Michael E. Woods, MD
Raj S. Pruthi, MD, FACS
BASICS
DESCRIPTION
• Clinically evident inguinal lymphadenopathy can be secondary to infection, inflammation, or malignancy.
• Lymph nodes (LNs) are generally considered enlarged if >1 cm.
• There is a <1% annual incidence of unexplained peripheral (including inguinal) lymphadenopathy.
• 14% of all abnormal lymphadenopathy present in inguinal region
EPIDEMIOLOGY
Incidence
• Malignancy
– Penile cancer (1)[A]
0.4–0.6% of male cancers in USA
Median age at diagnosis: 68 yr
50% of enlarged LN secondary to cancer
– Lymphoma: ∼80,000 cases/yr in USA
• Infectious (STD/STI) (2)[A]
– Approximately 15 million new Sexually Transmitted Infections (STI) cases/yr in USA
– Chancroid (Haemophilus ducreyi)–24 cases reported to the CDC in 2010
– Herpes simplex–775,000 cases/yr, 16% of 14–49-yr olds infected with HSV-2
– Lymphogranuloma venereum (LGV)–relatively rare; rise in USA and UK associated with men who have sex with men and persons with HIV
– Syphilis–In 2011, USA, men 8.2/100,000; women 1/100,000
– HIV–1.1 million people in USA infected
– Gonorrhea: 2nd commonest STI in USA
• Infectious (soft tissue of the leg/foot)
– Common causes: β-hemolytic streptococci and Staphylococcus aureus
RISK FACTORS
• Penile Cancer
– Circumcision (neonatal circumcision is protective)
– Poor genital hygiene; phimosis
– Number of sexual partners
– Human papilloma virus (HPV) infection (type 16 and 18)
– Incidence of LN metastases related to grade, stage, and lymphovascular invasion
• STI: High-risk sexual practices (ie, nonuse of condom, multiple partners, men who have sex with men)
PATHOPHYSIOLOGY
• Inguinal lymph nodes (ILNs) serve at the primary lymphatic drainage for the penis, scrotum, urethra, vulva, vagina, perineum, gluteal region, lower abdominal wall, lower anus, and lower extremities.
• ILNs 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.
• Penile squamous cell carcinoma (SCC) cancer spreads by a relatively reliable pattern: From superficial pelvic LNs to deep pelvic LNs
ASSOCIATED CONDITIONS
• Balanitis
• Phimosis
• Additional sexuallt transmitted infections (STI’s)
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
• Constitutional symptoms: Weight loss, night sweats
• Age: Penile cancer is more likely in older individuals, STI more common in younger patients
• Sexual history: Number and sex of partners, condom use
• Travel: International travel is common source of STI and other endemic diseases.
• Ethnicity: Higher penile cancer in South America
• History of other diseases, malignancy, lower extremity trauma, animal exposure
PHYSICAL EXAM
• Cachexia: Suggests systemic illness
– HIV, lymphoma
• Generalized lymphadenopathy (neck, axilla)
– Signs of systemic process (HIV, lymphoma)
• Abdominal exam
– Palpable masses, splenomegaly
• Lower extremities bilaterally for lesions
• Inguinal exam
– Size, fixation of LNs
– Erythema, tenderness, warmth, drainage/purulence
• Genital exam
– Penis, glans, foreskin, scrotum for lesions
– Erythema, drainage, purulence, abscess
– Ulcers (can be secondary to herpes, chancroid, granuloma inguinale, syphilis, neoplasias); vesicles with herpes
• Formal pelvic exam in women
DIAGNOSTIC TESTS & INTERPRETATION
Lab
• Suspected malignancy
– CBC, basic metabolic panel, liver function testing (LFT’s)
• Infectious/STD (2)
– Gonococcus
Nucleic acid amplification testing (ie, polymerase chain reaction [PCR]) of vaginal samples, urine, urethral samples—98% sensitive
Culture–72–95% sensitive, perform if drug resistance is suspected
– Syphilis
Darkfield microscopy of primary chancre, screen with nontreponemal test (RPR, VDRL) confirm with treponemal test (FTA-ABS)
– Herpes simplex
Viral culture of active lesion (50% sensitive)
PCR of specimen from genital ulcer
Direct fluorescent antibody of specimen
Serology for HSV-1/2 (90% and 95% sensitivity and specificity, respectively)
– LGV: Culture Chlamydia trachomatis from ulcer or LN aspirate
Serologic identification with complement fixation or microimmunofluorescence; PCR
– Chancroid: H. ducreyi culture (75% sensitive)
PCR >95% sensitive/specific (non-FDA approved)
– HIV: Serology for IgG antibody to HIV-1 antigens (positive test confirmed via western blot assays)
Imaging
• CT abdomen/pelvis: Extent of disease
– Evaluates other sites of lymphadenopathy lymphoma
• CT chest/CXR: Staging in setting of malignancy
• Inguinal US: Evaluate solid vs. cystic lesions; identify abscess
Diagnostic Procedures/Surgery
• Excisional biopsy of abnormal LN or primary lesion (preferred)
• Percutaneous biopsy/aspiration of abnormal LN
• Bone marrow biopsy (lymphoma workup)
DIFFERENTIAL DIAGNOSIS
• Nonspecific lymphadenitis
• Malignancy: In a historic study of over 200 patients the order of malignancy in inguinal lymphadenopathy was: Cutaneous malignancy of lower extremity (melanoma), cervical, vulva, cutaneous malignancy of the trunk, rectum/anus, ovary, and penile cancer.
• Infectious
– Soft-tissue infection of the lower extremity (ie, Staphylococcus)
– STD (HIV, gonococcus, herpes simplex, chancroid, LGV, syphilis)
• With more generalized lymphadenopathy consider a systemic disease
– Infections: Epstein–Barr, toxoplasmosis, cytomegalovirus, mycobacteria (TB, etc.), mononucleosis
– Lymphoma, lupus
• Medications: Cephalosporins, others
TREATMENT
GENERAL MEASURES
• Generalized lymphadenopathy should be referred for global evaluation.
• A period of observation for localized lymphadenopathy is reasonable if there are no other clinical findings.
• Penile cancer requires treatment of primary lesion (based on size and location), followed by inguinal lymphadenectomy if indicated.
• Infectious etiologies need to be accurately diagnosed so appropriate treatment can be initiated (see below).
• Gynecologic malignancies have a high predisposition for inguinal spread.
MEDICATION
First Line
• STD (2)[A]
– Chancroid: Azithromycin 1 g PO ×1 or ceftriaxone 250 mg IM ×1 or ciprofloxacin 500 mg PO BID ×3 days or erythromycin base 500 mg PO TID ×7 days
– Herpes simplex (primary): Acyclovir 400 mg PO TID ×7–10 days or acyclovir 200 mg PO 5×/day ×7–10 days or famciclovir 250 mg PO TID ×7–10 days or valacyclovir 1 g PO BID ×7–10 days
– LGV: Doxycycline 100 mg PO BID ×21 days OR erythromycin base 500 mg PO QID ×21 days
– Syphilis (primary and secondary): Benzathine penicillin G 2.4 million units IM ×1
– Syphilis (late latent): Benzathine penicillin G 2.4 million units 1×/wk ×3 wk
– Gonococcus: Ceftriaxone 400 mg IM ×1 plus azithromycin 1 g PO ×1 or doxycycline 100 mg PO BID ×7 days OR cefixime 400 mg PO ×1 plus azithromycin 1 g PO ×1 or doxycycline 100 mg PO BID ×7 days; if cephalosporin allergy: Azithromycin 2 g PO ×1
– HIV: Antiretroviral drug regimens (see Section 1 “HIV/AIDS, Urologic Considerations” and latest CDC guidelines)
SURGERY/OTHER PROCEDURES
• Penile cancer (1)[A]
– Management of primary lesion (local excision, partial penectomy, total penectomy)
– Non-palpable ILNs
– Up to 50% of all enlarged ILNs are benign in patients with newly diagnosed penile cancer. Treated with 6 wk of antibiotics (currently controversial) prior to consideration of inguinal lymph node dissection (ILND) or undergo a fine aspiration of the node in question if the primary tumor is low risk.
– Occult metastases ∼25%
TaG1-2/T1G1—surveillance
T1G2—surveillance vs. ILND or dynamic sentinel node biopsy (DSNB)
≥T2 or any G3—ILND or DSNB
– Palpable ILNs
Low risk—consider fine-needle aspiration to confirm malignancy; Intermediate/high risk—ILND
• Inguinal lymphadenectomy techniques
– Dynamic sentinel node biopsy (DSNB)
Use of blue dye + γ-emission (radio nuclide tracer)
False-negative 5%; expertise required
– Superficial ILND
Removal of LN above fascia lata
If lymph positive on frozen section, then compete ILND needed
Option for prophylactic ILND
– Modified ILND
Appropriate for prophylactic ILND
Decreased morbidity
Limited template (lateral border femoral artery, caudal border fossa ovalis)
Includes deep nodes medial to femoral vein
Smaller incision; preserve saphenous vein
Avoids transposition of sartorius muscle
Positive on frozen, then standard ILND
– Radical/standard ILND
Indicated for patient with metastatic disease to the ILNs
Larger template including tissue lateral femoral artery and distally to apex of the femoral triangle
Routine division of saphenous vein and sartorius transposition; higher morbidity
• Infectious etiology
– Fine-needle aspiration for culture
– Incision and drainage of abscess
• Lymphoma
– Excisional biopsy of ILN (may consider other site if generalized lymphadenopathy is present)
ADDITIONAL TREATMENT
Radiation Therapy
Penile Cancer: Palliation of bulky, unresectable inguinal lymphadenopathy
Additional Therapies
• Penile cancer
– Patients with fixed ILN or pelvic LNs should receive cisplatin-based chemotherapy followed by consolidative surgery when appropriate (3)[C]
Paclitaxel, ifosfamide, cisplatin—50% complete response (CR) or partial response (PR) and∼75% underwent planned surgery
ONGOING CARE
PROGNOSIS
• Penile Cancer
– Node negative: 46–100% 5-yr survival (mean ∼75%)
– Node positive: 0–86% 5-yr survival based on nodal burden (average ∼60%)
COMPLICATIONS
• ILND
– Seroma, lymphedema, wound infection, skin necrosis
– 25–50% risk
FOLLOW-UP
Patient Monitoring
• Penile Cancer (1)[A]
– Nx (surveillance)
Q3mo yr 1–2 then Q6mo yr 3–5
– N0, N1
Q6mo yr 1–2 then Q12mo yr 3–5
– N2, N3
Q3–6mo yr 1–2 then Q6–12mo yr 3–5
• Infectious (2)[A]
– Chancroid–3–7 days after initiating treatment
– LGV–evaluate for clinical resolution, timing variable
– Syphilis–clinical and serologic evaluation at 6 and 12 mo
– Gonorrhea–none if symptoms resolve
Patient Resources
N/A
REFERENCES
1. Spiess PE, Horenblas S, Pagliaro LC, et al. Current concepts in penile cancer. J Natl Compr Canc Netw. 2013;11:617–624.
2. Workowski KA, Berman S; Centers for Disease Control and Prevention (CDC). Sexually transmitted diseases treatment guidelines, 2010. MMWR Recomm Rep. 2010;59(RR-12):1–116.
ADDITIONAL READING
• Pagliaro LC, Williams DL, Daliani D, et al. Neoadjuvant paclitaxel, ifosfamide, and cisplatin chemotherapy for metastatic penile cancer: A phase II study. J Clin Oncol. 2010;28:3851–3857.
• Zaren HA, Copeland EM, III. Inguinal node metastases. Cancer. 1978;41(3):919–923.
See Also (Topic, Algorithm, Media)
• Chancroid
• Groin/Inguinal Mass, Male and Female
• Lymphadenopathy, Inguinal Image 
• Lymphadenopathy, Pelvic and Retroperitoneal
• Lymphogranuloma Venereum (LGV)
• Penis, Cancer, General Considerations
• Penis, Cancer, Lymphadenopathy
• Reference Tables: TNM Classification: Penis Cancer
• Sexually Transmitted Infections (STIs) (Sexually Transmitted Diseases [STDs]), General
CODES
ICD9
• 187.4 Malignant neoplasm of penis, part unspecified
• 202.80 Other malignant lymphomas, unspecified site, extranodal and solid organ sites
• 785.6 Enlargement of lymph nodes
ICD10
• C60.9 Malignant neoplasm of penis, unspecified
• C85.90 Non-Hodgkin lymphoma, unspecified, unspecified site
• R59.0 Localized enlarged lymph nodes
CLINICAL/SURGICAL PEARLS
• Differentiate inguinal adenopathy from more generalized LN involvement.
• The viability of the skin flaps developed during an inguinal 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.
• Use a modified technique in a clinically negative groin to decrease morbidity. The key components: Shorter incision (∼10 cm), preserve saphenous vein, minimize dissection lateral to the femoral artery, and avoid transposition of the sartorius muscle.