes equivalent to surgery for selected T1; local fibrosis rate ~20%.

T1b (G3 or LVI+) Lamina propria — high risk of occult lymph node involvement
✅ First choice
Total glansectomy ± partial penectomy

Extent of resection depends on MRI findings and intraoperative assessment. Urethral margin evaluated by frozen section. High probability of upstaging to T2 on final pathology (~20–30%).

⚠️ Highly selected cases only
Brachytherapy (T1b, glans, ≤4 cm)

Only if the patient refuses surgery or absolute contraindications exist. Requires rigorous follow-up for local recurrence (30–40% within 5 years with BT vs ~10–15% with surgery).

T2 — corpus spongiosum Corpus spongiosum invasion (± urethra)
✅ First choice
Partial penectomy

Penile resection with a distal margin of at least 5 mm. Residual stump sufficient for standing micturition (>3 cm ideally). Urethra–skin anastomosis. Optimal oncological control; local recurrence <5%.

🔵 Selected organ-sparing
Extended glansectomy with reconstruction

If MRI excludes corpus cavernosum invasion and the lesion is confined to the glans/distal corpus spongiosum. Requires dedicated surgical expertise.

⚠️ Non-surgical alternative
Brachytherapy (T2, ≤4 cm, glans)

Only for tumours confined to the glans without corpus cavernosum invasion, at expert centres. Local recurrence rate significantly higher than surgery for T2.

T3–T4 — corpus cavernosum / adjacent structures Locally advanced disease
✅ T3 — first choice
Partial or total penectomy

Total penectomy with perineal urethrostomy is required when clear margins cannot be guaranteed. Perineal reconstruction in selected cases.

✅ T4 — multimodal approach
Neoadjuvant chemotherapy → surgical reassessment

TIP regimen (3–4 cycles) or BMP. The goal is downstaging to enable R0 resection. In the absence of response or on progression: palliative surgery vs palliative chemotherapy.

📌 External beam radiotherapy (EBRT): indicated as an alternative for patients unfit for surgery or brachytherapy (60–66 Gy, 2 Gy/fr). Higher local recurrence rate; salvage options after in-field recurrence are limited.

🔗 Lymph Node Management

Inguinal lymph node status is the primary determinant of survival in penile carcinoma. The prevalence of occult positive nodes in cN0 ranges from 20% (T1a G1) to 50–70% (T2 G3). Optimal management depends on risk stratification.

Approach in cN0 — risk stratification

Low risk pTa, pT1a G1–2, no LVI
✅ EAU 2024 recommendation
Active surveillance

Clinical examination every 3 months for 2 years, then every 6 months. Inguinal ultrasound every 6 months. Probability of occult lymph node metastases <15%: the risk of lymphadenectomy (lymphoedema, infection) outweighs the benefit.

Intermediate risk pT1a G3 or pT1b (G1–2 with LVI)
✅ First choice — expert centres
Bilateral DSNB

Nanocolloid 99mTc + blue dye ± preoperative SPECT/CT. Performed simultaneously with or after primary tumour treatment. Sensitivity 88–90%; false-negative rate ~5–7%. Avoids complete LND in 70–80% of cases.

🔵 Alternative
Modified inguinal lymphadenectomy

Removal of lymph nodes within "modified" boundaries (medial to the superficial femoral vein). Lower morbidity than radical LND; false-negative rate ~10%. Preferred when DSNB is not available.

High risk pT2–T4, any G and LVI
✅ First choice — expert centres
Bilateral DSNB

Same technique as for intermediate risk. Strong EAU 2024 recommendation. DSNB negativity excludes lymph node disease with sufficient accuracy in pT2–T4.

🔵 Alternative
Bilateral modified inguinal lymphadenectomy

If DSNB is unavailable or not technically feasible (prior inguinal surgery, scarring). Acceptable morbidity at experienced centres.

Approach in cN+ — clinically evident lymph node disease

cN1–2 — mobile lymph nodes FNA first for cytological confirmation
✅ EAU 2024 recommendation
Bilateral radical inguinal lymphadenectomy

Removal of all superficial and deep inguinal lymph nodes, including nodes above the inguinal ligament. The clinically N0 side should be treated with modified LND or DSNB. Significant morbidity: lymphoedema (20–50%), wound infection, skin necrosis.

⚠️ Consider
Neoadjuvant chemotherapy → LND

Indicated when cN2 with LN >4 cm or suspected ENE on imaging. TIP regimen (3–4 cycles). Goal: improve resectability and reduce LND morbidity (less ENE, less skin involvement).

cN3 — fixed mass or pelvic LN Advanced lymph node disease
✅ First choice
Neoadjuvant chemotherapy (TIP ×3–4) → reassessment

If response to chemotherapy: radical inguinal LND + pelvic lymphadenectomy (external/internal iliac/obturator nodes). In case of progression or no response: palliative chemotherapy or multidisciplinary approach.

Pelvic lymphadenectomy — indications

  • ≥2 positive inguinal lymph nodes (pN2) on final pathology
  • Extranodal extension (ENE) at any level
  • pN3 (pelvic lymph node metastases suspected on imaging)
  • Positive pelvic nodes on PET/CT or CT

VEIL (video-endoscopic inguinal lymphadenectomy) is a minimally invasive alternative at high-volume centres: lower morbidity, equivalent oncological staging.

💊 Systemic Therapy

Neoadjuvant Resectable cN2–3 — downstaging before LND
✅ Reference regimen
TIP (paclitaxel + ifosfamide + cisplatin)

Paclitaxel 175 mg/m² day 1 + ifosfamide 1,200 mg/m²/day days 1–3 + cisplatin 25 mg/m²/day days 1–3, every 21 days × 3–4 cycles. ORR ~50%; pCR ~10%. De facto standard at specialised centres (Pagliaro 2010, LoE 2b).

⚠️ Alternative regimen
BMP (bleomycin + methotrexate + cisplatin)

Historical regimen; bleomycin pulmonary toxicity limits its use. Now reserved for patients ineligible for TIP (mild renal insufficiency, contraindication to paclitaxel).

Adjuvant pN2–3 / ENE — after radical LND
⚠️ Consider (low LoE)
Cisplatin-based adjuvant chemotherapy (TIP or cisplatin + 5-FU)

Not standard due to absence of RCT data. Retrospective evidence suggests benefit in pN2–3. NCCN Category 2B. Individualised decision in MDT. Alternative: adjuvant RT to lymph node stations.

Palliative Metastatic disease or unresectable recurrence
✅ First line
TIP or cisplatin + 5-FU

ORR 30–50%; mOS 6–12 months. TIP preferred for a more manageable toxicity profile compared to BMP. Continue until progression or unacceptable toxicity.

⚠️ Second line
Docetaxel monotherapy

ORR ~15–20% in second line; option in patients with good PS. Data limited to retrospective series.

🔵 Second line — biomarker-driven
Pembrolizumab (TMB-high / MSI-H) · Erdafitinib (FGFR3 mut.)

Pembrolizumab approved for TMB-high ≥10 mut/Mb solid tumours (tissue-agnostic). Erdafitinib for FGFR3 alterations (rare in penile carcinoma). Requires extended molecular profiling (NGS).

⚠️ NGS in advanced disease: request a comprehensive molecular profile (FGFR3, PIK3CA, TMB, MSI-H, PD-L1, HPV-driven alterations) to identify patients eligible for targeted therapy or immunotherapy and for clinical trial enrolment.

📅 Follow-up

Follow-up intensity depends on pathological stage and the approach taken for both the primary tumour and the lymph nodes. Local recurrence is treatable; inguinal recurrence after surveillance carries a less favourable prognosis than recurrence after LND.

Surveillance schedule

1
Years 1–2 — every 3 months

Clinical examination of the penis (local recurrence), bilateral inguinal palpation (lymph node recurrence). Inguinal ultrasound every 6 months in high-risk pN0. CT chest/abdomen/pelvis every 6 months in pN+.

2
Years 3–5 — every 6 months

Same schedule; imaging on clinical indication in pN0. Annual CT in pN+. Psychosexual counselling and assessment of residual erectile function.

3
Beyond 5 years — annually

Annual clinical examination; imaging on indication. Management of chronic lower limb lymphoedema (common after bilateral LND). Monitoring of voiding and urethral function in patients with perineal urethrostomy.

Recurrence management

🔄
Local recurrence

Organ-sparing re-excision if achievable margins; penectomy if not. Salvage RT in selected cases unfit for surgery.

🔁
Inguinal recurrence (after surveillance)

Radical LND ± neoadjuvant chemotherapy. Relatively favourable prognosis if isolated N1 at the time of recurrence.

⚠️
Systemic recurrence

Palliative cisplatin-based chemotherapy ± immunotherapy in TMB-high tumours. Poor prognosis; mOS <12 months. Early integrated palliative care.

📈 Prognosis

Survival is closely correlated with pathological lymph node status. Five-year disease-specific survival (DSS) data vary dramatically according to pN category.

pN0 — no positive LN
5-year DSS: 85–95%

Excellent prognosis. Low risk of systemic recurrence. Clinical follow-up alone sufficient for low-to-intermediate risk.

pN1 — 1–2 LN, no ENE
5-year DSS: ~75–80%

Documented benefit of radical LND. Consider adjuvant chemotherapy in pN1 with risk factors (G3, LVI, sarcomatoid histotype).

pN2 — ≥3 LN, bilat. or ENE
5-year DSS: ~35–50%

ENE is the most powerful negative prognostic factor in this category. Adjuvant chemotherapy and/or RT indicated in MDT. Clinical trial enrolment recommended.

pN3 — pelvic LN
5-year DSS: <15%

Poor prognosis. Multimodal approach (chemotherapy + surgery + RT) in patients with good PS. Early palliative care for the remainder.

📌 Independent prognostic factors: ENE, number of positive lymph nodes, bilateral lymph node involvement, sarcomatoid histotype, LVI, pT stage, response to neoadjuvant chemotherapy (in cN+), surgery-to-recurrence interval.

❓ Frequently Asked Questions

Not necessarily. The vast majority of penile cancers are diagnosed at an early stage, when it is possible to remove only the affected portion while preserving the rest of the organ — a strategy known as "organ-sparing." With these techniques, most patients can maintain normal urination and residual sexual function. The decision depends on the location, extent, and microscopic characteristics of the tumour. In advanced or recurrent cases, a more extensive procedure may be necessary, but even then reconstructive options exist to preserve quality of life.
Penile carcinoma frequently spreads to the inguinal lymph nodes even when they are not palpable — these are referred to as "occult" metastases. Clinical studies have shown that up to 20–50% of patients with apparently normal lymph nodes harbour tumour cells within them. For this reason, in intermediate- or high-risk patients, evaluation of the inguinal nodes is recommended even in the absence of clinically enlarged nodes. The most modern technique — dynamic sentinel node biopsy — identifies the "sentinel" nodes using a small injection of radiotracer, avoiding complete lymph node dissection in many cases.
HPV — the same virus involved in cervical cancer and other genital tumours — is present in approximately half of penile carcinomas, primarily in the "basaloid" and "warty" variants. HPV is sexually transmitted and in many cases remains latent for years before causing cellular abnormalities. Not all penile cancers are HPV-related: those arising on lichen sclerosus, chronic phimosis, or other aetiologies follow an HPV-independent pathway. HPV vaccination in adolescent males is recommended and reduces the risk of developing virus-related forms.
The sentinel lymph node is the first lymph node to receive tumour cells shed from the primary tumour. It acts as a "filter" through which the disease passes before spreading to other lymph nodes. By identifying and analysing it, one can determine whether the tumour has already begun to spread — without having to remove all inguinal lymph nodes (a more demanding procedure with greater complications such as lymphoedema). The dynamic sentinel node biopsy technique uses a radiotracer injected near the tumour: the tracer follows the same lymphatic pathways as the tumour and precisely localises the node to be analysed. However, this technique is reliable only at specialised centres with dedicated expertise.
Lower limb lymphoedema — chronic swelling caused by interruption of the lymphatic vessels — is the most frequent complication after inguinal lymph node dissection, affecting 20–50% of patients. At expert centres, its incidence has decreased thanks to more conservative surgical techniques and the use of sentinel node biopsy. Those who develop lymphoedema may benefit from specialised physiotherapy, compression stockings, and in some cases lymphatic stimulation or microsurgical procedures. It is important to report any swelling of the thigh, ankle, or foot early, so that treatment can begin in the initial phases when it is most effective.

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