Penile Cancer

Benign & Premalignant Lesions

Benign Tumours

• Pearly penile papules (papillomas) — normal findings on the glans or corona; no treatment needed.
• Zoon balanitis (plasma cell balanitis / balanitis plasmacellularis) — occurs in uncircumcised men from the 3rd decade onward as smooth, moist, erythematous, well-circumscribed plaques on the glans, often with shallow erosions and up to 2 cm in size; can be difficult to distinguish from carcinoma in situ. Histology shows angiofibromas (like the facial lesions of tuberous sclerosis) with a plasma cell infiltrate. Diagnose by biopsy (exclude malignancy and extramammary Paget's). Circumcision is curative in most cases; for patients avoiding it, topical corticosteroids relieve symptoms, and topical calcineurin inhibitors (tacrolimus, pimecrolimus) or laser may help.

Premalignant Lesions — HPV-related

• Bowenoid papulosis — multiple reddish-brown verrucous papules on the penile shaft, typically in young men; histologically resembles low-grade carcinoma in situ (Bowen's disease) and is linked to HPV 16. Progression to invasive cancer ~1%. Diagnose by biopsy (gold standard); treat with excision, electrocautery, cryotherapy, laser, or topical 5-fluorouracil.
• Verrucous carcinoma (Buschke-Löwenstein tumour, giant condyloma) — associated with HPV 6 and 11; progression to invasive cancer ~30%. It grows locally and destroys adjacent tissue by compression but does not metastasize (unlike condyloma acuminatum, which always stays superficial). Requires surgical excision — radiation is ineffective.
• Carcinoma in situ (CIS):
  • Erythroplasia of Queyrat — CIS of the glans or foreskin; progression ~30%.
  • Bowen's disease — CIS of the penile shaft, remaining genitalia, or perineum; progression ~5%.
  • Metastasis is extremely rare, and CIS is not associated with visceral malignancies.
• Condyloma acuminatum — associated with HPV 6 and 11; stays superficial and never invades.
• BXO (balanitis xerotica obliterans) is a synonym for lichen sclerosus.

Premalignant Lesions — Non-HPV-related

• Penile Kaposi sarcoma — associated with HHV-8; prompts evaluation for HIV/immunosuppression. Presents as a raised, painful, bleeding papule or ulcer with bluish discolouration. Four categories: classic (no known immunodeficiency, indolent), immunosuppression-related (e.g. transplant), African (young men, indolent or aggressive), and epidemic/HIV-related (AIDS). The classic and immunosuppressive forms are non-epidemic — penile-limited non-epidemic disease should be treated aggressively, as it rarely involves other organs. Management: in HIV, start/optimize HAART (often induces remission); local options include laser, cryotherapy, excision, and topical retinoids; disseminated/visceral disease needs combination chemotherapy.
• Penile cutaneous horn — rare; develops over a pre-existing lesion (wart, nevus, abrasion, or malignancy) as a cornified protuberance. It may recur and show malignant change on later biopsy even when initially benign, so careful histology of the base and close follow-up are essential.
• Leukoplakia.
• Lichen sclerosus (see the Penis and Urethra Surgery topic).
• Pseudoepitheliomatous micaceous and keratotic balanitis.

SCC: Epidemiology & Staging

Epidemiology & Risk Factors

Invasive squamous cell carcinoma accounts for >95% of penile malignancies, with an abrupt rise in incidence in the 6th decade of life.

Risk factors:

• Lack of circumcision — neonatal circumcision almost eliminates the risk of invasive penile cancer (it removes roughly half the tissue that can become cancer) but offers less protection against CIS; adult circumcision offers little to no protection.
• HPV — subtype 16 most frequent; oncogenic subtypes 16 and 18, non-oncogenic 6 and 11.
• Phimosis.
• Lichen sclerosus and chronic penile inflammation.
• Tobacco (smoking or chewing).
• Poor hygiene, rural residence, low socioeconomic status, being unmarried.
• Number of sexual partners and early age of first intercourse.
• Penile trauma.
• PUVA (psoralen + UVA phototherapy) for dermatologic conditions such as psoriasis.

TNM Staging (AJCC 8th)

Primary tumour (T):

Category	Definition
Tis	Carcinoma in situ
Ta	Non-invasive SCC (basaloid, warty, verrucous, papillary, or mixed)
T1	Invades subepithelial connective tissue — T1a without LVI/perineural invasion and not high grade; T1b with LVI, perineural invasion, or high grade (grade 3–4 or sarcomatoid)
T2	Invades corpus spongiosum
T3	Invades corpus cavernosum
T4	Invades other adjacent structures

Regional lymph nodes (N):

Stage	Clinical (cN)	Pathologic (pN)
N1	Unilateral, solitary, mobile node	Up to 2 unilateral positive nodes
N2	≥2 unilateral mobile nodes, or bilateral nodes	≥3 unilateral nodes, or bilateral nodes
N3	Fixed nodal mass (any size, uni- or bilateral)	Extranodal extension or pelvic node(s)

cN0 means no palpable or visibly enlarged inguinal nodes. A node >4 cm is often associated with extranodal extension. Note that AJCC separates these clinically versus pathologically: clinical N3 = a fixed nodal mass, whereas pelvic nodes are captured as pathologic pN3.

Distant metastasis (M): M1 = metastasis to nodes outside the true pelvis, or to visceral or bone sites. (There is no pathologic M0; clinical M completes the stage group.)

Natural History

• Tumour architecture — flat tumours metastasize to nodes earlier and carry worse survival than papillary tumours.
• The earliest route of spread is to the regional inguinal then pelvic nodes:
  • Superficial lymphatics drain the foreskin and shaft skin → superficial inguinal nodes.
  • Deep lymphatics drain the glans → superficial and deep inguinal nodes (femoral triangle).
  • Symphyseal crossover allows spread to contralateral inguinal nodes.
  • Drainage then proceeds to ipsilateral pelvic nodes (external iliac, internal iliac, obturator).
  • Untreated nodal enlargement leads to skin necrosis, chronic infection, and death from sepsis or hemorrhage (femoral vessel erosion).
• Distant metastasis — most often lung, bone, and liver; clinically detectable distant disease is uncommon, occurs late after the local lesion is treated, and most untreated patients die within 2 years.

Inguinal Anatomy

• The contents of the femoral triangle from lateral to medial follow the mnemonic "NAVEL": Nerve, Artery, Vein, Empty space, Lymphatics (→ lymph nodes).
• The fascia lata divides the superficial from the deep inguinal lymph nodes.
• The node of Cloquet is the most cephalad deep node and marks the inguinal/pelvic boundary.

Diagnosis & Evaluation

The work-up of a suspicious penile lesion: history and physical (including the inguinal nodes); laboratory (serum calcium, HPV status); imaging (of the primary if large/invasive, and for metastasis if indicated); and biopsy.

History & Physical Exam

• Delay in seeking care is common, and pain is uncommon.
• Penile lesion — note size, location, fixation, and corporeal involvement. Lesions are most often on the glans (48%) and foreskin (21%). Physical exam alone misclassifies the pathologic T stage in 26% of cases.
• Inguinal area — careful palpation is essential. Per EAU, palpably enlarged nodes are highly indicative of metastasis; record the number of nodes on each side and whether they are fixed or mobile (additional imaging does not change management here).

Laboratory

• Serum calcium — hypercalcemia can occur without osseous metastasis, from PTH-related substances produced by the tumour.
• HPV status — mandatory to determine in all patients diagnosed with penile cancer.

Imaging

• Primary tumour — no imaging for small glanular lesions; for larger or invasive-appearing lesions, ultrasound assesses corporal infiltration. Penile Doppler US has higher staging accuracy than MRI for corporal infiltration; MRI with an artificially induced erection can detect corporal invasion but is unpleasant; CT has poor soft-tissue resolution and is not useful for the primary.
• Regional nodes — physical exam of the groin is the clinical gold standard in non-obese patients. CT/MRI is reserved for obese patients or those with prior inguinal surgery (unreliable exam), and pelvic CT/PET assesses pelvic nodes; ultrasound helps when habitus or lymphedema limits the exam.
• Distant — CT of chest/abdomen/pelvis, bone scan, or CT/PET.

Biopsy & Grading

Biopsy before treatment to confirm the diagnosis and assess depth of invasion, vascular invasion, and histologic grade. SCC is graded 1–4 (Broders); low-grade (1–2) lesions are the majority (70–80%) at diagnosis. Risk factors for nodal metastasis: high grade, depth of invasion (pT stage), sarcomatoid histology, perineural invasion, and vascular invasion.

Differential Diagnosis

Condyloma acuminatum (HPV warts), verrucous carcinoma (Buschke-Löwenstein tumour), lichen sclerosus, STI lesions (chancre, chancroid, herpes, lymphogranuloma venereum, granuloma inguinale), and tuberculosis.

Management of the Primary & Radiotherapy

Carcinoma in Situ

• Topical — EAU advises circumcision before topical agents. Options: 5-fluorouracil 5% cream (BID × 6 weeks) or imiquimod 5% cream. Strict adherence and follow-up are essential, with prompt re-biopsy of non-responding lesions; failed topical therapy should not be repeated.
• Laser ablation — CO2 or Nd:YAG (efficacy for cancerous lesions is debated).
• Surgical — a foreskin lesion is treated by circumcision or excision with a 5-mm margin; a glans lesion by excisional strategies that preserve normal penile anatomy.
• Radiation — for lesions resistant to topical therapy, especially in non-surgical candidates.

Organ-sparing Approaches

The goal is to preserve glans sensation and maximize shaft length. Five options: Moh's surgery, laser ablation, radiotherapy, limited excision, and glansectomy. Because recurrence rates are higher than with amputation, follow-up compliance is a key consideration.

• Moh's micrographic surgery — the least invasive, with favourable functional outcomes but high long-term recurrence; best for small, superficial shaft lesions (favourable histology: Ta/T1, grade 1–2), not for large or high-risk tumours.
• Glansectomy — the most radical organ-sparing option with the highest local control; the glans is separated from the corporal heads, the urethra is transected and a distal urethrostomy created, and the defect is covered by advanced/split shaft skin or a full-thickness skin graft.

Penectomy

Indications for partial or total penectomy: high grade (≥3), stage ≥T2 / deep invasion into the glanular urethra or corpora cavernosa, or tumours >4 cm.

Treatment by Stage

Stage	Primary treatment
Tis (glans)	Laser therapy or glans resurfacing; alternative: topical therapy
Ta / Tis (foreskin, shaft skin)	Surgical excision to a negative margin; alternatives: laser, topical (Tis only)
Ta, T1 grade 1–3 (glans)	Excision, glans resurfacing, glansectomy, or radiotherapy — chosen by size/position (RT not for Ta)
Ta, T1 (foreskin, shaft)	Complete surgical excision to a negative margin
T2 (glans, no gross cavernosal involvement)	Total glansectomy ± corpora cavernosa transection to negative margins, partial penectomy, or radiotherapy
T2 (corporeal invasion), T3	Partial or total penectomy
T4	Neoadjuvant chemotherapy with surgical consolidation in responders if resectability is a concern
Local recurrence after conservative therapy	Complete excision to negative margins (may need partial/total penectomy); select superficial low-grade recurrences may have a repeat penile-conserving procedure

Radiotherapy

An option for invasive SCC in patients refusing surgery, delivered as brachytherapy (interstitial implant) or external beam. Primary radiotherapy suits select T1–T2 tumours <4 cm involving the glans/coronal sulcus, and circumcision is required first. Brachytherapy is more likely than EBRT to preserve erectile function. Adverse effects include desquamation, meatal stenosis, and soft-tissue ulceration; salvage penectomy may be needed for persistent/recurrent disease. Inguinal nodes are managed surgically by the same criteria as for surgical primaries — radiation to the groin is less effective than surgery, prophylactic nodal radiotherapy is not recommended, and palliative radiotherapy may benefit inoperable nodes.

Inguinal Node Management & Chemotherapy

Nodal involvement is the single most important prognostic factor for survival — 5-year survival is lower once nodes are involved (the node-positive figure ranges widely, ~0–86%, depending on the extent of involvement).

Clinically Negative Groins

• ~20% of patients with clinically non-palpable nodes harbour occult metastases.
• CT and MRI cannot reliably detect occult nodal disease and are used mainly to assess pelvic nodes.
• Immediate resection of clinically occult metastases improves survival versus delayed resection at the time of clinical detection.

Surgical Staging

Indicated for high-risk tumours (≥pT1b; optional for T1a G2); surveillance is an alternative for reliably compliant patients. Two options — dynamic sentinel node biopsy (DSNB, preferred) or modified inguinal lymphadenectomy.

DSNB removes the node(s) first affected by spread, relying on orderly stepwise lymphatic progression. Technique: inguinal ultrasound with FNA of suspicious nodes first (positive FNA → proceed straight to lymphadenectomy; negative FNA → lymphoscintigraphy with technetium-99m nanocolloid, patent blue dye, and intraoperative gamma-probe localization to resect the sentinel node).

• Advantages — much less morbid than modified or standard lymphadenectomy; bridges imaging and resection for clinically negative groins.
• Disadvantages — restricted to high-volume centres, requires dedicated experience, and should target a false-negative rate ≤5%.
• Accuracy is improved by preoperative inguinal US with needle biopsy of suspicious nodes, routine inguinal exploration even without radiotracer visualization, intraoperative palpation for abnormal nodes, and extended pathologic analysis of excised nodes.
• DSNB is diagnostic — it lets some men avoid a therapeutic lymphadenectomy; a positive DSNB mandates full therapeutic lymphadenectomy. It applies only to clinically negative nodes, not palpable adenopathy.

Palpable Lymphadenopathy

• Palpable adenopathy reflects metastasis in 43% of cases (inflammation in the rest); FNA can differentiate.
• Low-risk primary (Tis/Ta) with palpable nodes — give a course of empiric antibiotics for 4 weeks first (much of the adenopathy is inflammatory); if nodes persist, proceed to FNAC. For these low-risk primaries, a negative FNAC is followed by excisional biopsy of the node: if positive, proceed to lymphadenectomy; if negative, observe.
• Treat with bilateral inguinal lymphadenectomy (open or video-endoscopic) — it can be curative given the prolonged locoregional phase before distant spread. The superficial dissection is bilateral even if adenopathy is unilateral; complete ilioinguinal dissection (nodes deep to the fascia lata in the femoral triangle, plus pelvic nodes) follows if superficial nodes are positive on frozen section.
• Exception — verrucous carcinoma: metastasis is very unlikely, so palpable adenopathy is usually reactive and is observed; biopsy only if it persists/grows, and lymphadenectomy only for biopsy-proven metastasis.

Fixed & Pelvic Nodes

• Fixed nodes (cN3) — neoadjuvant chemotherapy followed by radical inguinal lymphadenectomy in responders.
• Favourable pN+ features (better long-term survival after curative resection): unilateral involvement, minimal disease (≤2 nodes, pN1), no extranodal extension, and no pelvic nodal metastasis — i.e. pN1 without pN2/pN3 features.
• There is no direct lymphatic drainage from the penis to the pelvic nodes — pelvic spread does not occur without inguinal involvement first.
• Pelvic lymph node dissection (distal common iliac, external iliac, obturator) is indicated during inguinal lymphadenectomy when ≥2 inguinal nodes are positive or extranodal extension is present; it serves as a staging tool to identify candidates for adjunctive therapy.

Nodal Treatment Summary

Node status	Management
cN0	Tis, Ta G1, T1 G1 → surveillance. ≥T1b or ≥T2 → invasive nodal staging by bilateral modified inguinal lymphadenectomy or DSNB
cN1/cN2 (palpable)	Surgically remove enlarged nodes, assess by frozen section; if positive, radical inguinal lymphadenectomy
cN3 (fixed)	Neoadjuvant chemotherapy, then radical inguinal lymphadenectomy in responders
Pelvic nodes	Ipsilateral pelvic lymphadenectomy if ≥2 inguinal nodes positive or extracapsular extension (pN3)
Adjuvant chemotherapy	For pN2/pN3 after radical lymphadenectomy
Radiotherapy	Not recommended for nodal disease except as palliation

Adjuvant Chemotherapy — Indications

After radical lymphadenectomy, adjuvant chemotherapy is indicated for any of:

1. ≥2 positive nodes
2. Bilateral metastases
3. Pelvic nodes
4. Extranodal extension

Chemotherapy

A cisplatin-containing regimen should be considered for advanced/metastatic penile cancer and may enable curative resection (the optimal regimen is undetermined). If the tumour progresses through chemotherapy, surgery is not recommended.

Non-Squamous Cancers

Basal Cell Carcinoma, Melanoma & Sarcoma

• Basal cell carcinoma — common on sun-exposed skin but rare on the penis; local excision is virtually always curative.
• Melanoma — aggressive but curable if diagnosed and surgically treated early; surgery is the primary treatment, with radiation and chemotherapy only adjunctive or palliative.
• Sarcoma — prone to local recurrence, with rare regional/distant metastasis; superficial lesions can be treated with less radical procedures.

Extramammary Paget Disease

An erythematous, eczematoid, well-demarcated lesion that cannot be clinically distinguished from erythroplasia of Queyrat, Bowen disease, or penile CIS; it presents with local discomfort, pruritus, and occasionally serosanguineous discharge of the penis, scrotum, or perianal area. It behaves as a slow-growing intraepithelial adenocarcinoma that may become invasive, with dermal deposits spreading to regional nodes via dermal lymphatics. It may be associated with other GU malignancies (prostate, bladder, renal) — evaluate for these.

• Management — resect skin and dermis with a gross margin of up to 3 cm, using frozen sections to guide the extent; positive margins carry higher recurrence and warrant further resection. Cover defects with local skin or scrotal flaps; deeper invasion needs more extensive resection and reconstruction. Inguinal adenopathy warrants radical node dissection, though the prognosis is poor.

Other & Metastases

• Adenosquamous carcinoma and lymphoreticular malignant neoplasms also occur.
• Metastases to the penis usually represent spread from a clinically obvious primary, carry a poor prognosis, and are managed toward the primary histology with local palliation. Priapism is the most frequent sign of metastatic penile involvement, and lymphomatous infiltration is usually secondary to diffuse disease.

Operative Procedures

The principal nodal operation in penile cancer has a dedicated step-by-step reference:

• Inguinal Lymphadenectomy — standard radical and modified complete inguinal node dissection (and the minimally invasive approach), covering femoral triangle anatomy, the node of Cloquet, sartorius flap coverage, and complication prevention.