Most Likely Diagnosis: Genital Herpes Simplex Virus (HSV)
In a patient presenting with painful penile ulcers without inguinal lymphadenopathy and a history of unprotected sex, genital herpes simplex virus infection is the most likely diagnosis, as it is the most common cause of genital ulcers in the United States and typically presents with painful ulcers without prominent lymphadenopathy. 1, 2
Clinical Reasoning
Why HSV is Most Likely
- Epidemiologic predominance: HSV is the most common cause of genital ulcers in the United States, making it the statistical frontrunner in any undifferentiated case 1, 2
- Pain profile: The presence of painful ulcers strongly favors HSV over syphilis (which typically causes painless chancres) 3
- Absence of lymphadenopathy: This clinical feature argues against chancroid, where tender inguinal adenopathy occurs in one-third of patients and is highly suggestive of the diagnosis 3
Why Not Chancroid
While chancroid classically presents with painful ulcers, the absence of inguinal lymphadenopathy makes this diagnosis less likely 3. The CDC guidelines specifically note that the combination of painful ulcer with tender inguinal adenopathy is suggestive of chancroid, and when accompanied by suppurative adenopathy is almost pathognomonic 3. Without lymphadenopathy, chancroid drops lower on the differential.
Why Not Syphilis
Primary syphilis typically presents with a painless chancre, not painful ulcers, making it inconsistent with this presentation 3, 1
Essential Diagnostic Workup
Despite the clinical suspicion, laboratory confirmation should always be sought because clinical diagnosis alone is often inaccurate 4, 1:
- HSV testing: PCR or culture from the ulcer base or vesicular fluid (gold standard) 4, 5
- Syphilis serology: Mandatory to exclude co-infection, as up to 10% of genital ulcer patients have HSV co-infected with T. pallidum 3, 4
- Darkfield microscopy or direct fluorescent antibody test for T. pallidum 3, 1
- HIV testing: Strongly recommended, as genital ulcers are associated with increased HIV risk 3
Critical Pitfall to Avoid
Even after complete diagnostic testing, 25% of patients with genital ulcers have no laboratory-confirmed diagnosis 3, 4. Therefore, empiric treatment based on the most likely diagnosis is often necessary before test results return 3.
Treatment Approach
For Presumed HSV (First Episode)
- Acyclovir for 7-10 days, or alternative agents famciclovir or valacyclovir 1
- Treatment should be initiated within 72 hours of symptom onset for optimal efficacy 5
If Diagnosis Remains Unclear
The CDC recommends that when the diagnosis is uncertain, treat for the most likely diagnosis based on clinical presentation 3. Many experts recommend empiric treatment for both chancroid and syphilis if the diagnosis is unclear and the patient resides in a community with notable chancroid morbidity 3.
Co-infection Considerations
Up to 10% of patients with chancroid may be co-infected with T. pallidum or HSV, and 3-10% of all genital ulcer patients have more than one pathogen present 3. This underscores the importance of comprehensive testing rather than relying solely on clinical impression.