Penile Cancer
Squamous cell carcinoma of the penis — organ-preserving approaches
DefinitionClick to collapse
Penile cancer is a rare malignancy that arises from the squamous epithelial cells of the penis, accounting for approximately 95% of penile neoplasms [28]. It predominantly presents as squamous cell carcinoma (SCC) or its precursor, penile intraepithelial neoplasia (PeIN). The primary lesion most commonly occurs on the glans (34.5% of cases in the United States), followed by the prepuce (13.2%), the shaft (5.3%), overlapping sites (4.5%), and unspecified locations (42.5%) [9]. Anatomically, the penis comprises the glans, inner preputial layer, coronal sulcus, and shaft, all of which can be involved. The embryological origin is from ectodermal and mesodermal tissues, with the squamous epithelium derived from ectoderm. Invasive SCC is characterized by penetration through the basement membrane into the lamina propria, with progressive invasion into corpus spongiosum (T2), corpora cavernosum (T3), or adjacent structures such as the scrotum, prostate, or pubic bone (T4) [29]. The clinical diagnosis requires thorough history and physical examination, histologic biopsy (punch, excisional, or incisional), and assessment of human papillomavirus (HPV) and HIV status [PN-1]. The disease has a high propensity for lymphatic spread, first to inguinal lymph nodes and subsequently to pelvic nodes; involvement of the inguinal lymph nodes is the single most important prognostic factor [32]. The 5-year survival rate is approximately 65% overall, ranging from 79% for localized disease to 10% for distant metastatic disease [5,6]. Early diagnosis is critical to avoid disfigurement and improve outcomes.
EpidemiologyClick to collapse
SubtypesClick to collapse
HPV-associated squamous cell carcinoma
Invasive SCC linked to high-risk HPV infection, particularly types 16, 6, and 18. Includes several histologic patterns. p16 immunohistochemistry is often used as a surrogate marker.
HPV-independent squamous cell carcinoma
SCC not associated with HPV infection; often arises in the setting of chronic inflammation, lichen sclerosus, or phimosis. Tends to have a worse prognosis.
Penile intraepithelial neoplasia (PeIN)
Premalignant high-grade intraepithelial lesion. Two main categories: HPV-associated (basaloid, warty, pagetoid, clear cell patterns) and differentiated (HPV-independent).
Aggressive histologic subtypes
Subtypes recognized as having aggressive behavior: basaloid, clear cell, and sarcomatoid SCC [PN-F].
Squamous cell carcinoma, not otherwise specified (NOS)
Invasive keratinizing carcinoma without special features; used when p16 evaluation is not available.
Other epithelial tumors
Rare variants including adenosquamous carcinoma, mucoepidermoid carcinoma, and extramammary Paget disease [PN-F].
Molecular PathogenesisClick to collapse
The molecular pathogenesis of penile SCC is not fully elucidated, but the guideline highlights two primary pathways: HPV-dependent and HPV-independent. Approximately 45–80% of penile cancers harbor HPV DNA, with a strong correlation to types 16, 6, and 18 [4,10,12-14]. HPV-mediated carcinogenesis involves E6 and E7 oncoproteins that inactivate p53 and Rb, leading to genomic instability and p16 overexpression. p16 positivity (by immunohistochemistry) is a favorable prognostic factor and is used as a surrogate for HPV status [15-17]. In HPV-independent tumors, chronic inflammation, lichen sclerosus, and phimosis are implicated, often associated with TP53 mutations (though specific gene frequencies are not provided in the guideline). Other driver mutations or signaling pathways are not enumerated in the NCCN text; however, the guideline recommends multigene panel testing (MGPT) in a CLIA-approved laboratory for patients with metastatic disease to identify rare but actionable mutations and fusions (e.g., MSI-H, dMMR, TMB-H) [PN-10]. The text notes that emerging knowledge of the molecular landscape may lead to future targeted therapies [MS-18]. No specific chromosomal abnormalities or recurrent mutations (e.g., NOTCH1, PIK3CA) are mentioned in the source, so they are not included here. The broad molecular profiling approach is intended to detect alterations that might qualify for tumor-agnostic treatments (e.g., pembrolizumab for MSI-H/dMMR or TMB-H tumors) [PN-D 3]. In summary, the primary known molecular drivers are HPV oncoproteins in the majority of cases, and p16 status is the only routinely used biomarker for prognosis and subtype classification.
Risk FactorsClick to collapse
Phimosis
Inability to retract the foreskin; hinders inspection and hygiene. Associated with a 25–60% increase in penile cancer risk [4,10,11].
Lack of neonatal circumcision
Neonatal circumcision is associated with lower risk; protective effect not seen in adults [20]. May reduce risk of invasive but not in situ cancer [21].
Tobacco use (cigarette smoking)
Smokers are 3 to 4.5 times more likely to develop penile cancer [12,22].
Human papillomavirus (HPV) infection
Overall, 45–80% of penile cancers are HPV-related; especially types 16, 6, and 18 [4,10,12-14]. HPV/p16 positivity is a favorable prognostic factor [15-17].
HIV infection
Increased risk of HPV acquisition and lower HPV clearance; oral HPV more common in HIV-positive males [18,19]. HIV status should be assessed [PN-1].
Lichen sclerosus
Patients have a 2–9% risk of developing penile carcinoma [23-25].
Chronic inflammation, balanitis, poor hygiene
Chronic inflammatory conditions and poor hygiene are recognized risk factors [4].
Psoralen plus ultraviolet A (PUVA) treatment
Patients with psoriasis undergoing PUVA have increased incidence of penile cancer (286 times the general population) [26]. Shielding during treatment is recommended.
Age >50 years
Risk increases with age; median age at diagnosis 68 years [9].
Penile trauma
Listed as a risk factor in the primary evaluation [PN-1].
Visceral metastases and ECOG performance status ≥1
Poor prognostic factors for overall survival and progression-free survival in advanced disease [27].
Clinical FeaturesClick to collapse
Typical Presentation
Penile squamous cell carcinoma (SCC) most commonly presents as a palpable, visible lesion on the penis, which may be associated with penile pain, discharge, bleeding, or a foul odor if the patient delays seeking medical treatment. The lesion may be characterized as nodular, ulcerative, or fungating, and may be obscured by phimosis. Patients may exhibit signs of more advanced disease, including palpable inguinal nodes and/or constitutional symptoms (eg, fatigue, weight loss) [MS-3]. The median age at diagnosis in the United States is 68 years, with an increase in risk for individuals >50 years [MS-3]. The most common sites are the glans (34.5% of cases), prepuce (13.2%), shaft (5.3%), overlapping (4.5%), and unspecified (42.5%) [MS-3]. Early diagnosis is critical, as the 5-year survival rate is approximately 65% overall, but drops to 57% with regional disease and 10% with distant disease [MS-2].
Symptoms
Penile lesion
A palpable, visible growth on the penis that may be nodular, ulcerative, or fungating. Often painless initially but can become painful with ulceration or infection.
Penile pain or discomfort
May occur due to ulceration, secondary infection, or tumor invasion into sensitive structures.
Penile discharge or bleeding
Blood or serosanguinous discharge from the lesion or urethra.
Foul odor
Associated with necrotic or superinfected tumors.
Constitutional symptoms
Fatigue, weight loss, malaise – indicate advanced or metastatic disease.
Signs
Palpable penile mass
The primary tumor is usually firm, irregular, and may be fixed to underlying structures. Location can be on glans, prepuce, or shaft.
Inguinal lymphadenopathy
Palpable inguinal lymph nodes (unilateral or bilateral) may be mobile or fixed. Fixed nodes indicate advanced disease (cN3).
Phimosis
Inability to retract the foreskin, which may obscure the underlying lesion. Patients with phimosis have a 25–60% increased risk of penile cancer [MS-3].
Lichen sclerosus
Chronic inflammatory condition of the glans/prepuce, associated with a 2–9% risk of developing penile carcinoma [MS-3].
Edema of penis, scrotum, or legs
Indicates lymphatic obstruction from bulky inguinal or pelvic nodal metastases.
Red FlagsClick to collapse
Phimosis that prevents complete examination of the glans and prepuce – requires manual retraction or dorsal slit to evaluate.
Non-healing ulcer or persistent lesion on the penis lasting more than 4–6 weeks.
Rapidly growing penile mass, especially with fixation to underlying corpora or skin.
Palpable inguinal lymph nodes that are firm, fixed, or matted (cN3) – indicates advanced nodal disease.
Constitutional symptoms (unexplained weight loss, fatigue, fever) in the setting of a penile lesion – suggests metastatic disease.
Prior history of HPV-related anogenital disease or HIV infection – high-risk populations warrant lower threshold for biopsy.
Psoriasis patients with PUVA therapy who develop any penile lesion – requires immediate evaluation due to 286-fold increased risk [MS-3].
Lichen sclerosus with any suspicious change in penile skin – carries 2–9% risk of malignant transformation [MS-3].
InvestigationsClick to collapse
Diagnostic
History and Physical (H&P)
Initial evaluation identifies risk factors (balanitis, chronic inflammation, penile trauma, lack of neonatal circumcision, tobacco use, lichen sclerosus, poor hygiene, sexually transmitted diseases including HIV). Lesion characteristics (diameter, location, number, morphology [papillary, nodular, ulcerous, or flat], relationship to other structures [submucosal, corpora spongiosa, cavernosa, urethra]) are documented [PN-1].
Punch, excisional, or incisional biopsy of primary lesion
Required for histologic diagnosis of squamous cell carcinoma and to determine grade, depth of invasion, lymphovascular invasion (LVI), perineural invasion (PNI), and HPV status [PN-1].
HPV status assessment
HPV (especially types 16, 6, 18) is associated with 45–80% of penile cancers. HPV/p16 positivity is a favorable prognostic factor for disease-specific survival (DSS). Assessment can be done by morphology, p16 immunohistochemistry, or molecular methods [PN-1, PN-F, MS-3].
HIV status assessment
HIV infection increases risk of HPV acquisition and persistence, and is associated with penile cancer risk [MS-3].
Staging
Imaging of chest/abdomen/pelvis
Required for initial staging to evaluate for nodal and distant metastases. Modalities include CT or MRI of abdomen/pelvis with contrast (preferred for nodal evaluation if difficult to assess clinically), and chest x-ray or CT chest [PN-E].
FDG-PET/CT (skull base to mid-thigh)
Considered in patients with suspected inguinal lymph node-positive disease to assess extent of nodal and distant metastases. PET/CT has high pooled sensitivity (96.4%) for cN+ disease but low sensitivity (56.5%) for cN0 disease [PN-E, MS-9].
MRI with contrast of pelvis/inguinal region
May be used to evaluate depth of tumor invasion and nodal involvement, especially when physical examination is limited (e.g., obesity, prior inguinal surgery) [PN-E, MS-9].
Ultrasound of inguinal region
Can be used at the time of clinical examination if abnormal findings, patient has obesity, or prior inguinal surgery. May be combined with fine-needle aspiration (FNA) for suspicious nodes [PN-E, MS-10].
Percutaneous lymph node biopsy (ultrasound- or CT-guided)
Recommended for patients with palpable inguinal nodes to confirm metastatic involvement before proceeding with definitive therapy. FNA or core biopsy of the most accessible node (inguinal or pelvic) [PN-4, PN-5].
Excisional biopsy of lymph node
If percutaneous biopsy is negative but clinical suspicion remains high, excisional biopsy of the most suspicious node can be performed [PN-4, PN-5].
Biomarkers
HPV/p16 status (p16 immunohistochemistry or molecular methods)
Prognostic significance – HPV/p16 positivity is associated with better disease-specific survival. Helps classify tumors as HPV-associated or HPV-independent, which may have different natural histories [PN-F, MS-3].
Multigene panel testing (MGPT) in CLIA-approved laboratory
Considered for patients with metastatic disease to identify rare but actionable mutations and fusions, including tumor-agnostic labels that cover penile cancer (e.g., MSI-H/dMMR, TMB-H) [PN-10, PN-D3].
Microsatellite instability (MSI) or mismatch repair deficiency (dMMR) testing
Identifies patients who may benefit from pembrolizumab if unresectable or metastatic and progressed on prior treatment [PN-D3].
Tumor mutational burden (TMB) testing
TMB ≥10 mut/Mb qualifies for pembrolizumab in patients with progressed advanced solid tumors [PN-D3].
StagingClick to collapse
AJCC 8th Edition (2017) TNM Staging System for Penile Cancer
T Categories
| Stage | Description |
|---|---|
| TX | Primary tumor cannot be assessed |
| T0 | No evidence of primary tumor |
| Tis | Carcinoma in situ (Penile intraepithelial neoplasia [PeIN]) |
| Ta | Noninvasive localized squamous cell carcinoma (including verrucous carcinoma which is by definition well-differentiated, see PN-3) |
| T1 | Glans: Tumor invades lamina propria. Foreskin: Tumor invades dermis, lamina propria, or dartos fascia. Shaft: Tumor invades connective tissue between epidermis and corpora regardless of location. All sites with or without lymphovascular invasion (LVI) or perineural invasion (PNI) and is or is not high grade (i.e., grade 3 or sarcomatoid). Subdivided into T1a (without LVI or PNI and not high grade) and T1b (exhibits LVI and/or PNI or is high grade) [ST-1]. |
| T1a | Tumor invades lamina propria (glans), dermis/lamina propria/dartos fascia (foreskin), or connective tissue (shaft) without LVI or PNI and is not high grade (grade 1–2). |
| T1b | Tumor invades lamina propria (glans), dermis/lamina propria/dartos fascia (foreskin), or connective tissue (shaft) with LVI and/or PNI or is high grade (grade 3 or sarcomatoid). |
| T2 | Tumor invades into corpus spongiosum (either glans or ventral shaft) with or without urethral invasion. |
| T3 | Tumor invades into corpora cavernosum (including tunica albuginea) with or without urethral invasion. |
| T4 | Tumor invades into adjacent structures (i.e., scrotum, prostate, pubic bone). |
N Categories
| Stage | Description |
|---|---|
| cNX | Regional lymph nodes cannot be assessed |
| cN0 | No palpable or visibly enlarged inguinal lymph nodes |
| cN1 | Palpable mobile unilateral inguinal lymph node |
| cN2 | Palpable mobile ≥2 unilateral inguinal nodes or bilateral inguinal lymph nodes |
| cN3 | Palpable fixed inguinal nodal mass or pelvic lymphadenopathy (unilateral or bilateral) |
| pNX | Lymph node metastasis cannot be established |
| pN0 | No lymph node metastasis |
| pN1 | ≤2 unilateral inguinal metastases, no extranodal extension (ENE) |
| pN2 | ≥3 unilateral inguinal metastases or bilateral metastases |
| pN3 | ENE of lymph node metastases or pelvic lymph node metastases (with or without ENE) |
M Categories
| Stage | Description |
|---|---|
| M0 | No distant metastasis |
| M1 | Distant metastasis present |
Stage Groupings
| Group | Criteria | Clinical Meaning | Five Yr Survival | Treatment Intent |
|---|---|---|---|---|
| Stage 0is | Tis, N0, M0 | Carcinoma in situ (PeIN); premalignant, high risk of progression to invasive SCC [MS-3]. | Excellent, >90% with appropriate local therapy | Curative - organ-sparing approaches (topical therapy, excision, laser). |
| Stage 0a | Ta, N0, M0 | Noninvasive localized SCC (includes verrucous carcinoma). | Excellent, >90% | Curative - organ-sparing approaches (excision, laser, or topical therapy for verrucous? Note: verrucous is well-differentiated, surveillance of nodes only required [PN-3]). |
| Stage I | T1a, N0, M0 | Low-risk primary tumor with no adverse features; low risk of occult nodal metastases (<17%) [MS-15]. | 79% (localized disease overall estimate) [MS-2] | Curative - organ-sparing approaches (wide local excision, glansectomy in select cases, laser, RT). |
| Stage IIA | T1b or T2, N0, M0 | Intermediate- to high-risk primary tumor; risk of occult nodal metastases 68–73% for T1b/T2 [MS-15]. Invasion into corpus spongiosum (T2). | Approximately 57% (regional disease) if nodal involvement develops; if node-negative, ~79%. | Curative - partial/total penectomy plus inguinal lymph node dissection (ILND) or DSNB for high-risk features [PN-2, PN-3]. |
| Stage IIB | T3, N0, M0 | Invasion into corpora cavernosum; associated with worse cancer-specific survival and higher lymph node metastasis rates compared to T2 [MS-5]. | Approximately 57% (regional disease) if node-negative; worse if node-positive. | Curative - partial/total penectomy + ILND (or DSNB if high-risk) [PN-2, PN-3]. |
| Stage IIIA | T1–3, N1, M0 | ≤2 unilateral inguinal metastases without ENE (pN1); regional disease with good prognostic features. | 57% (regional disease overall); higher with pN1 (70% range) [MS-13]. | Curative - ILND (standard or modified) with adjuvant therapy based on risk (if pN2–3 then PLND, RT, chemo). |
| Stage IIIB | T1–3, N2, M0 | ≥3 unilateral or bilateral inguinal metastases (pN2); high-risk nodal disease. | Approximately 30–50% depending on extent of nodal disease. | Curative - ILND + PLND + neoadjuvant/adjuvant therapy (chemotherapy, RT, or chemoradiotherapy). |
| Stage IV | Any of: T4, Any N, M0; Any T, N3, M0; Any T, Any N, M1 | T4 (invasion into adjacent structures); N3 (fixed inguinal mass or pelvic nodes, or ENE); M1 (distant metastases). Pelvic node metastasis is ominous with 5-year survival <10% [MS-17]. | 10% for distant disease; <10% for pelvic nodal disease; <20% overall for stage IV [MS-2, MS-17]. | Palliative or curative intent in selected cases (neoadjuvant chemotherapy + consolidation surgery if responsive). Systemic therapy + RT for local control. Best supportive care for refractory disease. |
Staging Pearls
- The distinction between T1a and T1b is based on LVI, PNI, and grade: T1b has LVI and/or PNI or is high grade (G3 or sarcomatoid) [ST-1].
- T2 now only includes corpus spongiosum invasion (not cavernosum). T3 is corpora cavernosum invasion (including tunica albuginea). This is a change from the 7th edition [MS-4].
- pN1 allows up to 2 unilateral inguinal metastases without ENE; pN2 is ≥3 unilateral or bilateral; pN3 includes ENE or pelvic node metastases. This subclassification better stratifies prognosis [MS-4].
- cN3 includes palpable fixed inguinal mass OR pelvic lymphadenopathy (unilateral or bilateral) [ST-1].
- Stage II splits into IIA (T1b/T2N0) and IIB (T3N0) recognizing different outcomes for corpus spongiosum vs cavernosum invasion [MS-4].
- Verrucous carcinoma (Ta) is by definition well-differentiated; it rarely metastasizes and surveillance of inguinal nodes is sufficient [PN-3].
- Imaging (CT/MRI) uses 4 cm threshold for defining bulky nodal disease; this size threshold is the maximum diameter of contiguous inguinal node tissue on physical exam or axial imaging [PN-4].
- The AJCC recommends recording site-specific factors: percentage of tumor poorly differentiated, depth of invasion in verrucous carcinoma, presence of LVI/PNI, size of largest LN metastasis, total number of lymph nodes removed [MS-4].
- About 20–30% of patients with positive inguinal nodes will also have pelvic node metastases, but skip metastases (pelvic without inguinal) are extremely rare [MS-12, MS-17].
Management PrinciplesClick to collapse
Penile squamous cell carcinoma (SCC) is a rare malignancy (0.4%–0.6% of male cancers in the US/Europe) with an estimated 2260 new cases and 450 deaths in 2026 [2]. A multimodal approach is essential, integrating surgical, radiation, and systemic therapies tailored to disease stage and patient fitness. Treatment philosophy emphasizes organ preservation when oncologically safe, particularly for early-stage (PeIN, Ta, pT1a) lesions, while radical surgery (partial/total penectomy) remains standard for invasive disease. Regional lymph node management is critical, as nodal status is the strongest prognostic factor [32]. The NCCN Panel relies on expert consensus due to limited prospective trials, with category 2A recommendations as default.
Curative
Localized disease (PeIN, Ta, T1–T2, N0)
Penile organ-sparing approaches (topical therapy, wide local excision, laser, glansectomy, Mohs surgery) for PeIN/Ta/T1a; partial or total penectomy for T1b/T2+; bilateral inguinal lymph node dissection (ILND) or dynamic sentinel node biopsy (DSNB) for intermediate/high-risk nodal basins. Surveillance for low-risk N0.
Curative with perioperative therapy
Regionally advanced (≥cN1, bulky inguinal nodes, pelvic nodes)
Neoadjuvant TIP (paclitaxel, ifosfamide, cisplatin) followed by ILND ± pelvic lymph node dissection (PLND) for responders; adjuvant chemotherapy, radiotherapy (RT), or chemoradiotherapy (CRT) for high-risk features (extranodal extension, ≥2 positive nodes, pelvic involvement).
Palliative
Metastatic (M1) or unresectable disease
First-line systemic therapy (preferred: TIP; alternatives: cisplatin/fluorouracil, cisplatin/fluorouracil + pembrolizumab, carboplatin/fluorouracil + pembrolizumab). Subsequent-line options include pembrolizumab for MSI-H/dMMR or TMB-H tumors (tumor-agnostic labels), paclitaxel, cetuximab, or clinical trials. RT for local control/palliation. Best supportive care per NCCN Palliative Care Guidelines.
The NCCN Panel includes urologists, medical oncologists, radiation oncologists, pathologists, radiologists, and patient advocates. Multidisciplinary review is recommended for treatment planning, especially for complex cases involving neoadjuvant therapy, combined modality treatment, or salvage surgery.
ECOG performance status (PS) is a relevant prognostic factor: a study of advanced penile SCC identified ECOG PS ≥1 and visceral metastases as poor prognostic factors for both overall survival (OS) and progression-free survival (PFS) [27]. Patients with ECOG 0–1 are generally candidates for intensive chemotherapy regimens (e.g., TIP). Those with ECOG ≥2 may require dose modifications or non-cisplatin-based alternatives; cisplatin eligibility should be assessed (renal function, hearing, neuropathy). For patients ineligible for neoadjuvant TIP, surgery without neoadjuvant chemotherapy is recommended [2].
Management PathwaysClick to collapse
Branching: Clinical diagnosis based on biopsy
Branching: Pathologic T stage, Histologic grade, Lymphovascular invasion (LVI), Perineural invasion (PNI)
Branching: T stage (T2, T3, T4), Tumor size (≥4 cm vs <4 cm), Resectability
Branching: Risk stratification based on primary lesion: low risk (PeIN, Ta, T1a) vs intermediate/high risk (T1b, any T2 or greater)
Branching: Unilateral node(s) <4 cm mobile, Risk of primary lesion (low vs high), Node biopsy result
Branching: Node size (≥4 cm mobile vs fixed), Laterality (unilateral vs bilateral), Biopsy result
Branching: Surgical candidacy, Biopsy result (if feasible)
Branching: Site of recurrence (local penile vs inguinal), Prior treatment (penile sparing, lymphadenectomy, RT)
Branching: Response to first-line therapy
Pretreatment EvaluationClick to collapse
History & Physical
Histologic Diagnosis
HPV & HIV Status
Imaging
Molecular Testing
SurgeryClick to collapse
Surgery is the primary curative modality for penile cancer, encompassing management of the primary tumor (organ-sparing, partial penectomy, total penectomy) and regional lymph nodes (inguinal and pelvic lymph node dissection). In select patients, surgery may be used as consolidation after systemic therapy or salvage for recurrence.
Intraoperative frozen sections are recommended to determine negative margins for all penectomy procedures [PN-B].
Partial penectomy is standard for high-grade primary tumors when a functional penile stump can be preserved and negative margins obtained. Total penectomy is required if partial penectomy cannot achieve negative margins.
Invasion into the corpora cavernosum necessitates partial or total penectomy to achieve negative margins.
Standard or modified ILND or DSNB is indicated in patients without palpable inguinal adenopathy if high-risk features for nodal metastasis are present: lymphovascular invasion, ≥pT1b or ≥T2 any grade, >50% poorly differentiated [PN-B].
DSNB is only recommended if the treating physician has experience with this modality. If positive nodes found, proceed to ILND.
PLND should be considered at the time of or following ILND in patients with ≥2 positive ipsilateral inguinal nodes or extranodal extension. Bilateral PLND should be considered if ≥4 positive inguinal nodes total [141].
Consolidation surgery (bilateral superficial/deep ILND + unilateral/bilateral PLND) is recommended for select patients with stable or responding disease after neoadjuvant chemotherapy for metastatic disease.
Procedures
Partial penectomy
High-grade primary tumors when adequate stump can be preserved; invasion into corpora cavernosum; primary treatment for T1b or T2-3 tumors.
Total penectomy
When partial penectomy cannot achieve negative margins; extensive tumors involving the shaft or base.
Inguinal lymph node dissection (ILND)
Intermediate/high-risk primary tumors with nonpalpable nodes; positive DSNB; palpable nodes with positive biopsy; bulky inguinal nodes (preferred after neoadjuvant TIP).
Pelvic lymph node dissection (PLND)
≥2 positive ipsilateral inguinal nodes or extranodal extension; enlarged pelvic nodes on imaging; ≥4 positive inguinal nodes (bilateral PLND recommended) [141].
Dynamic sentinel node biopsy (DSNB)
Intermediate/high-risk nonpalpable nodes, performed at experienced centers (≥20 procedures/year) [107,120].
Glansectomy
Select patients with distal tumors (PeIN, Ta, T1a) on glans or prepuce when organ-sparing desired; category 2B for PeIN/Ta.
Mohs micrographic surgery
Alternative to wide local excision in select cases, especially small superficial lesions on proximal shaft to avoid total penectomy [2,66]. Success rate declines with higher stage disease.
Radiation TherapyClick to collapse
Radiotherapy is used as primary treatment for penile preservation (T1-2 N0, tumors <4 cm preferred), adjuvant therapy after lymph node dissection (for high-risk features, positive pelvic nodes), and palliative treatment for metastatic disease. Evidence is limited; recommendations are category 2B (primary RT) or category 3 (chemo/RT) due to nonuniform consensus.
Principles
- Circumcision should always precede RT to prevent radiation-related complications.
- For primary RT, brachytherapy (interstitial implant) is preferred over EBRT for small (<4 cm) tumors confined to glans [PN-C]. EBRT uses conventional fractionation with appropriate bolus to primary lesion with 2 cm margins.
- Adjuvant EBRT to inguinal and pelvic nodes: 45–50.4 Gy; boost gross nodes and areas of extracapsular extension to 65–70 Gy.
- Palliative RT: consider 30 Gy in 10 fractions.
- Prophylactic EBRT to inguinal nodes (category 2B) is an option for patients who are not surgical candidates or decline surgery.
Dose Frameworks
| Name | Total Dose | Dose Per Fraction | Fractions | Schedule | Indication |
|---|---|---|---|---|---|
| Primary brachytherapy (T1-2 N0, tumor <4 cm) | 65–70 Gy (for EBRT equivalent); brachytherapy dose not specified in source but typical 60 Gy over 5-7 days | Not specified for brachytherapy; EBRT 1.8–2.0 Gy/fraction | Not specified for brachytherapy; EBRT 33–35 fractions | Daily, conventional fractionation | T1-2 N0, tumor <4 cm, after circumcision (category 2B) |
| Primary EBRT + concurrent chemo (T1-2, tumor ≥4 cm or T3-4 N+) | 45–50.4 Gy to whole penile shaft/pelvic/inguinal nodes, then boost primary + gross nodes to 60–70 Gy | 1.8–2.0 Gy | 25–28 initial + 10–13 boost | Daily, conventional fractionation | T3-4 or N+ surgically unresectable; T1-2 with tumor ≥4 cm (category 3 for chemo/RT) |
| Adjuvant EBRT (post-ILND for high-risk node-positive) | 45–50.4 Gy to inguinal and pelvic lymph nodes; boost to 65–70 Gy for gross nodes/extracapsular extension | 1.8–2.0 Gy | 25–28 initial + boost | Daily | pN2–3 disease, positive pelvic nodes, extranodal extension (category 2B for non-bulky; recommended for bulky and enlarged pelvic nodes) |
| Palliative RT | 30 Gy | 3 Gy | 10 | Daily | For local control of unresectable inguinal or bone metastases, after chemotherapy or for symptomatic relief |
| Prophylactic EBRT to inguinal nodes | Not specified; typically 45–50 Gy | 1.8–2.0 Gy | 25 | Daily | Patients with intermediate/high-risk primary who are not surgical candidates or decline surgery (category 2B) |
Approaches
| Name | Dose Fractionation | Concurrent Chemotherapy | Indication | Key Trial | Toxicities |
|---|---|---|---|---|---|
| Brachytherapy alone (T1-2 N0, <4 cm) | Interstitial implant; typical dose not explicitly stated in source | None | Category 2B; after circumcision; highest evidence for glans-confined tumors (10-year cause-specific survival 92% in one series [79]; 84% in another [77]) | de Crevoisier et al [79]: 144 patients with glans-restricted penile cancer, 10-year CSS 92%; larger tumors >4 cm had higher recurrence risk. Crook et al [77]: 67 patients T1-2 (select T3), 10-year CSS 84%. | Urethral stenosis, telangiectasia, necrosis, penile pain, erectile dysfunction; risk increases with tumor size >4 cm. |
| EBRT alone (T1-2 N0, <4 cm) | 65–70 Gy total, conventional fractionation, with bolus and 2 cm margins | None | Category 2B; alternative to brachytherapy | Limited data; outcomes from retrospective series. | Acute: skin desquamation, urethritis, cystitis. Late: fibrosis, urethral stricture, telangiectasia, penile necrosis. |
| EBRT with concurrent chemotherapy (primary, T1-2 N0 ≥4 cm or T3-4 N+) | 45–50.4 Gy to whole penile shaft, pelvic, and bilateral inguinal nodes; boost primary and gross nodes to 60–70 Gy | Preferred radiosensitizing agents: cisplatin ± fluorouracil, fluorouracil/mitomycin. Other recommended: capecitabine [PN-D3]. | Category 3 for primary treatment; greater acceptance for unresectable T3-4 or N+ disease. | No randomized trials in penile cancer; data extrapolated from anal/vulvar cancer [152-155]. Anecdotal reports with mixed results [156-159]. | Similar to EBRT plus systemic toxicity of chemotherapy (nephrotoxicity, myelosuppression, mucositis). Higher rates of acute skin and mucosal reactions. |
| Adjuvant EBRT or Chemo/RT (post-ILND/PLND) | 45–50.4 Gy to inguinal/pelvic nodes; boost to 65–70 Gy for gross residual or extracapsular extension | Cisplatin ± fluorouracil, fluorouracil/mitomycin, or capecitabine if chemo/RT chosen. | Recommended for palpable bulky inguinal nodes or enlarged pelvic nodes; consider for pN2–3 disease (category 2B) or local recurrence (category 2B). | Retrospective multicenter: adjuvant pelvic RT improved DSS (14.4 vs 8 months, P=.023) [149]; adjuvant RT for stage III penile cancer improved OS (HR 0.58 [0.39–0.86]) [150]. Systematic review by EAU showed no significant benefit [151]. | Lymphedema, wound healing complications, enteritis, cystitis, bone marrow suppression. |
Systemic TherapyClick to collapse
Systemic therapy for penile cancer is used in neoadjuvant, adjuvant, first-line metastatic, and subsequent-line settings. The backbone is platinum-based chemotherapy, with TIP (paclitaxel, ifosfamide, cisplatin) as the preferred regimen across neoadjuvant, adjuvant, and first-line metastatic settings. Cisplatin/fluorouracil is an alternative. The addition of pembrolizumab to platinum-based chemotherapy followed by pembrolizumab maintenance is a newer option for metastatic disease based on the HERCULES trial. There is no standard subsequent-line therapy; clinical trials are preferred. Tumor-agnostic indications (MSI-H/dMMR, TMB-H) may apply. Bleomycin-containing regimens are associated with unacceptable toxicity and are not recommended [6].
Key Regimens
Treatment Response AssessmentClick to collapse
Title
Treatment Response Assessment
Timing
Response assessment should be performed after neoadjuvant systemic therapy (typically after 4 cycles of TIP) using imaging of chest/abdomen/pelvis (CT, MRI, PET/CT, and/or chest x-ray). For patients on first-line metastatic therapy, reassess after 2-3 cycles. For patients undergoing consolidation surgery, restaging is done post-chemotherapy to determine resectability. For surveillance, schedule is based on initial treatment and nodal status per PN-8.
Response Logic
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Complete response (CR) or partial response (PR) or stable disease (SD) after neoadjuvant therapy: proceed with consolidation surgery (bilateral superficial/deep ILND and unilateral/bilateral PLND) in select patients.
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No response or disease progression after neoadjuvant or first-line systemic therapy: consider subsequent-line systemic therapy, clinical trial, RT for local control, and/or best supportive care per NCCN Palliative Care Guidelines.
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After ILND/PLND: if viable tumor present in surgical specimen, assess for adjuvant therapy (chemotherapy, RT, or chemo/RT) based on pathological features (pN2–3, extranodal extension, positive margins).
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For primary RT: response assessed by clinical examination and imaging; suspicious residual or recurrent disease should be biopsied and managed per recurrence pathways.
Imaging Recommendations
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Treatment response assessment: imaging of chest/abdomen/pelvis (CT or MRI of abdomen/pelvis, chest x-ray or CT). Consider FDG-PET/CT (skull base to mid-thigh) for suspected inguinal lymph node-positive disease [PN-E].
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Surveillance for pN0/N1: clinical examination every 6 months for years 1–2, then annually years 3–4; CT abdomen/pelvis and chest radiograph at same intervals.
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Surveillance for pN2/N3: clinical examination every 3 months year 1, then every 6 months years 2–4; CT abdomen/pelvis and chest CT at same intervals.
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If abnormal clinical examination, obesity, or prior inguinal surgery, consider ultrasound, CT with contrast, or MRI of inguinal region.
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For patients on active surveillance of clinically negative nodes (low risk): clinical examination of penis and inguinal region per schedule.
Biopsy Or Salvage Logic
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Persistent or suspicious inguinal lymph node after treatment: percutaneous biopsy (ultrasound- or CT-guided) of most accessible node. If negative, consider excisional biopsy.
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Biopsy-proven residual disease after neoadjuvant therapy: proceed with surgical resection (ILND/PLND) if resectable. If unresectable, consider RT or chemo/RT.
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Local recurrence of primary after penile-sparing treatment: treat according to recurrence stage per primary treatment pathways (PN-1, PN-2).
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Inguinal recurrence with prior lymphadenectomy or RT: consider chemotherapy followed by ILND (if resectable), ILND alone, or chemo/RT (if no prior RT).
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For metastatic disease progression: consider subsequent-line systemic therapy, clinical trial, RT for palliation, best supportive care.
SurveillanceClick to collapse
Clinical Follow Up Schedule
| Scenario | Schedule |
|---|---|
| Primary lesion treated with topical or local therapy | Clinical examination of penis and inguinal region: years 1–2 every 3 months; years 3–5 every 6 months; years 5–10 every 12 months [PN-8]. |
| Primary lesion treated with partial or radical penectomy | Clinical examination of penis and inguinal region: years 1–2 every 6 months; years 3–10 every 12 months [PN-8]. |
| Lymph nodes: pN0 or pN1 | Clinical examination: years 1–2 every 6 months; years 3–4 every 12 months. Imaging: CT abdomen/pelvis and chest radiograph at each visit [PN-8]. |
| Lymph nodes: pN2 or pN3 | Clinical examination: years 1–2 every 6 months; years 3–4 every 12 months. Imaging: CT abdomen/pelvis and chest CT: year 1 every 3 months; years 2–4 every 6 months [PN-8]. |
Imaging Strategy
- Initial workup/staging: imaging of chest/abdomen/pelvis (CT or MRI) with contrast when appropriate [PN-E]. For pelvic nodal evaluation, CT/MRI of pelvis. Consider FDG-PET/CT (skull base to mid-thigh) for suspected inguinal lymph node-positive disease [PN-E].
- Treatment response assessment: imaging of chest/abdomen/pelvis as above; consider FDG-PET/CT for response/progression in node-positive patients [PN-E].
- Surveillance: For pN0/N1: CT abdomen/pelvis + chest radiograph every 6–12 months. For pN2/N3: CT abdomen/pelvis + chest CT more frequently (every 3 months year 1, every 6 months years 2–4). If abnormal clinical exam, obesity, or prior inguinal surgery: consider ultrasound, CT, or MRI of groin [PN-8], [PN-E].
Laboratory Monitoring
- No specific laboratory surveillance recommended in the guideline. For patients on chemotherapy, standard complete blood counts and renal/hepatic function monitoring per drug-specific protocols. For pembrolizumab, monitor thyroid function and other immune-related labs as indicated.
Supportive Follow Up
- Survivorship care per NCCN Survivorship Guidelines [PN-8 footnote x].
- Distress screening using NCCN Distress Thermometer [PN-1 footnote b].
- Consider referral to sexual health specialist for erectile dysfunction or body image issues.
- Lymphedema management resources after ILND.
ComplicationsClick to collapse
Disease-Related
| Complication | Management |
|---|---|
| Inguinal lymph node metastases | ILND with or without neoadjuvant TIP chemotherapy; consider PLND for ≥2 positive inguinal nodes or extranodal extension [PN-4], [PN-5], [PN-6]. |
| Pelvic lymph node metastases | Neoadjuvant TIP followed by consolidation surgery (bilateral ILND + PLND) or chemoradiotherapy for nonsurgical candidates [PN-7], [PN-D]. |
| Distant metastases (visceral, bone, etc.) | Systemic chemotherapy (TIP, cisplatin/fluorouracil ± pembrolizumab), clinical trial, RT for local control, best supportive care [PN-10], [PN-D]. |
| Lymphedema of legs/genitalia | Supportive care; consider physical therapy, compression garments. Specific management per NCCN Survivorship guidelines [PN-8 footnote x]. |
Supportive CareClick to collapse
Supportive care is an integral part of penile cancer management. The NCCN guidelines emphasize use of the Distress Thermometer and Problem List to address social determinants of health [PN-1 footnote b]. Best supportive care is recommended for patients with no response or disease progression after systemic therapy, in accordance with NCCN Guidelines for Palliative Care [PN-10]. Survivorship care follows the NCCN Guidelines for Survivorship [PN-8 footnote x].
Not specifically addressed in the penile cancer guideline; standard oncology nutrition support per institutional practice.
Not detailed; for platinum-based chemotherapy (cisplatin, carboplatin), standard antiemetic prophylaxis (NK1 antagonist + 5-HT3 antagonist + dexamethasone) is recommended per NCCN Antiemesis Guidelines.
Not specifically mentioned; for neutropenic risk with TIP or cisplatin/fluorouracil, primary prophylaxis with G-CSF may be considered per NCCN Myeloid Growth Factors Guidelines.
Not specifically addressed; patients undergoing major surgery (ILND, PLND, penectomy) should receive VTE prophylaxis per institutional protocols and NCCN VTE Guidelines.
For palliative RT or advanced disease, consider RT for local control (e.g., 30 Gy/10 fractions) and best supportive care per NCCN Palliative Care Guidelines [PN-C], [PN-10].
NCCN Distress Thermometer and Problem List to identify distress; referrals to psychosocial services, support groups, or sexual health counseling as needed [PN-1 footnote b].
Not addressed. For patients receiving RT to the penile area, standard dental evaluation prior to RT is prudent, but no specific recommendations given.
PrognosisClick to collapse
Penile squamous cell carcinoma (SCC) is a rare disease with a 5-year survival rate of approximately 65% overall. For patients with localized disease, the 5-year survival rate is 79%; for regional disease, 57%; and for distant metastatic disease, 10% [5], [6]. The median age at diagnosis in the United States is 68 years, and earlier diagnosis is associated with improved outcomes [9]. HPV or p16 positivity is reported as a favorable prognostic factor, associated with better disease-specific survival (DSS) [15], [16], [17]. Visceral metastases and an Eastern Cooperative Oncology Group (ECOG) performance score ≥1 are poor prognostic factors for both overall survival (OS) and progression-free survival (PFS) [27]. The presence and extent of inguinal lymph node metastases is the single most important prognostic indicator [32]. Pathologic prognostic factors include histologic subtype (e.g., verrucous carcinoma has best prognosis; basaloid, clear cell, sarcomatoid are aggressive), histologic grade (3-tiered), depth of invasion/tumor thickness, perineural invasion, lymphovascular space invasion, resection margin status, and pathologic stage [PN-F].
By Stage
| Stage | Five Yr Survival | Context |
|---|---|---|
| Localized (confined to penis, no nodal/distant metastases) | 79% | Based on American Cancer Society data from the NCCN guideline overview [5], [6]. Includes Stage 0is, 0a, I, IIA, IIB per AJCC 8th edition. |
| Regional (inguinal or pelvic lymph node involvement, no distant metastases) | 57% | Includes stage IIIA, IIIB, and some stage IV (T4 any N M0, or any T N3 M0) [5], [6]. |
| Distant (distant metastases present, M1) | 10% | Stage IV with M1 disease [5], [6]. |
Prognostic Factors
- HPV/p16 positivity - favorable DSS [15], [16], [17]
- Visceral metastases and ECOG PS ≥1 - poor OS/PFS [27]
- Inguinal lymph node involvement (number, site, extracapsular extension) - strongest prognostic factor [6], [32]
- Histologic subtype: verrucous (best prognosis), basaloid/clear cell/sarcomatoid (aggressive) [PN-F]
- Histologic grade (3-tiered): grade 3 poorly differentiated/undifferentiated is high risk [29], [38]
- Depth of invasion/tumor thickness
- Perineural invasion and lymphovascular space invasion
- Resection margin status
- Pathologic stage (AJCC 8th edition) [29]
Follow UpClick to collapse
Post Curative Treatment
Follow-up schedule is stratified by initial treatment of primary lesion and nodal status. For patients treated with topical/local therapy: clinical examination of penis and inguinal region every 3 months for years 1–2, then every 6 months for years 3–5, then every 12 months for years 5–10 [PN-8]. For partial/radical penectomy: clinical examination every 6 months for years 1–2, then every 12 months for years 3–10 [PN-8]. For lymph node management: pN0/N1 patients: clinical examination every 6 months for years 1–2, then every 12 months for years 3–4; with CT abdomen/pelvis and chest radiograph. pN2/N3 patients: clinical examination every 6 months for years 1–2, then every 12 months for years 3–4; with CT abdomen/pelvis and chest CT: year 1 every 3 months, years 2–4 every 6 months [PN-8]. If abnormal clinical examination, obesity, or prior inguinal surgery, consider ultrasound, CT with contrast, or MRI of inguinal region [PN-8 footnote y,z].
Surveillance Rationale
A large retrospective review of 700 patients found that 92% of all recurrences were detected within 5 years of primary treatment [136]. Penile-sparing therapies carry a significantly higher risk of local recurrence (28%) than partial/total penectomy (5%) and thus require closer surveillance [136]. Nodal recurrences tend to occur earlier: median time to recurrence 10 months for distant, 12 months for inguinal, 10.5 months for pelvic, and 44.5 months for local (with >95% of distant/inguinal/pelvic recurrences within 48 months, while it took 127 months for 95% of local recurrences) [160].
Late Effects Screening
- Not explicitly detailed in the penile cancer guideline; refer to NCCN Survivorship Guidelines for general late effects screening after cancer treatment [PN-8 footnote x].
- Late effects from RT: penile fibrosis, urethral stricture, erectile dysfunction, secondary malignancies (rare).
- Late effects from chemotherapy: peripheral neuropathy (taxanes), nephrotoxicity (cisplatin), ototoxicity.
- Lymphedema screening and management after ILND/PLND.
Recurrence Patterns
Local recurrence after penile-sparing treatment: 28% vs 5% after penectomy [136]. Nodal recurrence: N0 patients 2%, node-positive 19% [136]. Inguinal recurrence after ILND: median time 12 months; pelvic recurrence 10.5 months; distant recurrence 10 months [160]. Most recurrences occur within 5 years, but late local recurrences can occur up to 127 months [160]. Management of recurrence is guided by extent: local recurrence after penile-sparing is re-staged; isolated inguinal recurrence may be treated with salvage surgery/chemoradiation [PN-9].
Key TrialsClick to collapse
| Acronym | Full Name | Year | N | Intervention | Comparator | Population | Primary Endpoint | Key Result | Secondary Outcomes | Practice Change | Journal |
|---|---|---|---|---|---|---|---|---|---|---|---|
| TIP (Phase II) | Neoadjuvant paclitaxel, ifosfamide, and cisplatin chemotherapy for metastatic penile cancer: a phase II study | 2010 | 30 | Neoadjuvant TIP (paclitaxel 175 mg/m2 IV day 1, ifosfamide 1200 mg/m2 IV days 1-3, cisplatin 25 mg/m2 IV days 1-3) every 3-4 weeks for 4 courses, followed by consolidative surgery | None (single arm) | Patients with stage N2 or N3 (stage III or IV) penile cancer without distant metastases | Objective response rate (ORR) | ORR 50%; 22 patients (73.3%) underwent surgery. Estimated long-term progression-free survival for intent-to-treat was 36.7%. Improved PFS and OS associated with objective response to chemotherapy (P < .001 and P = .001). | Absence of bilateral residual tumor, extranodal extension, and skin involvement were associated with better outcomes. | Established TIP as preferred neoadjuvant regimen for bulky inguinal or unresectable penile cancer. Still standard of care. | Journal of Clinical Oncology |
| HERCULES (LACOG 0218) | Pembrolizumab Plus Platinum-Based Chemotherapy for Patients With Advanced Penile Cancer: The Nonrandomized HERCULES (LACOG 0218) Clinical Trial | 2025 | 37 | Cisplatin 70 mg/m2 IV day 1 (or carboplatin AUC 5 IV day 1) + continuous infusion fluorouracil 1000 mg/m2/day days 1-4 + pembrolizumab 200 mg IV day 1 every 3 weeks for 6 cycles, followed by pembrolizumab maintenance 200 mg IV every 3 weeks up to 34 cycles | None (single arm) | Patients with locally advanced or metastatic penile SCC, first-line systemic therapy | ORR per RECIST 1.1 | ORR 39.4% (1 complete response, 12 partial responses). Median PFS 5.4 months, median OS 9.6 months at median follow-up 24 months. Manageable safety profile. | Safety, duration of response, overall survival. | Introduced pembrolizumab + platinum/fluorouracil as a first-line treatment option for advanced penile cancer (category 2A). | JAMA Oncology |
| KEYNOTE-158 | Efficacy of Pembrolizumab in Patients With Noncolorectal High Microsatellite Instability/Mismatch Repair-Deficient Cancer (cohort) and Association of Tumour Mutational Burden with Outcomes | 2020 | 233 (MSI-H/dMMR cohort for efficacy) and 790 evaluable for TMB (TMB-H n=102)" | Pembrolizumab 200 mg IV every 3 weeks for up to 2 years | None (single arm per cohort) | Patients with previously treated advanced noncolorectal MSI-H/dMMR solid tumors (for the MSI-H analysis) and patients with advanced solid tumors for TMB analysis | ORR (MSI-H/dMMR cohort); ORR by TMB status (exploratory) | MSI-H/dMMR: ORR 34.3%, median PFS 4.1 months, median OS 23.5 months; grade ≥3 AEs 14.6%, one treatment-related death (pneumonia). TMB-H (≥10 mut/Mb): ORR 29% vs 6% for non-TMB-H. | Disease control rate, duration of response, safety. | Supported tumor-agnostic FDA approvals of pembrolizumab for MSI-H/dMMR and TMB-H solid tumors. Used in penile cancer for subsequent-line therapy. | Lancet Oncology (TMB analysis) and Journal of Clinical Oncology (MSI-H/dMMR analysis) |
| InPACT | International Penile Advanced Cancer Trial (InPACT) | Ongoing | Target 400+ | Two sequential randomizations: 1) Neoadjuvant randomization: ILND alone vs neoadjuvant chemotherapy vs neoadjuvant chemoradiotherapy; 2) Pelvic randomization: prophylactic PLND vs surveillance with adjuvant chemoradiotherapy for high-risk features | Variable per randomization | Patients with locally advanced penile cancer (stage III/IV) with inguinal node metastases | Overall survival | Trial not yet reported; accrual ongoing. | Progression-free survival, quality of life, toxicity. | Will define role of neoadjuvant therapy and prophylactic PLND in node-positive penile cancer. | None |
Clinical PearlsClick to collapse
- Pearl 1: Penile cancer is rare but aggressive; early diagnosis is critical. Any suspicious penile lesion warrants biopsy (punch, excisional, or incisional) with assessment of HPV and HIV status [PN-1].
- Pearl 2: Inguinal lymph node status is the strongest prognostic factor. For intermediate/high-risk primary tumors (T1b or ≥T2), bilateral ILND or DSNB is recommended even if nodes are nonpalpable, because occult metastases occur in up to 68–73% [64], [99], [135].
- Pearl 3: Neoadjuvant TIP chemotherapy prior to ILND is preferred for bulky inguinal nodes (≥4 cm fixed) or enlarged pelvic nodes. The phase II study showed 50% response rate and 36.7% estimated long-term progression-free survival [1].
- Pearl 4: Penile-sparing approaches (topical therapy, laser, wide local excision) are appropriate for PeIN, Ta, and pT1a lesions but require close surveillance due to higher local recurrence (28% vs 5% for penectomy) [136].
- Pearl 5: Radiation therapy as primary treatment is controversial; brachytherapy with interstitial implant (category 2B) or EBRT (category 2B) may be considered for T1–2 N0 tumors <4 cm. Chemoradiotherapy is category 3 for primary treatment due to limited data [PN-C].
- Pearl 6: Chemotherapy regimens containing bleomycin are contraindicated because of unacceptable pulmonary toxicity [6].
- Pearl 7: For metastatic disease, first-line options include TIP (preferred), cisplatin/fluorouracil, or platinum/fluorouracil + pembrolizumab followed by maintenance pembrolizumab. Subsequent-line: clinical trial preferred, or pembrolizumab if MSI-H/dMMR/TMB-H, or paclitaxel/cetuximab [PN-D].
- Pearl 8: The HERCULES (LACOG 0218) trial demonstrated an ORR of 39.4% with pembrolizumab + platinum/fluorouracil as first-line therapy in advanced penile cancer, with median PFS 5.4 months and OS 9.6 months [5], [173].
- Pearl 9: Bilateral PLND is indicated when ≥4 positive inguinal nodes are present (total both sides) [141].
- Pearl 10: Surveillance imaging intensity depends on nodal status: for pN2/N3, CT chest/abdomen/pelvis every 3–6 months for first 2–4 years; for pN0/N1, less frequent [PN-8].
Special SituationsClick to collapse
Verrucous carcinoma (Ta)
HIV-positive patients with penile cancer
Patients with psoriasis on PUVA therapy
Patients with lichen sclerosus
Unresectable T4 primary tumors
Patients not eligible for cisplatin (e.g., renal impairment, hearing loss, neuropathy)
Patients with MSI-H/dMMR or TMB-H tumors
Guidelines ResourcesClick to collapse
NCCN Clinical Practice Guidelines in Oncology: Penile Cancer
EAU-ASCO Collaborative Guidelines on Penile Cancer
AJCC Cancer Staging Manual, 8th Edition
WHO Classification of Tumours of the Urinary System and Male Genital Organs
PDQ® Penile Cancer Treatment
Protective FactorsClick to collapse
- Neonatal circumcision: Associated with a lower rate of penile cancer, likely due to elimination of phimosis and reduced incidence/duration of HPV infections [20]. The protective effect is not observed in adults who undergo circumcision later in life [20]. A small study suggests circumcision may reduce the risk of invasive penile cancer but not carcinoma in situ (PeIN) [21]. The number needed to treat to prevent one case is relatively high due to disease rarity.