Igor I. Kislinger, MD
Fernando J. Bianco, Jr., MD
BASICS
DESCRIPTION
• Most common: Squamous cell carcinomas (SCCs)
– SCC in situ or CIS: Erythroplasia of Queyrat (glans or prepuce), Bowen disease (shaft)
– Low-grade noninvasive (eg, verrucous carcinoma)
– Progression risk 5–33% if untreated
• Other penile cancer histology: 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, leukemia most common)
EPIDEMIOLOGY
Incidence
• In 2014 in the United States the American Cancer Society estimates that about 1,640 new cases of penile cancer will be diagnosed and 320 men will die of penile cancer
• In the United States
– Hispanics (6.6 per million)
– Blacks (4.0 per million)
– Whites (3.9 per million)
Prevalence
• Rare in developed countries
• Most common genitourinary malignancy in Uganda
– In Brazil 6–14/100,000 males (1)
RISK FACTORS
• Poor hygiene (2)
• Presence of foreskin and/or phimosis
• STD: HPV types 16, 18, and 33 or HIV
• Genital ultraviolet radiation, alone or combined with 8-methoxypsoralen
• Multiple partners, smoking
• Premalignant conditions:
– Leukoplakia, Lichen sclerosus
– Balanitis xerotica obliterans (BXO)
– Giant condylomata
Genetics
Viral genes E6 & E7 expressed on high-risk HPV, E-cadherin (16q22) immunoreactivity correlates with increased risk of nodal metastases
PATHOPHYSIOLOGY
• Invasive SCC is thought to be preceded by superficial CIS (Bowen disease or erythroplasia of Queyrat). Invasive SCC grows into the skin locally before invading the corporal bodies and extending locally.
• Penile SCC spreads by a relatively reliable pattern: Form superficial pelvic lymph nodes to deep pelvic lymph nodes.
• SCC is found on the glans in 48%, prepuce in 21%, glans and prepuce in 9%, coronal sulcus in 6%, and shaft <2%.
ASSOCIATED CONDITIONS
• Phimosis
• Balanitis
• Sexually transmitted infections (STIs)/STDs
GENERAL PREVENTION
• Good hygiene, avoid smegma accumulation
• Newborn circumcision more protective than circumcision later in life
• HPV vaccines may reduce the risk of HPV and, consequently, penile cancer (unproven)
ALERT
Presentation at advanced stage is not uncommon due to denial and poor hygiene.
DIAGNOSIS
HISTORY
• Persistent induration, erythema, nodularity of prepuce and/or glans. Usually has been treated with several agents, lotions
• Growth or sore on the penis that doesn’t heal within 4 wk
• Patients often denies or ignores lesions and present at later stages
• Bleeding ulcer
• Penile pain—infection
– New onset of priapism with a mass suggests metastatic corporeal body lesion (eg, melanoma)
PHYSICAL EXAM
• Induration, erythema, nodularity of prepuce and/or glans
• Bleeding ulcer
• Foul smell with purulence
• Phimosis
• Inguinal adenopathy
DIAGNOSTIC TESTS & INTERPRETATION
Lab
CBC, urinalysis, urine culture
Imaging
• Penile ultrasound
• CT pelvis—evaluate pelvic adenopathy
• Penile MRI—surgical planning
Diagnostic Procedures/Surgery
• Superficial lesion
– Biopsy, preferably excisional
– Circumcision
• Large or extensive
– Partial penectomy
Pathologic Findings
• Most malignancies involve the epithelial surface of the penis
• 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
• Invasive cancer:
– 95% are SCCs
– Tongues of invasive atypical keratinocytes with multiple mitosis invade the lamina propria or deeper. Sites with foci of aberrant and ectopic keratinization called squamous pearls
– SCCs are graded using the Broders System:
Grade I: Well-differentiated, keratin pearls, prominent intercellular bridges
Grade II–III: Greater nuclear atypia, increased mitotic activity, decreased keratin pearls
Grade IV: Cells deeply invasive, marked nuclear pleomorphism, nuclear mitoses, necrosis, lymphatic and perineural invasion, no keratin pearls
DIFFERENTIAL DIAGNOSIS
• BXO
• Erythroplasia of Queyrat; shiny red patches on mucosal surfaces (glans and prepuce if uncircumcised)
• Bowen disease (red, scaly patches on the keratinized skin of the penis typically penile shaft)
• Bowenoid papulosis (multiple flat, warty lesions, sometimes pigmented)
• Condyloma acuminatum, lata
• Giant condylomata
• Extramammary Paget disease: Adenocarcinoma of apocrine gland bearing skin, often pruritic
• Kaposi sarcoma: Friable nodular lesions of varying size and varying color (purplish, red, blue, dark brown black) often ulcerate/ bleed
• Lichen sclerosis
• Psoriasis
• Seborrheic keratosis
• Ulcer from STD
• Zoon balanitis
TREATMENT
GENERAL MEASURES
• 1st line is surgical excision of lesion on penis.
• Wound care issues are paramount after excision of the primary and after inguinal node dissections.
• Surgical care should be taken to minimize the complications of penile deformity and/or meatal stenosis after excising the primary and diligent attention to avoiding infection, hematoma, and lymphocele after inguinal node dissection is necessary.
• Treatment based on extent of disease and specific tumor type. Recommendations below are for invasive SCC (3). For other tumor types, see specific sections.
MEDICATION
First Line
• Topical 5-fluorouracil for cases of CIS
• For invasive SCC of the penis, after resection of the primary tumor, inguinal adenopathy should be treated with 6 wk of broad-spectrum antibiotics (augmentin or cephalosporin such as keflex) to determine if the enlarged nodes resolve
– Consideration to early fine-needle aspiration biopsy of enlarged nodes can be considered
• Some authors recommend immediate fine-needle aspiration of enlarged inguinal nodes
Second Line
• There is no established chemotherapeutic regimen for metastatic disease.
– Potential active agents include 5-FU, bleomycin, methotrexate, and cisplatin.
SURGERY/OTHER PROCEDURES
• Initial dorsal slit may be necessary to assess the lesion in phimosis
• Circumcision, if preputial and noninvasive
• Laser ablation, if small and noninvasive
• Mohs micrographic surgery, if small and noninvasive or minimally invasive (4)
• Wide local excision for small lesions. A 2-cm margin considered necessary
• Partial or total penectomy should be considered in patients exhibiting adverse features for cure by organ preservation strategies, including tumors 4 cm or more, grade III lesions and tumors invading deeply into the glans urethra or corpora cavernosa
– Partial penectomy must achieve a 2-cm safety surgical margin
• Inguinal lymphadenectomy is mandatory for persistent lymphadenopathy after antibiotics and control of the primary lesion
• Inguinal lymphadenectomy is controversial if inguinal nodes are palpably normal before and after eradication of the primary
• Lymph node sampling (either sentinel node biopsy or modified inguinal dissection) may be offered for patients with palpable normal inguinal nodes and T2 or above lesion:
– Usually, bilateral dissections are recommended
– A total inguinal and pelvic lymphadenectomy is necessary if metastases are noted on sentinel or modified dissection
ADDITIONAL TREATMENT
Radiation Therapy
• External radiation to primary lesion if patient refuses surgical excision
• Some advocate this as primary therapy with salvage surgery with recurrences
• Typical doses are 50–60 Gy over 4–6 wk
• Overall local control provided by interstitial brachytherapy appears superior to that provided by external beam radiation therapy with 5-yr local control rates of 70%–87%
Additional Therapies
Chemotherapy-based clinical trails
Complementary & Alternative Therapies
• Ketogenic diet
• Holistic approaches
ONGOING CARE
PROGNOSIS
• Depends on T-stage and nodal status
• AJCC staging
– Stage I: Cancer is moderately or well-differentiated and only affects the subepithelial connective tissue
– Stage II: Cancer is poorly differentiated, affects lymphatics, or invades the corpora or urethra
– Stage IIIa: Deep invasion into the penis and metastasis in one lymph node.
– Stage IIIb: Deep invasion into the penis and metastasis into multiple inguinal lymph nodes
– Stage IV: The cancer has invaded into structures adjacent to the penis, metastasized to pelvic nodes, or distant metastasis is present
• 5-yr overall survival for men with node-negative disease is 80–90%.
• 5-yr survival for N+ men 30–40%
• Married or previously married men have better prognosis
• African Americans tend to present with more advanced disease and have a poorer prognosis
COMPLICATIONS
• Infections
• Erosion of lymphadenopathy into femoral artery
• After radiation or brachytherapy urethral fistula, stricture, or stenosis with or without penile necrosis, pain, and edema. Radical penectomy may be required
FOLLOW-UP
Patient Monitoring
• Close inspection for local recurrence usually every 3 mo for 5 yr
• Consider imaging for ambiguous findings on physical exam
Patient Resources
• http://www.cancer.gov/cancertopics/types/penile. Accessed 1/3/2014.
• The American Cancer Society: Penile Cancer: What is penile cancer? American Cancer Society. Last revised: 8/31/2013.
• http://www.cancer.net/cancer-types/penile-cancer. Last revised: 8/31/2013.
REFERENCES
1. Pow-Sang MR, Ferreira U, Pow-Sang JM, et al. Epidemiology and natural history of penile cancer. Urology. 2010;76(2 suppl 1):S2–S6.
2. Minhas S, Manseck A, Watya S, et al. Penile cancer–prevention and premalignant conditions. Urology. 2010;76(2 suppl 1):S24–S35.
3. 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.
4. Mohs FE, Snow SN, Larson PO. Mohs micrographic surgery for penile tumors. Urol Clin N Am. 1992;19:291–304.
ADDITIONAL READING
• Pettaway CA, Davis JD. Contemporary management of penile cancer: Part I. AUA Update Series. 2012;31:15.
• Pettaway CA, Pagliaro L. Penile SCC Contemporary management of inguinal region: Part II. AUA Update Series. 2012;31:16.
See Also (Topic, Algorithm, Media)
• Balanitis Xerotica Obliterans (BXO)
• Bowen Disease and Erythroplasia of Queyrat
• Penis, Cancer, General Considerations Images
• Penis, Cancer, Lymphadenopathy
• Penis, Cutaneous Lesion
• Penis, Mass (Corporal Body Mass)
• Penis, Squamous Cell Carcinoma
• Penis, Squamous Cell Carcinoma Algorithm
• Reference Tables: TNM: Penis Cancer
CODES
ICD9
• 187.2 Malignant neoplasm of glans penis
• 187.3 Malignant neoplasm of body of penis
• 187.4 Malignant neoplasm of penis, part unspecified
ICD10
• C60.1 Malignant neoplasm of glans penis
• C60.2 Malignant neoplasm of body of penis
• C60.9 Malignant neoplasm of penis, unspecified
CLINICAL/SURGICAL PEARLS
• A painless lesion on the penis is the most common presentation.
• 40% of cases of penile cancer in the United States derive from HPV infections.
• 2-cm surgical margin is critical for a successful partial penectomy.
• Historically 6 wk of antibiotics are required to appropriate assessment of inguinal region adenopathy; consideration can also be given to early fine-needle biopsy.