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Background
An epidemic of infectious syphilis has emerged worldwide among men who have sex with men (MSM), a condition with myriad manifestations and one that frequently eludes clinicians. Current common diagnostic methods rely on the laboratory detection of antibodies to Treponema pallidum and cardiolipin, the use of dark field microscopy and clinical acumen. Molecular tests are becoming available but are less useful for non-mucosal lesions. We report a recent case of syphilis mimicking a lymphoproliferative disorder where a unifying diagnosis only became apparent when a novel but underused test was employed: the spirochaete immunostain.
Case
A 29-year-old, previously well MSM was admitted to hospital for investigation of 3 weeks of painless bilateral inguinal and cervical lymphadenopathy. He reported malaise, night sweats and joint pain that had started when he was travelling in the Middle East 2 weeks prior. He was apyrexial and routine bloods were normal apart from mildly raised liver enzymes (alanine transferase 69 IU/l (10–35), alkaline phosphatase 149 IU/l (36–126)). Tests done by his general practitioner included heterophile antibodies for mononucleosis and HIV antibody tests; both were negative.
He was evaluated by haematology who felt that the presentation was highly suggestive of lymphoma. A CT scan showed multiple enlarged lymph nodes in the neck and small bowel mesentery. An open cervical lymph node biopsy was performed under general anaesthetic. Histopathology showed florid reactive features with expansion of the interfollicular zone. Suppurating granulomas with extensive paracortical and interfollicular necrotising lymphadenitis and follicle centre lysis with intrusion of Mantle cells were noted. Immunohistochemistry was positive for CD3, CD20 and CD30. There was no evidence of lymphoma. Moderate numbers of EBER (Epstein Barr Virus (EBV) encoded small nuclear RNA)+EBV infected cells were seen. Stains for HIV p24, acid-fast bacilli and fungi were negative. The suggested differential included lymphogranuloma venereum, cat scratch disease and melioidosis.
At a genitourinary clinic consultation the following week he reported sex with multiple male partners in the preceding 6 months and underwent a full sexually transmitted infection screen, which included antibody tests for T pallidum and HIV as well as PCR for Neisseria gonorrhoeae and Chlamydia trachomatis. There was no prior history of syphilis. He had some maculopapular lesions on his penis and scrotum and was thus treated with doxycycline to cover possible lymphogranuloma venereum and secondary syphilis. His original lymph node biopsy was retrieved and polyclonal spirochaete immunostaining (A. Menarini Diagnostics, Winnersh-Wokingham, Berkshire, UK) was performed, which revealed a profuse infiltrate of spirochaetes (figure 1). At review 2 weeks later his lymphadenopathy had mostly abated. Serum T pallidum antibodies were positive, rapid plasma reagin was also positive with high titre, 1:256. Molecular tests for chlamydial and gonococcal infections were negative from urethra, pharynx and rectum.
Treponema immunostain on syphilitic lymph node. Access the article online to view this figure in colour.
Discussion
Apart from the lost art of dark field microscopy still practised by a few clinicians, serological tests remain the gold standard for diagnosis of syphilis. Where the physician has failed to rule out syphilis in routine diagnostic tests, the pathologist should be mindful of HIV and syphilis as causes of lymphadenopathy and initiate appropriate investigations. T pallidum can now be successfully localised with immunohistochemical techniques; the process involves using a purified IgG antibody to detect spirochaetes in formalin-fixed paraffin-embedded tissue. In the past, histological tests for syphilis have included Warthin-Starry or Steiner's silver staining for spirochaetes; however, immunohistochemistry shows greater sensitivity when compared with Warthin-Starry staining.1 ,2 In addition, the immunohistochemical pattern of T pallidum distribution may even permit the diagnostic differentiation of primary from secondary syphilis.1
In this case, the spirochetal immunostain was unable to rule out the possible EBV co-infection given the EBER positive cells; however, the patient's heterophile antibody test was negative. Other general limitations of the test include the fact that false positive results have been reported with mycobacterial and helicobacter infection.3 In addition, one study has reported lower sensitivity than PCR for mucocutaneous lesions.4
Wider use of spirochetal immunostaining in relevant specimens is warranted in cases with signs or lesions suggestive of syphilis and where the diagnosis from biopsy specimens remains equivocal despite application of routine histopathological tests. It can also be used as a diagnostic aid when clinical suspicion is high but serology has not yet become positive.
Key messages
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The spirochaete immunostain is a novel and important diagnostic test in the diagnosis of syphilis.
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Spirochaete immunostain can be used when clinical suspicion is high but serology is not yet positive
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Rates of syphilis amongst MSM are increasing worldwide
Footnotes
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Contributors MT: Original author, compiled haematological data and laboratory investigations, obtained patient consent. JW: Edited article, obtained data on spirochaete immunostain test. JV: Edited article, provided histological advice—compiled histological report, provided histological images for article.
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Competing interests None.
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Provenance and peer review Not commissioned; externally peer reviewed.