Michael A. Poch, MD
Philippe E. Spiess, MD
BASICS
DESCRIPTION
• The majority of penile carcinomas are squamous cell carcinoma (SCC) histology
• Can be SCC in situ (erythroplasia of Queyrat, Bowen disease of the penis, bowenoid papulosis), low-grade noninvasive (eg, verrucous carcinoma), or invasive carcinoma
• Other rare types of penile cancer histologies include adeno- and adenosquamous carcinoma, basal cell carcinoma, melanoma, sarcomas, Kaposi sarcoma, neuroendocrine (small cell) undifferentiated carcinoma, sebaceous gland carcinoma, and rarely, metastases from other sites (prostate, bladder, colon, kidney)
• Inguinal and pelvic lymph nodes are common sites of metastases
EPIDEMIOLOGY
Incidence
• Rare in developed countries. Approximately 1,640 new cases annually in US with approximately 320 deaths in 2014.
• Hispanics are more commonly affected than whites.
• Circumcision is protective.
• Accounts for up to 10% of cancers in men in South America.
Prevalence
Accounts for 0.4–0.6% of cancers in men
RISK FACTORS
• Human papilloma virus (HPV) types 16, 18, 31, and 33 (associated with 45–80%)
• Presence of foreskin and/or phimosis
• Poor hygiene
• Sexually transmitted disease (STD)
• HIV infection
• Chronic inflammation
• Lichen sclerosis
• Smoking
Genetics
N/A
PATHOPHYSIOLOGY
• HPV-associated DNA and chromosomal changes
• Smegma that forms from desquamated epithelial cells is thought to be a primary instigating factor in penile cancer; good hygiene and circumcision limit smegma accumulation
• Penile SCC spreads by a reliable pattern: Superficial inguinal lymph nodes to deep inguinal lymph nodes to pelvic lymph nodes
ASSOCIATED CONDITIONS
• Balanitis xerotica obliterans (BXO)
• Bowen disease
• Chronic inflammation
• Erythroplasia of Queyrat
• Giant condylomata
• Leukoplakia
• Phimosis
• Premalignant lesions that predispose to the development of invasive SCC of the penis and penile cancer
• STIs
GENERAL PREVENTION
• Good penile hygiene
• Newborn circumcision more protective than circumcision later in life
DIAGNOSIS
HISTORY
• Induration, erythema, nodularity of prepuce, glans, and/or shaft
• Bleeding ulcer on glans and/or penile shaft
• Inguinal adenopathy
• Penile pain if lesion infected
• Patients often deny or ignore symptoms resulting in presentation at advanced stage
• New onset priapism with a mass suggests a metastatic corporal body lesion
• Constitutional symptoms may suggest metastatic disease
PHYSICAL EXAM
• Induration, erythema, nodularity of prepuce and/or glans
• Fungating mass emanating from glans or shaft
• Bleeding ulcer on glans
• Purulence suggests concomitant infection
• Inguinal adenopathy
– Location, number, unilateral, bilateral, mobility or fixation
DIAGNOSTIC TESTS & INTERPRETATION
Lab
• Serum CBC, electrolytes (including calcium), and liver function studies
• Urinalysis, urine culture
Imaging
• US or MRI of penis for local tumor (T) staging
• CT/MRI of pelvis and inguinal regional to evaluate for lymphadenopathy and metastatic disease
Diagnostic Procedures/Surgery
• Biopsy; punch, excisional, or incision
• Shave biopsy will not give adequate local tumor (T) staging
Pathologic Findings
• Most malignancies involve the epithelial surface of the penis
• Subtypes of SCC
– Usual, papillary, verrucous, warty, basaloid, sarcomatoid
• CIS (erythroplasia of Queyrat, Bowen disease of the penis, bowenoid papulosis)
• Verrucous carcinoma, warty carcinoma, Buschke–Löwenstein tumor, and giant condyloma are terms used to describe infrequently seen rare tumors that may invade locally but do not metastasize. Mostly considered to be benign, but malignant degeneration has been reported
• Grade:
– Broder’s classification used
Keratinization, nuclear pleomorphism, number of mitosis
– SCC grade classification: Grade strong predictor for metastatic nodal involvement
Grade I: Well differentiated, no evidence of anaplasia
Grade II: Moderately differentiated (<50% anaplastic cells)
Grade III: Poorly differentiated (>50% anaplastic cells)
Grade IV: Undifferentiated
• Vascular invasion is associated with prognosis
DIFFERENTIAL DIAGNOSIS
• BXO
• Bowen disease (red, scaly patches on the keratinized skin of the penis typically penile shaft)
• Erythroplasia of Queyrat; shiny red patches on mucosal surfaces (glans and prepuce if uncircumcised)
• Bowenoid papulosis (multiple flat, warty lesion sometimes pigmented)
• Condyloma acuminatum
• Condyloma lata
• Extramammary Paget disease
• Giant condylomata
• Kaposi sarcoma
• Lichen sclerosis
• Psoriasis
• Seborrheic keratosis
• Ulcer from STI
• Balanitis of Zoon
TREATMENT
GENERAL MEASURES
• Treatment typically based on grade and stage of primary tumor (1)
• Palpable lymphadenopathy
– Fine-needle aspiration (FNA)
– 6-wk course of oral antibiotics followed by repeat physical exam
MEDICATION
First Line
• Tis/Ta lesions
– Topical: Imiquimod 5% cream applied for 5 d/wk for 4–6 wk or 5-FU 5% cream every other day for 4–6 wk
Second Line
N/A
SURGERY/OTHER PROCEDURES
• Primary lesions
– Tis/Ta lesions
Laser ablation: CO2 or neodymium
Circumcision (preputial lesions)
Wide local excision, Mohs surgery, glansectomy, glans resurfacing
– T1 grade 1–2
Mohs, wide local excision
External beam radiation therapy
Brachytherapy (with interstitial placement)
Laser ablation
– T1 grade 3–4 or ≥T2
Partial penectomy (with intraoperative frozen section)
Traditionally 2-cm margin is required
Total penectomy with perineal urethrostomy
• Regional nodes (2)
– Sentinel node biopsy
High false-negative rate (25%)
– Nonpalpable nodes
High-risk T2 or G3 and intermediate-risk cancer with lymphovascular invasion—inguinal node dissection (ILND)
– Unilateral palpable nodes <4 cm
FNA or ILND if high risk
6 wk of oral antibiotics less recommended
– Palpable nodes ≥4 cm
Standard or modified ILND
Possible preoperative EBRTchemotherapy
• Pelvic lymph nodes
– Pelvic Lymph node dissection if >2 inguinal nodes positive on frozen section at the time of ILND
ADDITIONAL TREATMENT
Radiation Therapy
• External radiation to primary lesion or inguinal lymph nodes
• Typical doses are 50–60 Gy over 4–6 wk
• Interstitial brachytherapy for clinically indicated lesions
Additional Therapies
• Neoadjuvant chemotherapy
– TIP: Ifosfamide, paclitaxel, cisplatin
• Adjuvant for high-risk disease
– Bilateral inguinal nodal disease
– Pelvic lymph node involvement
– Extranodal extension
– >4 cm nodes
• Metastatic disease
– TIP
– Clinical trial
– Supportive/palliative care
Complementary & Alternative Therapies
N/A
ONGOING CARE
PROGNOSIS
• Depends on T-stage and nodal status
• Overall survival for men with node-negative disease is 80–90%.
• 20–30% of men with inguinal lymph node metastasis will have pelvic lymph node metastasis
– Pelvic nodal metastasis have a 10% 5-yr survival
• When applicable, ILND associated with improved disease-specific survival
COMPLICATIONS
• Infections
• Erosion of lymphadenopathy into femoral vessels
• Partial penectomy and total penectomy
– Urethral stenosis
– Loss of erective function
• ILND
– Infection (43%)
– Seroma (24%)
– Wound breakdown (16%)
– Lymphedema
– Vascular injury
FOLLOW-UP
Patient Monitoring
• Close inspection for local recurrence usually every 3 mo for 5 yr (frequency depends on grade and stage)
• Consider imaging for ambiguous findings on physical exam
Patient Resources
National Cancer Institute. http://www.cancer.gov/cancertopics/types/penile
REFERENCES
1. National Comprehensive Cancer Network. Penile Cancer Version 1. 2013. http://www.nccn.org/professionals/physician_gls/pdf/penile
2. Johnson TV, Hsiao W, Delman KA, et al. Extensive inguinal lymphadenectomy improves overall 5-year survival in penile cancer patients: Results from the surveillance, epidemiology, and end results program. Cancer. 2010;2960–2966
ADDITIONAL READING
• Burgers JK, Badalament RA, Drago JR. Penile cancer: Clinical presentation, diagnosis, and staging. Urol Clin N Am. 1992;19:247–256.
• McDougal WS, Kirchner FK Jr, Edwards RH, et al. Treatment of carcinoma of the penis: The case for primary lymphadenectomy. J Urol. 1986;136:38–41.
• Mohs FE, Snow SN, Larson PO. Mohs micrographic surgery for penile tumors. Urol Clin N Am. 1992;19:291–304.
• Ornellas AA, Seixas AL, Marota A, et al. Surgical treatment of invasive squamous cell. J Urol. 1994;151(5):1244–1249.
• Pagliaro LC, Williams DL, Daliani D, et al. Neoadjuvant paclitaxel, ifosfamide and ciplatin chemotherapy for metastatic penile cancer. A phase II Study. J Clin Oncol. 2010;3851–3857.
• Pettaway CA, Pisters LL, Dinney CP, et al. Sentinel lymph node dissection for penile carcinoma: The MD Anderson Cancer Center experience. J Urol. 1995;154:1999–2003.
See Also (Topic, Algorithm, Media)
• Balanitis Xerotica Obliterans (BXO)
• Bowen Disease and Erythroplasia of Queyrat
• Genital Ulcer Algorithm
• Penis, Bowenoid Papulosis
• Penis, Lesion, General
• Penis, Leukoplakia
• Penis, Mass (Corporal Body Mass)
• Penis, Squamous Cell Carcinoma Algorithm 
• Penis, Squamous Cell Carcinoma Images 
• Reference Tables: TNM: Penis Cancer
CODES
ICD9
• 176.0 Kaposi’s sarcoma, skin
• 187.4 Malignant neoplasm of penis, part unspecified
• 233.5 Carcinoma in situ of penis
ICD10
• C46.0 Kaposi’s sarcoma of skin
• C60.9 Malignant neoplasm of penis, unspecified
• D07.4 Carcinoma in situ of penis
CLINICAL/SURGICAL PEARLS
• Grade and stage associated with prognosis FNA of palpable nodes is preferred over 6-wk course of oral antibiotics.
• Modified ILND is associated with improved morbidity.
• Bulky inguinal lymph node metastases should be managed by multimodal therapy consisting of neoadjuvant systemic chemotherapy followed by surgical resection (± radiotherapy).