Jonathan H. Huang, MD
Viraj A. Master, MD, PhD, FACS
BASICS
DESCRIPTION
• Penile cancer spreads systematically to inguinal lymph nodes (LNs) before spreading to the common iliac and para-aortic LNs and becoming metastatic disease
– Drainage is bilateral in 81% of cases
• The inguinal LNs are classified as either superficial or deep
– Superficial inguinal LNs (up to 25 nodes) are located under dermis and above the fascia lata in Scarpa’s triangle
– Deep inguinal LNs are located in the region of the fossa ovalis, medial to the femoral vein
• Extent of LN metastasis determines survival
• Lymphadenectomy (LAD) for penile cancer is associated with significant morbidity, but can improve long-term survival
• LAD is the primary form of treatment for localized lymphatic spread
– Extent of LAD (radical vs. modified) remains controversial
EPIDEMIOLOGY
Incidence
1 in 100,000 men in the United States and Europe develop penile cancer
Prevalence
• LN spread occurs in 10–15% of patients with nonpalpable inguinal LNs
• LN spread occurs in 50% of patients with palpable inguinal LNs
– Palpable inguinal LNs are present in 60% of presenting patients
RISK FACTORS
• Inguinal LN spread is correlated with an increase in clinical grade of primary tumor (0–29% in grade 1 vs. 33–50% in grade 3)
• Inguinal LN spread is correlated with an increase in local stage of primary tumor (<10% in pT1/pTis, 50–70% in pT2 disease, and 50–100% in pT3/pT4)
Genetics
HPV contributes to the development of penile cancer through interactions with tumor protein 53 (p53) and retinoblastoma (RB) tumor suppressor proteins
PATHOPHYSIOLOGY
• Inguinal LNs serve at the primary lymphatic drainage for the penis, scrotum, urethra, vulva, vagina, perineum, gluteal region, lower abdominal wall, lower anus, and lower extremities
• Inguinal LNs lie within the femoral triangle (inguinal ligament, sartorius, and adductor longus) and are separated into superficial and deep groups by the fascia lata of thigh
ASSOCIATED CONDITIONS
• Balanitis
• Phimosis
• STDs
GENERAL PREVENTION
• Prepubertal circumcision is protective against penile cancer
• Good genital hygiene
• STD education and safe sexual practices
• Sun protection against melanoma
• HPV vaccination may reduce risk (unproven)
DIAGNOSIS
HISTORY
• Circumcision
• Phimosis
• HPV infection
• Penile condylomata
• Penile cancer
• Sexual history (multiple partners, early age of initial intercourse)
• Smoking history
• Balanitis xerotica obliterans
• Treatment with sporalene and ultraviolet A phototherapy
PHYSICAL EXAM
Palpable inguinal LNs
DIAGNOSTIC TESTS & INTERPRETATION
Lab
No tissue parameters, including HPV and p53 status, are predictive of LN involvement
Imaging
• No imaging studies are currently utilized extensively in the diagnosis of LN involvement
• Ultrasound and PET-CT can be used to detect recurrences
• Chest x-ray and CT abdomen/pelvis can be used for staging
Diagnostic Procedures/Surgery
• Ultrasound-guided fine-needle aspiration cytology (FNAC)
– Palpable LNs: Sensitivity of 93% and specificity of 91%
– Nonpalpable LNs: Sensitivity of 39% and specificity of 100%
• Dynamic sentinel node biopsy (DSNB): Lymphoscintigraphy and blue dye staining for identification of positive LNs
– False-negative rate of 5%
– Should only be offered in experienced centers
Pathologic Findings
Squamous cell carcinoma accounts for 95% of penile cancers
DIFFERENTIAL DIAGNOSIS
• Reactive LNs
• Infections: Syphilis, herpes, chancroid, lymphogranuloma venereum, pedal fungal disease
• Malignant diseases: Metastatic melanoma, lymphoma
• Systemic diseases: Mononucleosis, rubella, human immunodeficiency virus, cytomegalovirus
• Autoimmune diseases: Sarcoidosis, lupus
TREATMENT
GENERAL MEASURES
• Tis, Ta primary tumors (1)
– Nonpalpable inguinal LNs
Surveillance
– Palpable inguinal LNs
Antibiotics for 1 mo to rule out infection vs. immediate fine-needle aspiration biopsy
If persistent LNs and either FNAC or excisional biopsy are positive, ipsilateral inguinal and pelvic LAD and contralateral superficial or modified inguinal LAD
• T1 grade 1 and grade 2 primary tumors
– Nonpalpable inguinal LNs
Surveillance
– Palpable inguinal LNs
If FNAC is negative and no resolution with antibiotics, excisional biopsy or inguinal LAD
If FNAC is positive, ipsilateral inguinal and pelvic LAD and contralateral superficial or modified LAD
• T2–T4 primary tumors
– Nonpalpable inguinal LNs should undergo bilateral superficial inguinal LAD or DSNB
If frozen section is negative, surveillance
If frozen section is positive, that side should undergo ipsilateral inguinal and pelvic LAD
– Palpable unilateral LNs should undergo ipsilateral inguinal and pelvic LAD and contralateral superficial or modified inguinal LAD
If contralateral frozen section is negative, surveillance
If contralateral frozen section is positive, deep inguinal or pelvic LAD
– Palpable bilateral LNs should undergo FNAC to determine the extent of LAD
If FNAC is negative, at least bilateral superficial inguinal LAD or DSNB
If FNAC is positive, bilateral inguinal and pelvic LAD and chemotherapy is warranted
• Fixed or LNs >4 cm
– Neoadjuvant chemotherapy potentially followed by surgery
• Pelvic LNs spread is more likely if (1) 2 or more inguinal node involvement, (2) extranodal metastasis, (3) Cloquet node involvement
• LAD should involve at least 8 LNs, as this improves 5-yr survival
MEDICATION
First Line
• Antibiotics
– Use of antibiotics has become controversial for enlarged LNs
– Historically, a 4–6-wk course of antibiotics (such as a cephalosporin or augmentin) was recommended to rule out infection in Tis and Ta tumors with palpable LNs
– Delay in LAD, a potentially curative treatment, has brought the use of antibiotics into question
– FNAC can help determine if LNs are due to metastasis or infection
Second Line
N/A
SURGERY/OTHER PROCEDURES
• Radical LAD (2,3)
– Superior margin: Superior margin of the external ring to the anterior superior iliac spine (ASIS)
– Lateral margin: ASIS to 20 cm inferiorly
– Medial margin: Pubic tubercle to 15 cm inferiorly
– Inferior margin: 20 cm inferior from the ASIS to 15 cm inferior from the pubic tubercle
• Modified LAD (after Catalona)
– Excludes area lateral to the femoral artery and caudal to the fossa ovalis
– Preservation of the saphenous vein
– No transposition of the sartorius muscles
– Conversion to radical LAD if there are positive LNs
• Techniques to minimize complications of LAD
– Careful skin-flap management
– Meticulous LN dissection
– Prophylactic antibiotics: Cephalosporins for 2 mo
– Vacuum drains
– Elastic and/or pneumatic stocking
– Early ambulation
• Endoscopic LAD (4)
– Complete radical LAD can be completed through 3 endoscopic ports
– Node yield is equivalent to open surgery
– Decreased complications
• The viability of the skin flaps developed during an inguinal LN dissection are based on the anastomotic vessels within the superficial fatty layer of Camper’s fascia which course lateral to medial along the skin lines. This is a key anatomic dissection plane as the lymphatic drainage of the penis lies beneath Camper’s fascia allowing this superficial fatty layer to remain attached to the skin flaps during a groin dissection
• When performing an inguinal LN dissection for a clinically negative groin, a modified technique should be used to decrease morbidity. The key components of this technique include the following: Shorter incision (∼10 cm), preservation of the saphenous vein, minimizing dissection lateral to the femoral artery, and avoiding transposition of the Sartorious muscle
ADDITIONAL TREATMENT
Radiation Therapy
• Adjuvant radiotherapy may improve locoregional control in patients with extensive metastases and/or extranodal disease
– Side effects include edema and pain
• Radiotherapy in clinical N0 patients is not recommended
Additional Therapies
• Adjuvant chemotherapy
– 3 courses of cisplatin and 5-fluorouracil for pN2–3
– No adjuvant chemotherapy for pN1
Complementary & Alternative Therapies
None are effective
ONGOING CARE
PROGNOSIS
• 5-yr cancer-specific survivals:
– 90–100% in pN0 disease
– 70–80% in pN1 disease
– <30% in pN2–pN3 disease
– 15% in patients with positive pelvic LNs who had inguinal and pelvic LAD
• Predictors of cancer-specific survival: Pathologic stage of LNs, vascular and/or lymphatic involvement, primary tumor thickness
COMPLICATIONS
• LAD complications
– Wound infection
– Skin necrosis
– Wound dehiscence
– Thigh numbness
– Lymphedema
– Lymphorrhea
– Scrotal swelling
– Suprapubic swelling
– Pulmonary embolism
FOLLOW-UP
Patient Monitoring
• Recurrences occur most often within 2 yr after inguinal LAD
• Nomograms available (5)
• Evaluation should include an exam and ultrasound-guided FNAC
• Maximum follow-up length of 5 yr
• Surveillance (patient did not have LAD)
– Every 3 mo for yr 1 and 2
– Every 6 mo for yr 3, 4, and 5
• LAD and pN0 disease
– Every 6 mo for yr 1 and 2
– Every 6 mo for yr 3, 4, and 5
• LAD and pN+ disease
– Every 3 mo for yr 1 and 2
– Every 6 mo for yr 3, 4, and 5
Patient Resources
National Cancer Institute: Penile Cancer Treatment (http://www.cancer.gov/cancertopics/pdq/treatment/penile/HealthProfessional)
REFERENCES
1. Pizzocaro G, Algaba F, Horenblas S, et al. EAU penile cancer guidelines 2009. Eur Urol. 2010;57:1002–1012.
2. Horenblas S. Lymphadenectomy for squamous cell carcinoma of the penis. Part 2: The role and technique of lymph node dissection. BJU Int. 2001;88:473–483.
3. 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;116:2960–2966.
4. Master VA, Jafri SM, Moses KA, et al. Minimally invasive inguinal lymphadenectomy via endoscopic groin dissection: Comprehensive assessment of immediate and long-term complications. J Urol.2012;188:1176–1180.
5. Kattan MW, Ficarra V, Artibani W, et al. Nomogram predictive of cancer specific survival in patients undergoing partial or total amputation for squamous cell carcinoma of the penis. J Urol.2006;175:2103–2108; discussion 2108.
ADDITIONAL READING
Spiess PE, Horenblas S, Pagliaro LC, et al. Current concepts in penile cancer. J Natl Compr Canc Netw. 2013;11:617–624.
See Also (Topic, Algorithm, Media)
• Groin/Inguinal Mass, Male and Female
• Lymphadenopathy, Inguinal
• Penis, Cancer, General Considerations
• Penis, Cancer, lymphadenopathy Image 
• Penis Cutaneous Lesion
• Penis, Squamous Cell Carcinoma
• Reference Tables: TNM: Penis Cancer
CODES
ICD9
• 187.4 Malignant neoplasm of penis, part unspecified
• 196.5 Secondary and unspecified malignant neoplasm of lymph nodes of inguinal region and lower limb
• 785.6 Enlargement of lymph nodes
ICD10
• C60.9 Malignant neoplasm of penis, unspecified
• C77.4 Sec and unsp malig neoplasm of inguinal and lower limb nodes
• R59.0 Localized enlarged lymph nodes
CLINICAL/SURGICAL PEARLS
• Penile cancer metastasizes to regional LNs before disseminating systemically.
• Treatment is dependent on the clinical presence of LNs, tumor stage, and tumor grade.
• Inguinal LAD is potentially curative and can improve long-term outcomes in penile cancer with nodal metastases.
• Careful tissue management, antibiotics, vacuum drains, and compression stockings can minimize the morbidities associated with LAD.