In a 52-year-old cisgender female with a year-long bleeding ulcer and immunohistochemistry positive for Treponema pallidum, but negative TPPA and non-reactive non-treponemal serology, how should I manage her?

Management of Discordant Syphilis Testing with Positive IHC but Negative Serology

Do not treat this patient for syphilis based solely on the positive immunohistochemistry stain, as the repeatedly negative TPPA and non-reactive non-treponemal tests strongly suggest a false-positive IHC result from cross-reactivity with other spirochetes.

Understanding the Diagnostic Discordance

The combination of positive T. pallidum IHC with negative TPPA and non-reactive non-treponemal serology represents a critical diagnostic pitfall that has been increasingly recognized in the literature 1, 2. This pattern is inconsistent with true syphilis infection for several key reasons:

Why This is Likely NOT Syphilis

• Serologic testing remains the gold standard for syphilis diagnosis 3, 4, 3. Both nontreponemal (RPR/VDRL) and treponemal tests (TPPA/FTA-ABS) should be reactive in active syphilis
• A year-long ulcer with active syphilis would produce robust serologic responses - patients with primary or secondary syphilis virtually always have reactive serology
• The TPPA is highly specific (>99%) and would be expected to be positive in any patient with sufficient treponemal burden to show organisms on IHC 5, 6

The Cross-Reactivity Problem

T. pallidum IHC antibodies are known to cross-react with other spirochetes 1, 2:

• Borrelia burgdorferi (Lyme disease)
• Brachyspira species (intestinal spirochetes)
• Other commensal spirochetes, particularly in genital/perianal regions

Given the genital location and chronicity of this ulcer, colonization by non-treponemal spirochetes is the most likely explanation 1.

Recommended Diagnostic Approach

Step 1: Verify Serologic Testing Was Adequate

• Confirm both treponemal (TPPA or TP-PA) and non-treponemal (RPR or VDRL) tests were performed
• Ensure testing was quantitative for non-treponemal tests
• Consider prozone phenomenon only if clinical suspicion is extremely high - request dilution testing (though unlikely given negative TPPA) 2

Step 2: Additional Confirmatory Testing

• Repeat treponemal testing with a different platform: FTA-ABS or Western blot 2, 7
• Consider PCR testing on fresh tissue if biopsy can be repeated - PCR is more specific than IHC 8
• Test for other spirochetal infections if clinically indicated (Lyme serology if endemic area)
• Screen for conditions causing false-positive serology: antiphospholipid antibodies, recent EBV infection, autoimmune conditions 7

Step 3: Clinical Correlation

Assess for any clinical features of syphilis:

• Primary syphilis: painless chancre (but this ulcer is bleeding and chronic)
• Secondary syphilis: rash (palms/soles), mucous patches, condyloma lata, lymphadenopathy
• Constitutional symptoms: fever, malaise, weight loss
• Sexual history: high-risk contacts, partners with known syphilis

Step 4: HIV Testing

• All patients with suspected syphilis should be tested for HIV 4, 9
• HIV infection can cause atypical serologic responses, though negative TPPA would still be unusual

Management Decision Algorithm

If repeat treponemal testing (FTA-ABS or Western blot) is NEGATIVE:

• Do NOT treat for syphilis
• Pursue alternative diagnoses for the chronic ulcer
• Consider: malignancy (biopsy for dysplasia/carcinoma), inflammatory conditions (Behçet's, pyoderma gangrenosum), chronic infection (HSV, fungal), trauma

If repeat treponemal testing is POSITIVE but non-treponemal remains negative:

• This suggests treated or very old syphilis 3, 4, 3
• The chronic ulcer is NOT due to active syphilis
• No treatment indicated unless CSF examination shows neurosyphilis
• Pursue alternative diagnoses for the ulcer

If both become positive on repeat testing:

• This would be extremely unusual given the initial results
• Treat according to stage of syphilis per CDC guidelines 4, 9
• Primary/secondary/early latent: Benzathine penicillin G 2.4 million units IM single dose 4, 9, 10

Critical Pitfalls to Avoid

1. Do not treat based on IHC alone - this leads to misdiagnosis and delays appropriate treatment for the actual cause 1, 2

2. Do not assume prozone effect without evidence - prozone is rare and would not explain negative TPPA 2

3. Do not overlook malignancy - a year-long bleeding genital ulcer warrants thorough evaluation for squamous cell carcinoma or other neoplasms

4. Recognize specimen contamination is possible - particularly if spirochete stains show organisms but serology is persistently negative 2

Alternative Diagnoses to Pursue

Given the clinical presentation of a chronic bleeding ulcer with negative syphilis serology:

• Malignancy: Squamous cell carcinoma, basal cell carcinoma, melanoma
• Chronic HSV: Particularly in immunocompromised patients
• Granulomatous infections: Tuberculosis, atypical mycobacteria, deep fungal
• Inflammatory dermatoses: Pyoderma gangrenosum, Behçet's disease
• Lymphogranuloma venereum: Though this typically causes lymphadenopathy 3, 4, 3

Request appropriate biopsies with special stains (AFB, fungal), bacterial/fungal cultures, HSV PCR, and careful histologic examination for dysplasia or malignancy.