What are the differential diagnoses for vesicular lesions in the genital area?

Differential Diagnoses for Vesicular Genital Lesions

Herpes simplex virus (HSV-1 or HSV-2) is the most common cause of vesicular genital lesions and should be your primary consideration, but you must also test for syphilis and consider herpes zoster, varicella-zoster virus, and non-infectious causes in your differential. 1

Primary Infectious Differentials

Herpes Simplex Virus (Most Common)

• HSV is the most common cause of sexually acquired genital vesicular lesions, presenting classically as patches of redness followed by papules, then vesicles containing clear fluid with thousands of viral particles that burst to form shallow ulcers 1
• Primary episodes show multiple bilateral vesicular or pustular ulcerative lesions lasting mean 19 days, with systemic symptoms in 67% of cases, local pain/itching in 98%, dysuria in 63%, and tender adenopathy in 80% 2
• Recurrent episodes present with smaller, unilateral vesicular or ulcerative lesions lasting mean 10.1 days, with 25% being asymptomatic 2
• Both HSV-1 and HSV-2 cause genital herpes, with HSV-1 now accounting for half of new cases in developed countries 3

Syphilis (Treponema pallidum)

• Must always test for syphilis in any patient with genital vesicles, as it can coexist with HSV in the same lesion 1
• Secondary syphilis can rarely present with vesicular eruptions (vesicular syphilid), though this is uncommon 4
• Follmann balanitis represents an atypical vesicular manifestation of syphilis that can be misdiagnosed as genital herpes 5

Herpes Zoster (Varicella-Zoster Virus)

• Consider herpes zoster when vesicles follow a unilateral dermatomal distribution involving S2-S4 dermatomes, typically preceded by dermatomal pain 24-72 hours before rash 6
• Often misdiagnosed as genital herpes due to similar vesicular appearance 6
• In children, consider atypical VZV presentation rather than assuming HSV 1

Chancroid (Haemophilus ducreyi)

• Should be considered in endemic areas where chancroid is prevalent 1
• All patients with genital vesicles should be evaluated for H. ducreyi where chancroid is common 1

Non-Infectious Differentials

Inflammatory/Autoimmune Conditions

• Behçet syndrome can cause mucosal ulcerations mimicking genital herpes 1
• Crohn disease (inflammatory bowel disease) may present with genital ulceration 1
• Fixed drug eruption can be confused with genital herpes 1

Pediatric Considerations

• Hand, foot, and mouth disease (HFMD) in the genital region presents with vesicular lesions that burst to form shallow ulcers, distinctly different from diaper rash but can mimic HSV 7

Essential Diagnostic Approach

Laboratory Testing Algorithm

• Never rely on clinical diagnosis alone—laboratory confirmation is mandatory because clinical differentiation is difficult and leads to both false positive and false negative diagnoses 1, 8
• For vesicular lesions, obtain fluid from vesicles using sterile needle aspiration and collect with swab for testing 1
• NAAT/PCR is the most sensitive diagnostic method and provides HSV typing, especially valuable for suboptimal specimens or non-vesicular lesions 1
• Viral culture is more likely positive with vesicular (vs ulcerative) lesions, first episodes (vs recurrent), and immunosuppressed (vs immunocompetent) patients 1
• All patients must receive syphilis serology testing regardless of clinical appearance 1
• HIV screening is recommended because genital lesions enhance HIV transmission risk 1

Critical Clinical Distinctions

• Bilateral or non-dermatomal distribution suggests HSV, while unilateral dermatomal distribution (S2-S4) suggests herpes zoster 6
• Multiple simultaneous infectious etiologies can coexist in the same patient 1
• Immunocompromised patients may present with extensive, deep, nonhealing ulcerations rather than typical vesicles 8

Common Diagnostic Pitfalls

• Atypical presentations are common—most genital herpes cases have mild, atypical lesions that cannot be diagnosed by examination alone 8
• Herpes zoster in genital region is frequently misdiagnosed as genital herpes 6
• HFMD in genital region may be misdiagnosed as genital herpes in children 7
• Point-of-care antibody tests should not be used in low-risk populations due to high false-positive rates with low index values 1
• Serology cannot distinguish HSV-1 from HSV-2 unless type-specific glycoprotein G-based assay is used 1