Page 12 of 21

PA28.{2,6} | Penile Carcinoma & Male Genital Morphology — SDL Guide (Part 2)

Invasive Squamous Cell Carcinoma of the Penis — Risk Factors & Pathogenesis

Penile squamous cell carcinoma (SCC) is uncommon in developed countries (1% of male cancers) but accounts for up to 10–20% of male cancers in parts of Africa, South America, and Asia. Understanding risk factors is testable and clinically important.

Risk factors and their mechanisms:

1. HPV infection (types 16, 18) — present in ~40–50% of penile SCCs. HPV E6 protein binds and degrades p53 (guardian of genome); HPV E7 protein inactivates pRb (cell cycle brake). Result: uncontrolled proliferation + blocked apoptosis → SCC.

2. Lack of circumcision — intact foreskin traps smegma (desquamated cells + secretions), causing chronic inflammation. Circumcision at birth reduces risk by ~3–5-fold. (Penile carcinoma is virtually absent in populations with universal neonatal circumcision: Jewish, Muslim communities.)

3. Phimosis — inability to retract the foreskin causes stasis of smegma under the prepuce, chronic inflammation, and occasionally secondary HPV trapping. Present in >50% of penile carcinoma patients.

4. Smoking — tobacco carcinogens excreted in urine and concentrated in preputial space; ~4-fold increased risk.

5. Chronic inflammatory conditions — lichen sclerosus (balanitis xerotica obliterans), lichen planus of the glans.

Two pathogenic pathways:
- HPV-associated pathway (younger patients, ~40%): condyloma → PeIN (basaloid/warty subtype) → basaloid SCC
- HPV-independent pathway (older patients, ~60%): chronic inflammation (lichen sclerosus, phimosis) → differentiated PeIN → keratinizing SCC

Side-by-side schematic flowchart comparing HPV-associated and HPV-independent inflammatory pathways leading to different subtypes of penile squamous cell carcinoma. — **Panel A:** HPV-associated pathway: HPV 16/18 infection, E6/E7 oncoproteins, p53 inactivation, Rb inactivation, high-grade undifferentiated PeIN, warty-basaloid SCC, basaloid atypical cells, papillary/warty surface.. **Panel B:** HPV-independent inflammatory pathway: chronic irritation, lichen sclerosus, squamous epithelial injury, differentiated PeIN, keratinizing SCC, sclerotic dermis, differentiated atypical keratinocytes, keratin pearl formation.. **Inset:** Distal penile site map showing glans, inner prepuce/coronal sulcus, and common sites of penile SCC..

Gross Morphology of Penile SCC — Papillary vs Flat/Ulcerative

Penile SCC most commonly arises on the glans (~48%) or the inner prepuce/coronal sulcus (~21%), corresponding to the highest HPV exposure and chronic irritation sites.

Two major gross types — exam-critical distinction:

1. Papillary (exophytic) type:
- Irregular, cauliflower-like, or warty papillary mass
- Often gray-white or tan
- May have areas of surface necrosis
- Usually less deeply invasive at presentation
- Corresponds to warty or verrucous histological subtype

2. Flat/ulcerative (endophytic) type:
- Flat, indurated plaque that ulcerates centrally
- Ulcer has raised, rolled/everted margins and a dirty necrotic base
- Surrounding induration from desmoplastic stromal reaction
- Deeper invasion at presentation
- Higher grade, worse prognosis

Cut surface: Firm, gray-white tumor infiltrating the underlying corpus spongiosum or corpora cavernosa; irregular, infiltrating borders.

Medical diagram showing papillary exophytic penile squamous cell carcinoma as a cauliflower-like gray-white mass on the glans with labels for tumor surface, glans, urethral meatus, and prepuce margin. — **Panel A:** Gross distal penile view showing cauliflower-like gray-white tumor surface on the glans, urethral meatus, and prepuce margin. **Panel B:** Inset close-up of papillary tumor projections and gray-white keratinous surface, plus orientation sketch highlighting urethral meatus and prepuce margin.

Medical illustration of ulcerative penile squamous cell carcinoma on the glans, labeling the rolled margin, necrotic floor, indurated tissue, and urethral meatus. — **Panel A:** Gross anterior view of glans penis showing ulcerative SCC with rolled everted margin, necrotic floor, indurated surrounding tissue, and urethral meatus.. **Panel B:** Simplified cutaway of ulcer edge showing raised rolled margin, central necrotic debris, and firm fibrotic indurated tissue beneath the ulcer..

Microscopy of Penile SCC — What to Look For

The majority of penile SCCs are keratinizing (conventional) squamous cell carcinoma. The microscopic features must be committed to memory for practical examination.

Key histological features:

Irregular nests and cords of malignant squamous cells invading the underlying stroma (dermal or subepithelial connective tissue)

Keratin pearls (squamous pearls, epithelial pearls) — concentric whorls of squamoid cells with central laminated keratin. A near-pathognomonic feature of well-differentiated (Grade 1) keratinizing SCC.

Individual cell keratinization — single cells with dense pink cytoplasm and dark nuclei throughout the tumor nests (even in moderately differentiated tumors)

Intercellular bridges (desmosomes) visible between adjacent tumor cells at high power — confirms squamous lineage

Stromal desmoplasia — reactive fibrous stroma surrounding tumor nests, dense collagen, inflammatory infiltrate

Cytological atypia — enlarged, pleomorphic nuclei; prominent nucleoli; abnormal mitoses (tripolar, bizarre forms)

In poorly differentiated SCC: sheets of anaplastic cells, few or no keratin pearls, more abnormal mitoses

Grading (Grade 1–3):
- Grade 1 (well-differentiated): abundant keratin, good squamous maturation, few mitoses
- Grade 2 (moderately differentiated): moderate keratin, intermediate features
- Grade 3 (poorly differentiated): minimal keratin, marked atypia, many mitoses

A labeled H&E-style histology diagram of well-differentiated invasive penile squamous cell carcinoma showing keratin pearls, invasive nests, desmoplastic stroma, dysplastic epithelium, and an inset of intercellular bridges. — **Panel A:** 100x H&E overview showing overlying dysplastic squamous epithelium, irregular invasive squamous nests, multiple keratin pearls, desmoplastic stroma, nuclear pleomorphism, and mitotic activity.. **Panel B:** 400x inset showing polygonal malignant squamous cells with eosinophilic cytoplasm, pleomorphic nuclei, keratinization, and labeled intercellular bridges.. **Panel C:** Risk-factor and pathogenesis schematic showing HPV 16/18 E6-mediated p53 degradation, E7-mediated pRb inactivation, lack of circumcision with smegma retention, chronic inflammation, and progression to invasive penile SCC..

Histology illustration of moderately differentiated penile squamous cell carcinoma showing invasive squamous nests with cytological atypia, abnormal mitosis, individual cell keratinization, and stromal inflammation. — **Panel A:** Main H&E 200x field showing invasive squamous cell carcinoma nests, cytological atypia, abnormal mitosis, individual cell keratinization, stromal inflammatory infiltrate, and collagenous stroma.. **Panel B:** Magnified tumor nest showing cytological atypia: enlarged hyperchromatic nuclei, prominent nucleoli, pleomorphism, and eosinophilic squamous cytoplasm.. **Panel C:** Magnified abnormal mitotic figure within an atypical squamous tumor cell.. **Panel D:** Magnified individual cell keratinization with isolated intensely eosinophilic keratinized tumor cells within squamous nests..