A patient presents with a sudden‑onset painful vulvar ulcer that feels like a nodule; what are the differential diagnoses and how should it be evaluated and managed?

Sudden-Onset Painful Vulvar Ulcer with Nodular Presentation

For a sudden-onset painful vulvar ulcer that feels like a nodule, you should immediately test for herpes simplex virus (HSV) via culture or PCR from the ulcer base, obtain syphilis serology, and consider Lipschütz ulceration (acute non-sexually acquired genital ulceration) if the patient is young, sexually inactive, and recently had a flu-like illness. 1, 2, 3

Differential Diagnosis Priority

Most Likely Infectious Causes

• Genital herpes (HSV) accounts for approximately 49% of all genital ulcers in the United States and is the single most common etiology 1, 4
• HSV typically presents with multiple shallow, tender ulcers that may be preceded by vesicles, though initial presentation can include painful nodular swelling before ulceration 1, 4
• Primary syphilis is the second most common cause, classically presenting as a painless indurated chancre, though the "painless" presentation occurs in only 31% of cases—many syphilitic ulcers are actually painful 5, 1
• Chancroid (Haemophilus ducreyi) presents as painful ulcers with ragged, undermined edges and purulent bases, often with tender inguinal adenopathy 6, 1

Critical Non-Sexually Transmitted Cause

• Lipschütz ulceration (ulcus vulvae acutum) should be strongly considered if the patient is ≤20 years old, sexually inactive, and recently experienced a flu-like illness or infectious mononucleosis 3, 7
• This condition affects almost 90% of cases in sexually inactive young women, presents with 1-3 painful, well-delimited ulcers ≥10 mm with fibrinous necrotic centers, and resolves within 3 weeks 3
• Most commonly associated with infectious mononucleosis (N=40 cases) or Mycoplasma infections (N=11 cases), though influenza A has been documented 3, 7

Other Non-Infectious Causes to Consider

• Aphthous spectrum ulcers can occur on genital mucosa, particularly after viral illnesses like influenza or Epstein-Barr virus, and are clinically indistinguishable from complex aphthosis 6, 2
• Behçet syndrome, Crohn disease, fixed drug eruption, or sexual trauma should be reconsidered if initial infectious workup is negative 2, 4

Mandatory Diagnostic Workup

Immediate Testing Required

• HSV culture or PCR from the ulcer base or vesicular fluid—this is the gold standard and must be obtained given HSV's 49% prevalence 1, 2
• Serologic testing for syphilis (nontreponemal test: RPR or VDRL) is mandatory for all genital ulcers, though sensitivity in primary syphilis is only 62-78% 5, 1
• Darkfield examination or direct immunofluorescence for Treponema pallidum provides immediate diagnosis when available 6, 5, 1
• HIV testing is strongly recommended at initial presentation and repeated at 3 months if initially negative, as genital ulcers facilitate HIV transmission 6, 1, 2

Additional Testing Based on Clinical Context

• Culture for Haemophilus ducreyi if practicing in an area with high chancroid prevalence, though sensitivity is only 80% 6, 1
• Epstein-Barr virus (EBV) serology or PCR if Lipschütz ulceration is suspected based on recent mononucleosis-like symptoms 3, 7
• Mycoplasma pneumoniae testing if recent respiratory symptoms preceded the ulcer 3
• Influenza testing if flu-like symptoms occurred 1-2 days before ulcer onset 7

Critical Diagnostic Pitfalls

• Co-infection occurs in 3-10% of patients with genital ulcers—never rely on a single positive test to exclude other pathogens 6, 1, 2
• At least 25% of genital ulcers have no laboratory-confirmed diagnosis even after complete testing, making empiric treatment essential 6, 1, 4
• Negative initial syphilis serology does not exclude early primary syphilis—if the chancre appeared recently, repeat serologic testing at least 7 days after ulcer onset 5
• Clinical diagnosis based only on history and physical examination is often inaccurate—laboratory confirmation is essential 6, 5

Specific Physical Examination Findings to Document

• Number, size, and distribution of ulcers (Lipschütz typically presents with 1-3 symmetric ulcers ≥10 mm) 3
• Ulcer characteristics: fibrinous/necrotic center, well-delimited borders, undermined edges, or clean base 6, 3
• Presence of vesicles preceding ulceration (suggests HSV) 1, 4
• Inguinal lymphadenopathy: enlarged painful nodes suggest STI including syphilis or HSV; tender unilateral adenopathy suggests chancroid 6
• Voiding disorders (present in large subset of Lipschütz cases) 3
• Oral canker sores (noted in 10% of Lipschütz patients) 3
• Bartholin gland swelling at 4 and 8 o'clock positions (suggests bacterial infection including STI pathogens) 6

Empiric Treatment Algorithm

If HSV is Most Likely (Multiple Shallow Tender Ulcers, Vesicles)

• Acyclovir 400 mg orally 5 times daily for 7-10 days (first episode) or 5 days (recurrent episode), initiated within 72 hours of symptom onset for maximal efficacy 1, 4
• Alternative: Valacyclovir 1 g orally twice daily for 7-10 days or Acyclovir 200 mg orally 5 times daily 1, 4

If Syphilis Cannot Be Excluded

• Benzathine penicillin G 2.4 million units intramuscularly as a single dose for empiric coverage of primary syphilis 1, 4

If Chancroid is Suspected (Endemic Area, Painful Ragged Ulcer)

• Azithromycin 1 g orally as a single dose OR Ceftriaxone 250 mg intramuscularly as a single dose 1, 4

If Lipschütz Ulceration is Suspected (Young, Sexually Inactive, Recent Viral Illness)

• Clobetasol 0.05% ointment applied 4 times daily with tapering over several days as ulcers heal 7
• Viscous lidocaine gel as needed for symptomatic pain relief 7
• Systemic corticosteroids do NOT reduce disease duration and are not recommended 3
• Reassure that the condition resolves spontaneously within 3 weeks without recurrences in most cases 3

When Diagnosis is Unclear

• Many experts recommend treating for both chancroid and syphilis empirically if the diagnosis is unclear or if the patient resides in a community with notable chancroid morbidity 6
• Consider empiric HSV treatment given its 49% prevalence while awaiting test results 1

Follow-Up and Reassessment

• Clinical reassessment at 3-7 days after therapy initiation to evaluate symptom improvement 1
• Ulcers should improve subjectively within 3 days and objectively within 7 days of appropriate treatment 1
• Large or extensive ulcers may require more than 2 weeks for complete healing even with correct therapy 1

If No Improvement by Day 3-7, Consider:

• Incorrect initial diagnosis 1
• Co-infection with another pathogen (occurs in 3-10% of cases) 1
• Underlying HIV infection (affects healing and treatment response) 1
• Antimicrobial resistance 1
• Non-infectious etiology (Behçet syndrome, Crohn disease, fixed drug eruption, sexual trauma) 2, 4

Special Populations and Considerations

Young, Sexually Inactive Patients

• Lipschütz ulceration should be the primary consideration if recent viral illness occurred 3, 7
• Avoid forcing pelvic examination—this is always contraindicated 6
• Emphasize that non-infectious ulcers can occur without sexual transmission 2

HIV-Positive or Immunocompromised Patients

• Expect slower healing, higher treatment failure rates, and atypical serologic responses 1
• May require prolonged therapy courses beyond standard regimens 1
• False-negative syphilis serology has been reported despite documented infection 5

Sexual Contact Management

• Sexual contacts from the past 3 months should be evaluated and treated for primary syphilis regardless of test results if syphilis is diagnosed 5
• Advise avoidance of sexual activity until ulcers heal completely to prevent trauma and potential transmission 2

Patient Counseling

• Explain that up to 25% of genital ulcers remain undiagnosed despite comprehensive testing 6, 1, 4
• Emphasize gentle hygiene with mild, unscented cleansers and avoidance of potential irritants 2
• Warn about secondary infections when using potent corticosteroids like clobetasol 2
• Reassure that if Lipschütz ulceration is confirmed, it typically resolves within 3 weeks without recurrence 3