Differential Diagnosis for Superficial Ulceration of the Glans Penis
The most common causes of superficial penile ulceration are genital herpes (most frequent), primary syphilis, and chancroid, with 3-10% of patients having co-infections with multiple pathogens. 1, 2
Primary Differential Diagnoses (Infectious Causes)
Most Common Etiologies
Genital Herpes Simplex Virus (HSV) - The most common cause of genital ulcers in the United States, accounting for approximately 49% of cases, typically presenting with multiple shallow, tender ulcers that may be preceded by vesicles 1, 2, 3
Primary Syphilis (Treponema pallidum) - The second most common cause, classically presenting as a painless, indurated chancre with a clean base, though this classic presentation occurs in only 31% of cases 1, 4
Chancroid (Haemophilus ducreyi) - Endemic in many U.S. areas with discrete outbreaks, presenting as painful ulcers with ragged, undermined edges and purulent bases, with tender inguinal adenopathy in one-third of patients 1, 5, 6
Less Common but Important Infectious Causes
Lymphogranuloma Venereum (LGV) - Caused by invasive serovars L1, L2, or L3 of Chlamydia trachomatis, may present with a self-limited genital ulcer at the inoculation site, though most patients present after this has resolved with inguinal/femoral lymphadenopathy 1, 7
Granuloma Inguinale (Donovanosis) - Rare in the U.S., caused by Klebsiella granulomatis, presenting as progressive, painless, beefy-red ulcers that bleed easily on contact 1
Genital Tuberculosis - An important consideration in non-healing ulcers, presenting as multiple superficial ulcers that fail to respond to standard antibiotics and antivirals, confirmed by histopathology showing granulomatous inflammation and positive PCR for Mycobacterium tuberculosis 8, 9
Non-Infectious Differential Diagnoses
Inflammatory/Autoimmune Causes
Necrotizing Granulomatous Inflammation - Rare presentation that can mimic malignancy, associated with positive antinuclear and perinuclear antineutrophil cytoplasmic antibodies suggesting autoimmune etiology, requiring biopsy for diagnosis 10
Behçet's Disease - Should be considered in patients with recurrent oral and genital ulcers, particularly in those of Mediterranean or Asian descent 7
Neoplastic Causes
- Squamous Cell Carcinoma - Must be excluded in persistent, non-healing ulcers, particularly in older patients, requiring biopsy before definitive surgical intervention 10
Critical Diagnostic Approach
Immediate Laboratory Testing Required
Serologic test for syphilis - Mandatory in all cases, with 90% of primary syphilis cases showing positive titers 1, 2
HSV culture or PCR from ulcer base - Gold standard for HSV diagnosis, as HSV remains the most common cause 2, 3
HIV testing - Strongly recommended at initial presentation and repeated at 3 months if initially negative, as genital ulcers facilitate HIV transmission and are established co-factors for HIV acquisition 1, 2, 5
Darkfield examination or direct immunofluorescence for T. pallidum - When available, provides immediate diagnosis of syphilis 1
Culture for H. ducreyi - If chancroid is suspected, though sensitivity is only 80% even with special media 1
Key Clinical Discriminators (Though Often Unreliable)
Pain characteristics: Painful ulcers strongly favor HSV or chancroid over syphilis, though clinical diagnosis based on examination alone is inaccurate in the majority of cases 3, 4
Lymphadenopathy pattern: Tender inguinal adenopathy occurs in one-third of chancroid patients and when suppurative is almost pathognomonic; painless, firm adenopathy suggests syphilis 1, 3
Ulcer morphology: The classic presentations (painless indurated chancre for syphilis, deep undermined purulent ulcer for chancroid, multiple shallow tender ulcers for HSV) are only 31-35% sensitive, meaning 65-69% of cases do not present classically 4
Critical Management Pitfalls
Co-infection is common: 3-10% of patients with genital ulcers have more than one pathogen present, and up to 10% of chancroid patients are co-infected with T. pallidum or HSV 1, 2, 3
Clinical diagnosis is unreliable: Even experienced clinicians can make accurate diagnoses based on physical examination alone in only a minority of patients, necessitating laboratory confirmation 4
Empiric treatment is often necessary: When diagnosis is unclear, the CDC recommends treating for the most likely diagnosis, and many experts recommend covering both chancroid and syphilis in high-risk communities while awaiting test results 1, 3
Special populations require modified approaches: HIV-positive patients have slower healing, higher treatment failure rates, and may require prolonged therapy courses beyond standard regimens 2, 5
Non-healing ulcers warrant biopsy: Persistent ulcers despite appropriate antimicrobial therapy should prompt consideration of tuberculosis, autoimmune causes, or malignancy, requiring histopathologic evaluation 10, 9
Risk Stratification Factors
High-Risk Features Requiring Aggressive Workup
Sex workers, men who have sex with men (MSM), or recent travel to endemic areas - Increased risk for all STIs including chancroid and LGV 2, 7
Immunocompromised states (HIV, diabetes) - Associated with atypical presentations, slower healing, and increased risk for opportunistic infections including tuberculosis 2, 5, 8
Multiple sexual partners or partners with known STIs - Increases likelihood of co-infections and need for comprehensive testing 1, 2