Penile Cancer: March 2026 Update

Introduction and Aim

The European Association of Urology (EAU) – American Society of Clinical Oncology (ASCO) Guidelines on Penile Cancer represent a comprehensive, multidisciplinary update for March $2026$. These guidelines are designed to focus clinical decision-making on the diagnosis and management of penile squamous cell carcinoma (SCC) while emphasizing the necessity of individual expertise and patient values.

• Aims and Objectives: To provide the most up-to-date, evidence-based recommendations for the care of patients with penile SCC.
• Panel Composition: An international team including urologists, pathologists, medical oncologists, radiation oncologists, and patient advocates.
• Guideline Nature: These are not legal mandates or standards of care but provide the best available evidence.
• Updates for $2026$: This version is a complete revision of the $2023$ publication, incorporating new sections on genomic testing, restructured immunotherapy sections, and new data on centralized care and quality of life (QoL).

Epidemiology and World Trends

Penile cancer incidence shows significant geographic and socioeconomic variation.

• Global Incidence:
  • Industrialized Countries: Incidence is low, approximately $0.94/100,000$ males in Europe and $0.5/100,000$ in the United States ($USA$).
  • Developing Regions: High incidence in parts of South America, Southeast Asia, and Africa, where it can account for $1\%$–$2\%$ of male malignancies.
  • Specific National Data: Age-adjusted incidence is $0.7$–$3.0$ in India, $8.3$ in Brazil, and significantly higher in regions like Uganda.
• European Heterogeneity:
  • Highest Incidence: Lithuania, Latvia, and Ireland.
  • Intermediate: Czechia, Belgium, Germany, Estonia.
  • Lowest: Austria.
  • Trends: Norway reported an increase from $0.65/100,000$ in $1956$–$1960$ to $0.91/100,000$ in $2011$–$2015$. The Netherlands saw an increase from $0.92$ to $1.83/100,000$ per year between $1990$ and $2020$.
• Demographics: Risk increases with age, peaking in the sixth decade ($60$–$69$ years), though it occurs in younger patients.
• Epidemiological Drivers: The rise in Western countries is likely driven by higher Human Papillomavirus ($HPV$) infection rates, similar to trends seen in oropharyngeal carcinoma.

Risk Factors and Prevention

• Human Papillomavirus ($HPV$): The main risk factor. Deoxyribonucleic acid ($DNA$) of $HPV$ is identified in approximately $50.8\%$ (95\% $CI$: $44.8$–$56.7$) of penile cancers. Genotype $HPV16$ is the most frequent ($68.3\%$).
• Phimosis: Strongly associated with invasive cancer due to chronic infection and inflammation.
• Other Factors: Lichen sclerosus, chronic penile inflammation, cigarette smoking, low socioeconomic status, and low education levels.
• Prevention:
  • Neonatal Circumcision: Reduces the incidence of invasive cancer (Odds Ratio [$OR$]: $0.41$), though the effect is weaker in men without phimosis ($OR$: $0.79$). It does not necessarily reduce the risk of Penile Intraepithelial Neoplasia ($PeIN$).
  • Vaccination: Gender-neutral $HPV$ vaccination is encouraged. While precise estimates for penile invasive carcinoma reduction are pending, vaccination reduces infections in other sites ($Anal\,RR: 0.42;\,Oral\,RR: 0.16;\,Cervical\,RR: 0.22$).

Pathological Classification and Subtypes

More than $95\%$ of penile cancers are SCCs. The $2022\,WHO$ Classification categorizes them by $HPV$ association.

HPV-Independent Subtypes

• Usual SCC: $45\%$–$75\%$ frequency. Diagnosis of exclusion. $20\%$–$38\%$ mortality.
• Verrucous: $3\%$–$8\%$ frequency. Well-differentiated, pushing front, $0\%$ reported metastasis.
• Sarcomatoid: $1\%$–$7\%$ frequency. Epithelial and spindle cell neoplasia. Most aggressive with $45\%$–$90\%$ mortality.
• Cuniculatum: Endophytic labyrinthine growth. $0\%$ mortality.
• Papillary: Covered by well-differentiated cells. 0\%$–6\% mortality.\n\n### HPV-Associated Subtypes\n* **Basaloid**: 4\%$–$10\%$frequency. Nests or sheets of cells with comedonecrosis.$21\%$–$67\% mortality.\n* **Warty**: 5\%$–$10\%$frequency. Condylomatous papillae with koilocytes.$0\%$–$10\%$ mortality.
• Mixed Warty-Basaloid: The most common mixed form ($50\%$–$60\%$ of mixed cases).

Penile Intraepithelial Neoplasia ($PeIN$)

PeIN is the precursor of SCC, categorized as $HPV$-independent (Differentiated PeIN) or $HPV$-associated (Basaloid, Warty, or Mixed). Historical terms like Erythroplasia of Queyrat or Bowen's disease are discouraged.

Pathology Reporting and Diagnostic Procedures

• Standardized Reporting: Use of the International Collaboration on Cancer Reporting ($ICCR$) dataset is mandatory. Required elements include anatomical site, histological type, grade, perineural invasion, depth of invasion (in millimeters), lymphovascular invasion ($LVI$), and $p16$ status.
• p16 Immunohistochemistry ($IHC$): Used as a surrogate marker for high-risk $HPV$ activity. High intensity "en-bloc" staining is considered positive.
• Grading ($WHO/ISUP$):
  • Grade 1: Well-differentiated, abundant keratinization.
  • Grade 2: Moderately differentiated, less prominent keratinization.
  • Grade 3: Poorly differentiated, anaplasia, abundant mitotic activity.
• Biopsy: Punch biopsies ($2$–$3\,mm$) are often sufficient for diagnosis, but incisional biopsies are preferred when the assessment of invasion depth is critical for staging.

Classification Systems: TNM and Cancer Grouping

According to the $UICC/AJCC$ 8th and 9th Editions ($2025$):

T – Primary Tumour

• $Tis$: Carcinoma in situ (PeIN).
• $Ta$: Non-invasive verrucous carcinoma.
• $T1a$: Invades subepithelial connective tissue without $LVI$, without perineural invasion ($PNI$), and not poorly differentiated.
• $T1b$: Invades subepithelial connective tissue with $LVI$, $PNI$, or is poorly differentiated.
• $T2$: Invades corpus spongiosum (with or without urethral invasion).
• $T3$: Invades corpus cavernosum (with or without urethral invasion).
• $T4$: Invades other adjacent structures (e.g., scrotum, prostate, pubic bone).

N – Regional Lymph Nodes

• $cN0$: No palpable or visibly enlarged nodes.
• $cN1$: Palpable mobile unilateral inguinal node.
• $cN2$: Palpable mobile multiple or bilateral inguinal nodes.
• $cN3$: Fixed inguinal mass or pelvic lymphadenopathy.
• $pN1$: Metastasis in $1$ or $2$ inguinal nodes.
• $pN2$: Metastasis in $> 2$ unilateral or bilateral inguinal nodes.
• $pN3$: Pelvic node metastasis or extranodal extension ($ENE$).

Diagnostic Evaluation and Staging

• Primary Lesion: Physical examination is reliable for determining size and clinical T stage. Magnetic Resonance Imaging ($MRI$) is recommended when there is uncertainty regarding cavernosal invasion ($cT3$) or the feasibility of organ-sparing surgery.
• Lymph Node ($LN$) Staging:
  • Presence and extent of nodal metastasis is the most important prognostic factor.
  • $5$-year Cancer-Specific Survival ($CSS$): $cN0 = 95\%;\,pN1 = 80\%;\,pN2 = 65\%;\,pN3 = 35\%$.
  • Evaluation: Ultrasound ($US$) with Fine-Needle Aspiration Cytology ($FNAC$) facilitates early detection.
• cN0 Management: Surgical staging is required for high-risk patients ($T1b$ and higher). Low-risk ($pTa, pTis, pT1a\,G1$) can be monitored. Intermediate-risk ($pT1a\,G2$) requires shared decision-making.
• Dynamic Sentinel Node Biopsy ($DSNB$): Preferred surgical staging technique for $cN0$. Sensitivity is $92\%$–$96\%$, with false-negative rates of $4\%$–$8\%$.
• Imaging for cN+: Presence of palpable nodes ($cN+$) requires staging of the pelvis and chest with $CT$ or $^{18}F-FDG-PET/CT$.

Disease Management: Primary Tumour

• Superficial Non-Invasive (PeIN):
  • Topical Therapies: $5$-Fluorouracil ($5-FU$, $48\%$–$74\%$ response) or Imiquimod ($IQ$, $40\%$–$100\%$ response).
  • Laser Ablation: Carbon dioxide ($CO_{2}$) or $Nd:YAG$ lasers. Recurrence rates range from $7\%$–$48\%$.
  • Surgery: Glans resurfacing provides excellent engraftment and low recurrence ($0\%$–$20\%$).
• Invasive Disease (T1/T2):
  • Organ Preservation: Glansectomy, wide local excision, or laser ablation.
  • Surgical Margins: Historically $5$–$10\,mm$; recent evidence suggests $< 1\,mm$ increases recurrence, but margins of $1\,mm$ are acceptable in low-grade cases.
  • Radiotherapy: Brachytherapy ($70\%$–$90\%$ control for lesions $< 4\,cm$) or external beam radiotherapy ($EBRT$, limited efficacy for stages beyond $T1$).
• Advanced Disease (T3/T4): Partial or total penectomy is standard. Resectable $T3$ involves partial amputation with reconstruction. Non-resectable disease requires induction chemotherapy (Taxane-platinum combinations).

Regional Lymph Node Management

• Radical Inguinal Lymph Node Dissection ($rILND$): Standard of care for mobile nodes ($cN1/cN2$).
  • Complications: High morbidity ($21\%$–$55\%$), including wound infection ($2\%$–$43\%$), lymphoedema ($3.1\%$–$30\%$), and skin necrosis ($3\%$–$50\%$).
  • Fascial-Sparing ILND ($fsILND$): May reduce morbidity while maintaining oncological control in $cN1$ disease.
• Pelvic Lymph Node Dissection ($PLND$): Indicated if $> 2$ unilateral nodes are involved or if $ENE$ is present.
• Clinical N3 ($cN3$):
  • Neoadjuvant chemotherapy ($NAC$) is the preferred initial strategy.
  • Response rates for $NAC$ ($TIP$ or $TPF$) are approximately $53\%$.
  • Responders undergo consolidative surgery ($rILND + PLND$).

Systemic and Multimodal Therapies

• Neoadjuvant Chemotherapy ($NAC$):
  • Regimens: $TIP$ (Paclitaxel, Ifosfamide, Cisplatin) or $TPF$ (Docetaxel, Cisplatin, $5-FU$).
  • $TIP$ results in an Objective Response Rate ($ORR$) of $50\%$ with $10\%$ Pathological Complete Response ($pCR$).
• Adjuvant Chemotherapy: Considered for $pN3$ patients (pelvic node involvement), though data for overall survival improvement is limited.
• Adjuvant Radiotherapy: Recommended for $pN2/pN3$ disease. Doses should be at least $54\,Gy$ for $ENE$ and $57$–$60\,Gy$ for gross residual disease.
• Immunotherapy:
  • $ORR$ for immune checkpoint inhibitors like Atezolizumab or Retifanlimab is approximately $16.7\%$.
  • The $HERCULES$ trial showed a $39.4\%\,ORR$ when combining Pembrolizumab with platinum-based chemotherapy.
• Palliative Therapy: Platinum-based doublets or triplets for distant metastasis ($M1$). Avoid bleomycin due to pulmonary toxicity risks.

Follow-up and Quality of Life

• Surveillance Rationale: Most recurrences occur within $2$ years ($79.5\%$ of local and nearly all regional recurrences).
• Schedule:
  • First 2 years: Every $3$ months.
  • Years 3–5: Every $6$ months.
  • Beyond 5 years: Discretionary, based on patient ability to self-examine.
• Quality of Life ($QoL$): Treatments have high impact on body image, sexual function, and urination.
  • Urinary spraying occurs in $83\%$ of partial penectomy patients versus $43\%$ in organ-sparing cases.
  • Erectile function is generally preserved in organ-sparing surgery but diminished in amputative procedures.
• Lymphoedema Management: Skin care, compression, exercise, and manual lymphatic drainage are critical. Prophylactic antibiotics (Penicillin V) are recommended after cellulitis episodes.

Centralisation of Care

Centralized care in high-volume expert centers significantly improves outcomes.

• Advantages: Higher rates of organ-sparing surgery ($80\%$ in the $UK$), better guideline adherence, and improved survival ($5$-year CSS up to $85\%$).
• Survivorship: Access to specialist lymphoedema services, psychological support, and specialized pathology review.
• Survival Benefit: In the Netherlands, five-year relative survival was $86\%$ in national reference centers versus $76\%$ in regional hospitals ($p < 0.001$).

Questions & Discussion

• Unmet Needs Table: Identifies Emotional (Loss of masculinity, Depression), Relational (Sexual performance anxiety, Stigma), and Medical (Lack of rehabilitation/support, Missed diagnosis) needs.
• Shared Decision-Making: The panel emphasizes that guidelines cannot replace clinical expertise and must account for individual patient circumstances. Access to palliative care should be available throughout the cancer pathway, not just at the end-of-life stage.