Most Likely Diagnosis: Secondary Syphilis
Based on the clinical presentation described, secondary syphilis is the most likely diagnosis and should be at the top of your differential, particularly if the patient presents with a widespread rash that could mimic other dermatologic conditions.
Why Secondary Syphilis Should Be Your Primary Consideration
Secondary syphilis is famously known as "the great imitator" because it can present with an extraordinarily wide spectrum of clinical manifestations that mimic numerous other dermatologic conditions 1, 2. The CDC emphasizes that secondary syphilis can present with varied and often subtle clinical manifestations, making it essential to maintain a high index of suspicion 3, 4.
Key Clinical Features That Point to Secondary Syphilis
Rash characteristics: The classic presentation includes a maculopapular rash that evolves from macules to small reddish-brown papules, often with minor scaling 5. However, the rash can be highly variable and atypical 4.
Distribution patterns: While truncal involvement is common, palmoplantar involvement is particularly suggestive of secondary syphilis and should significantly raise your suspicion 5.
Associated systemic symptoms: Fever, lymphadenopathy, malaise, and constitutional symptoms frequently accompany the rash 4, 1.
Mucocutaneous lesions: The presence of condyloma latum (genital or perineal lesions) is highly specific for secondary syphilis 1.
How Secondary Syphilis Mimics Your Other Differential Diagnoses
Mimicking Psoriasis
Secondary syphilis can present with prominent scaling that makes it difficult to differentiate from guttate psoriasis 5. Histologically, it can show psoriasiform features with irregular acanthosis and elongated rete ridges 2, 6.
Mimicking Lichen Planus
Secondary syphilis can present as a lichen planus-like eruption, even mimicking a lichenoid drug eruption histologically 7. The skin biopsy may show psoriasiform lichenoid dermatitis 5.
Mimicking Seborrheic Dermatitis
The scaling and distribution patterns can overlap with seborrheic dermatitis, particularly when involving the scalp or face 4.
Mimicking Atopic Dermatitis
The pruritic nature of some secondary syphilis presentations can suggest atopic dermatitis 5, 7.
Critical Diagnostic Approach
Serologic Testing (Essential First Step)
- Screen with nontreponemal tests: RPR or VDRL 4, 1.
- Confirm with treponemal-specific tests: FTA-ABS or MHA-TP 4, 1.
- Both tests are necessary: Nontreponemal tests alone are insufficient for diagnosis 4.
Histopathologic Clues When Biopsy Is Performed
Plasma cells: Present in 86.4% of cases and are the most common finding overall 2. In specimens with fewer diagnostic features, plasma cells are still present in 48.3% of cases 6.
Necrotic keratinocytes: Found in 66.1% of secondary syphilis specimens and represent a characteristic feature 2.
Endothelial swelling: Present in 87.7% of cases overall 6.
Interstitial inflammatory pattern: The most common characteristic in specimens with fewer diagnostic features (75.9%) 6.
Combination of features: The presence of endothelial swelling, interstitial inflammation, irregular acanthosis, and elongated rete ridges should significantly raise suspicion for syphilis 6.
Treponema pallidum detection: Spirochetes are most commonly detected at the dermal-epidermal junction using anti-T. pallidum antibody staining 2, 5.
High-Risk Populations Requiring Extra Vigilance
HIV-positive patients: They may present with more apparent clinical lesions, atypical presentations (including nodular syphilis), and potentially accelerated disease progression 4, 8, 5.
Patients with hepatitis C: Co-infection increases risk 5.
Patients presenting with neurologic symptoms, uveitis, or cholestatic hepatitis: These atypical syndromes should raise suspicion, especially if palmoplantar lesions are present 5.
Critical Pitfalls to Avoid
Don't rely solely on clinical appearance: The highly variable presentation means you cannot exclude syphilis based on morphology alone 1, 2.
Don't miss the sexual history: Secondary syphilis is a sexually transmitted infection, and risk factor assessment is essential 1.
Don't forget HIV testing: All patients diagnosed with syphilis should be tested for HIV 4, 8.
Don't assume a negative nontreponemal test excludes syphilis: Confirm with treponemal-specific testing 4.
Don't overlook subtle palmoplantar involvement: This is a key distinguishing feature from other dermatoses 5.
When to Strongly Suspect Secondary Syphilis Over Other Diagnoses
You should prioritize secondary syphilis when:
- The patient has palmoplantar involvement 5
- There are systemic symptoms (fever, lymphadenopathy, malaise) accompanying the rash 4, 1
- The patient has risk factors for sexually transmitted infections 1
- The rash is widespread and polymorphic 4
- Histopathology shows plasma cells, especially with endothelial swelling and interstitial inflammation 2, 6
- The patient is HIV-positive or has hepatitis C 8, 5
Immediate Management Once Diagnosed
First-line treatment: Benzathine penicillin G 2.4 million units IM as a single dose for primary and secondary syphilis 4, 8.
Penicillin-allergic patients (non-pregnant): Doxycycline 100 mg orally twice daily for 14 days 4, 8.
Pregnant patients: Must be desensitized and treated with penicillin, as it is the only effective option 4.
Warn about Jarisch-Herxheimer reaction: An acute febrile reaction with headache and myalgia may occur within 24 hours after treatment 4.