The Great Imposter: When Syphilis Mimics Lymphoma
"A rare case of rupioid syphilis mistaken for aggressive cutaneous lymphoma reveals the importance of accurate diagnosis in complex cases."
Syphilis, famously known as the 'great imitator' since the late 19th century, can present with a variety of symptoms that resemble other diseases. Today, cutaneous lymphoma, a type of skin cancer, is also considered a master of disguise. This makes diagnosing skin conditions particularly challenging, as different diseases can manifest with similar skin lesions.
One rare and perplexing presentation is rupioid syphilis, a form of secondary syphilis characterized by thick, crusty lesions. These lesions can closely mimic cutaneous lymphoma, leading to misdiagnosis and potentially inappropriate treatment. Prompt and accurate diagnosis is crucial to avoid unnecessary interventions, such as chemotherapy, and to ensure the best possible outcome for the patient.
This article delves into a case of a 36-year-old HIV-positive man initially misdiagnosed with aggressive cutaneous lymphoma. His actual condition was rupioid syphilis, likely triggered by immune reconstitution inflammatory syndrome (IRIS). This case underscores the importance of considering syphilis in patients presenting with unusual skin lesions, especially in the context of HIV and IRIS.
Syphilis Data and Health Impact
The CDC’s county-level syphilis data include rates of primary and secondary syphilis among women aged 15–44 years. The CDC page dated November 12, 2024, reports data from 2023 and directs readers to its provisional 2024 surveillance for the latest national data. WHO describes syphilis as a curable infection caused by Treponema pallidum that can persist for years untreated and cause serious health problems; untreated or inadequately treated maternal syphilis can also harm birth outcomes. California’s health department publishes STI tables, presentations, and annual reports that include syphilis data.
Serology as the Usual Diagnostic Route
CDC’s laboratory recommendations cover serologic testing and methods to identify Treponema pallidum, the organism that causes syphilis. The CDC describes syphilis laboratory testing as traditionally based on serologic algorithms that detect a humoral response. UpToDate reports that most patients receive a presumptive diagnosis through serologic testing of blood specimens. It also notes that methods for directly detecting the organism are not generally available.
Unmasking the Imitator: How Rupioid Syphilis Tricks the Eye
Rupioid syphilis, also known as syphilis maligna, is a rare and aggressive form of secondary syphilis. It manifests as multiple, ulcerated nodules covered with thick, dark crusts resembling oyster shells (hence, 'rupioid,' derived from 'rupia,' meaning oyster). Although rare, its incidence has increased with the HIV epidemic, making it crucial for clinicians to recognize.
- Skin biopsies often show few spirochetes (the bacteria causing syphilis).
- Standard staining techniques and dark field microscopy may not detect the bacteria.
- The lesions can closely resemble other skin conditions, particularly cutaneous lymphoma.
Recent Reports on Unusual Syphilis Presentations
A 2023 review of syphilis-associated immune reconstitution inflammatory syndrome (IRIS) reported a median of 28 days from antiretroviral therapy initiation to IRIS-syphilis development; it classified 10 cases as unmasking IRIS and 4 as paradoxical IRIS. A report on intraoral primary syphilis notes that about 12 published cases of secondary syphilis initially suggesting a lymphoproliferative disorder had been described, all but one at extraoral sites. A 2024 case report describes a 28-year-old man with uncontrolled HIV and extensive ulcerated lesions with dark, layered crusting on his face, torso, and limbs. A review describes malignant syphilis as a rare, severe form of secondary syphilis associated with HIV, also called syphilis maligna praecox, lues maligna, or rupioid syphilis.
IRIS Risk Factors Despite a Noncritical CD4 Count
In a case of rupioid syphilis masquerading as aggressive cutaneous lymphoma, the authors note that the patient’s CD4 count was not critically low before antiretroviral therapy began. They nevertheless report several other risk factors for immune reconstitution inflammatory syndrome: high viral load before therapy, a strong CD4-count increase after therapy, being ART-naïve, black ethnicity, and subclinical infection. The case discussion cites French et al. and Martin-Blondel et al. in its account of these risk factors. This is a report about one patient, not evidence that every listed factor is necessary or sufficient.
Case Comparisons and Test Performance
A report proposing diagnostic criteria for ulceronodular-rupioid syphilis compared 29 cases plus its current case with 45 cases reviewed by Wibisono et al. from reports published between 2014 and 2018. The comparison covered demographics, risk factors, time to presentation, syphilis serologic titers, histopathology, and treatment response. In a separate study, immunohistochemistry (IHC) detected Treponema pallidum in 24 of 40 syphilis skin samples and was negative in all 36 non-syphilis controls, for 60% sensitivity and 100% specificity. Another study reported IHC sensitivity of 64% versus 9% for silver staining (p=0.04), illustrating that reported IHC sensitivity varies across these studies.
- Compatible gross and microscopic morphology.
- A high-titer serologic test for syphilis.
- Jarisch-Herxheimer reaction.
- Dramatic response to antibiotic therapy.
Averting Disaster: The Importance of Accurate Diagnosis
This case underscores the critical need to differentiate rupioid syphilis from cutaneous lymphoma, especially in HIV-positive individuals. Misdiagnosis can lead to inappropriate and potentially harmful treatments, such as chemotherapy, which would not address the underlying syphilitic infection.
Consider Syphilis Before Lymphoma
A report on HIV-positive secondary syphilis mimicking cutaneous T-cell lymphoma cautions that plasma cells, although a useful indicator of malignant syphilis in skin histology, may be scarce in some cases. Its authors recommend considering malignant secondary syphilis before diagnosing primary cutaneous peripheral T-cell lymphoma or HIV-associated lymphoma. Two 2016 case-report listings describe rupioid syphilis as resembling an oyster shell and emphasize the importance of recognizing syphilis’s diverse presentations. Those reports also characterize syphilis as a public health concern, particularly among men who have sex with men.
Research Needs and Future Data
A Wellcome Sanger Institute blog says that further funding investment will shape whether the research discussed can contribute to downstream preventive vaccine or treatment development. A JAMA Network Open article calls for future data collection to report whether pregnant women diagnosed with syphilis received treatment and whether their offspring developed congenital syphilis. A market forecast on LinkedIn projects that the global syphilis rapid test kit market will grow from USD 475 million in 2025 to USD 811 million by 2035, at a 5.5% CAGR from 2027 to 2035. That figure is a market projection, not a clinical or public-health outcome.
A Persistent and Systemic Infection
A 2024 report describes syphilis as an infection caused by Treponema pallidum and transmitted predominantly through sexual contact. It says the infection can affect several organs, producing skin, mucous-membrane, and systemic lesions, and continues to pose a major challenge. The report describes a severe secondary-syphilis presentation using several names: malignant syphilis, lues maligna, ulceronodular syphilis, and rupioid syphilis. It proposes “ulceronodular-rupioid syphilis” as a single descriptive name and reports that its patient’s rash resolved with hyperpigmented scarring after penicillin and doxycycline treatment.
The patient's initial diagnosis of peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), prompted consideration of aggressive chemotherapy. However, a thorough evaluation, including repeat biopsies and serological testing, revealed the true culprit: rupioid syphilis.
Ultimately, the patient responded well to intravenous penicillin, highlighting the importance of considering infectious etiologies in patients with unusual skin presentations. This case serves as a reminder to integrate clinical findings with pathological results and to maintain a broad differential diagnosis, especially in immunocompromised individuals.