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Malignant syphilis: History in the making

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By Warren R. Heymann, MD, FAAD
Jan. 3, 2024
Vol. 6, No. 1

Dr. Warren Heymann photo
As our new academic year commences, soon I will remind our new residents of Sir William Osler's famous aphorism, “He who knows syphilis knows medicine.” As the great mimicker, our trainees will never go astray by including syphilis (lues) in their differential diagnosis (in addition to sarcoidosis and cutaneous T-cell lymphoma).

I have noticed increasing cases of malignant syphilis (MS, aka lues maligna, noduloulcerative syphilis, rupioid syphilis, syphilis maligna praeocox) in the literature. MS is a rare, severe form of secondary syphilis, characterized by cutaneous ulcers with central necrosis that a black-brown rupioid crust may accompany. (1) (The term “rupioid” [from the Greek rhupos, meaning filth] is used to describe oyster or limpet shell-shaped thick keratotic lesions.) (2) First, a point of clarification — as Vinay et al affirm: “The term ‘malignant’ has been used to describe the grotesque clinical features and is not related to the clinical event of malignancy.” (3) This commentary will focus on MS.

Syphilis was first recognized in the late 15th century and is caused by infection with the spirochetal bacterium Treponema pallidum var pallidum. (4) MS was first recognized by Bazin in 1859 and Dubuc in 1864 as a nodular variant of syphilis. (5) Neisser described the rupioid appearance in 1897. (1) Since its modern-day nadir in 2001 of 5,979 cases per year, or 2.1 cases per 100,000 population, primary and secondary syphilis incidence has rapidly increased. In 2021, 53,767 cases, or 16.2 cases per 100,000, were reported, more than a 5-fold increase. (6) In the 21st century, the increased incidence of syphilis has disproportionately affected men who have sex with men and persons living with HIV infection. (4) There has also been a vast increase in congenital syphilis. (6)

Images for DWII of malignant syphilis
Image from reference 4.

Only 14 cases of MS were reported between 1900 and 1988. (7) This situation changed dramatically with the onset of HIV/AIDS. In their systematic review of MS between 2014 and 2018, of 45 published case reports, 33 cases (73%) occurred in HIV-positive individuals with a majority having CD4 counts < 500 cells/mm3. Of the 12 cases (27%) in HIV-negative individuals, half had comorbidities such as diabetes mellitus, alcoholism, drug abuse, psoriasis, and hepatitis. The most frequent cutaneous manifestation of MS was ulceronodular cutaneous lesions with central adherent crust, affecting the face, trunk, and limbs. The authors concluded, “Given the increasing number of MS regardless of the immune status, dermatologists and general practitioners should be vigilant to allow early diagnosis and treatment, hence reducing their morbidity.” (8)

In 1969, Fisher et al stated that in most cases of MS only a presumptive diagnosis can be made because of the extreme scarcity of Treponema pallidum in skin lesions. They proposed four diagnostic criteria: (1) compatible gross and microscopic morphology; (2) a high titer serology test for syphilis; (3) [Jarisch]-Herxheimer reaction; and (4) dramatic response to antibiotic therapy. (9) Not every criterion is necessary — even their patient with MS did not experience a Jarisch-Herxheimer reaction. (9) Karanfilian et al proposed expanding the definition of MS to include systemic manifestations, stressing musculoskeletal, central nervous system, ocular, ear, cardiovascular, rectal, liver, lung, and renal involvement. (1) Although the systemic manifestations are protean, realistically, dermatologists will diagnose MS by cutaneous criteria that are confirmed serologically.

MS tends to have a short incubation period, beginning with a pronounced prodrome of systemic symptoms, commonly fever, chills, myalgias, arthralgias, malaise, anorexia, weight loss, and headache. Cutaneous manifestations of MS usually start with papules, which then become pustular before ulcerating. The ulcers have well-defined, raised edges with central necrosis and can develop rupioid crusts. Nodular lesions may also become ulcerated. Mucous membranes may be affected. The differential diagnosis of MS is broad, including inflammatory disorders (acne, erythema multiforme, pyoderma gangrenosusm, pitryriasis lichenoides), infectious ulcers (bacterial, mycobacterial, viral, fungal, parasitic), and lymphoproliferative disorders. (1)

Characteristic histological features include a dermal plasmacytic infiltrate that may be accompanied by vasculitis and vascular obstruction. Treponema pallidum are usually not visualized by silver stains, but immunohistochemical stains have increased sensitivity and specificity. Fortunately, MS responds well to standard anti-syphilitic regimens, with parenteral penicillin as recommended treatment (a single intramuscular dose of benzathine pencillin, 2.5 million units), with alternatives such as doxycycline, tetracycline, or ceftriaxone in penicillin-allergic non-pregnant patients. (1,10) Public health implications (reporting, empiric treatment) are the same as for other types of secondary syphilis.

Regarding the pathogenesis of MS, Fisher et al ask, “Why should the disease in certain individuals progress to such a severe obliterative vasculitis?” They hypothesize, “The common features in many cases have included malnutrition, self-neglect, and poor general health. These patients, perhaps because of constitutional factors, are unable to summon the usual immune response limiting secondary lues and affecting involution. In any event, the progression of the vasculitis in syphilis maligna praecox is presumably due to an undefined abnormality in the individual’s immune response.” (9) MS’s pathophysiology is based on the interplay of the spirochete’s virulence countered by the host's immune response. The ample number of cases of LM in immunosuppressed hosts, most notably in those infected with HIV, is not surprising. (11,12) What is disconcerting is the increasing number of case reports of MS in immunocompetent hosts. (10,13,14,15) Future research is needed to decipher the complexities of the host-pathogen interaction to answer the question posed by Fisher et al.

New residents may not be aware that the American Board of Dermatology (ABD) was initially the American Board of Dermatology and Syphilology (ABDS) when it was incorporated in 1932. In 1955, the ABDS changed its official name as syphilis had been on the decline since 1943 when penicillin was successfully introduced as therapy for syphilis. Dermatologists should heed Osler’s advice. Nobody wants the ABD to revert to its original name.

Point to Remember: Malignant syphilis has been increasingly reported in both immunocompromised and immunocompetent patients. Dermatologists should consider this diagnosis when encountering patients with an acute onset of well-defined necrotic ulcers that may be associated with rupioid crusts. 

Our expert’s viewpoint

Kenneth A. Katz, MD, MSc, FAAD
Chief, Outpatient Pharmacy and TherapeuticsKaiser Permanente – San Francisco Medical Center

“Malignant syphilis” is a misleading moniker. There is no “benign syphilis,” after all, and even “malignant” is not used the way it typically is medically. Moreover, “malignant syphilis” lacks a specific case definition. And it’s diagnosed, treated, and reported like other cases of secondary syphilis. Indeed, the Centers for Disease Control and Prevention does not specifically call out “malignant syphilis” in its STI Treatment Guidelines (16) or in its Sexually Transmitted Disease Surveillance summaries. (17)

Why, then, even bother? A major stumbling block to diagnosis syphilis is neglecting to include it in the differential diagnosis. That in part reflects syphilis epidemiology. Many dermatologists trained during times and in places where syphilis was uncommon. And even though incidence of primary and secondary syphilis in the United States has increased nearly 8-fold in the past two decades, it’s still relatively rare, and relatively concentrated in certain areas and populations.

Its problematic name and nosology notwithstanding, “malignant syphilis” is a useful reminder that the infection can have protean, and severe, mucocutaneous and systemic manifestations that themselves can vary over time.

  1. Karanfilian KM, Almohssen AA, Kapila R, Schwartz RA. Malignant syphilis: a new and revised definition. Int J Dermatol. 2023 Mar;62(3):369-375. doi: 10.1111/ijd.16444. Epub 2022 Oct 17. PMID: 36250867.

  2. Gómez-Arias PJ, García-Nieto AJV. Rupioid psoriasis on the hands. CMAJ. 2020 Nov 9;192(45):E1407. doi: 10.1503/cmaj.200517. PMID: 33168763; PMCID: PMC7669303.

  3. Vinay K, Kanwar AJ, Narang T, Saikia UN. Malignant syphilis. Int J Infect Dis. 2013 Oct;17(10):e930-1. doi: 10.1016/j.ijid.2013.03.020. Epub 2013 May 18. PMID: 23688548.

  4. Forrestel AK, Kovarik CL, Katz KA. Sexually acquired syphilis: Historical aspects, microbiology, epidemiology, and clinical manifestations. J Am Acad Dermatol. 2020 Jan;82(1):1-14. doi: 10.1016/j.jaad.2019.02.073. Epub 2019 Apr 12. PMID: 30986477.

  5. Sá Lopes R, Monteiro AS, Saez R, Candeias C, Mendonça C. Malignant Syphilis: A Rare Case of Early Secondary Syphilis in an Immunocompetent Patient. Eur J Case Rep Intern Med. 2023 Jan 11;10(1):003721. doi: 10.12890/2023_003712. PMID: 36819650; PMCID: PMC9930879.

  6. https://www.cdc.gov/std/statistics/2021/tables/1.htm

  7. Sands M, Markus A. Lues maligna, or ulceronodular syphilis, in a man infected with human immunodeficiency virus: case report and review. Clin Infect Dis. 1995 Feb;20(2):387-90. doi: 10.1093/clinids/20.2.387. PMID: 7742445.

  8. Wibisono O, Idrus I, Djawad K. Malignant Syphilis: A Systematic Review of the Case Reports Published in 2014-2018. Actas Dermosifiliogr (Engl Ed). 2021 Mar 31:S0001-7310(21)00135-6. English, Spanish. doi: 10.1016/j.ad.2021.02.011. Epub ahead of print. PMID: 33811833.

  9. Fisher DA, Chang LW, Tuffanelli DL. Lues maligna. Presentation of a cas and a review of the literature. Arch Dermatol. 1969 Jan;99(1):70-3. doi: 10.1001/archderm.99.1.70. PMID: 5761808.

  10. Nguyen CN, Shaw FM, Li MM, Blalock TW. A rare case of lues maligna in an HIV-negative woman. Dermatol Online J. 2022 Oct 15;28(5). doi: 10.5070/D328559250. PMID: 36809140.

  11. Kim MG, Kamath V, Martinello M, Overton K. Case report of a man with HIV presenting with malignant syphilis. Sex Health. 2023 Feb;20(1):83-86. doi: 10.1071/SH22161. PMID: 36508716.

  12. Ghanian S, Dalla Costa R, Singer H, Robinson-Bostom L. Extensive lues maligna syphilis in an immunocompromised male. Int J Dermatol. 2022 Oct;61(10):e410-e411. doi: 10.1111/ijd.15880. Epub 2021 Sep 1. PMID: 34468018.

  13. Demirbaş A, Şikar Aktürk A, Odyakmaz Demirsoy E, Kıran R, Bayramgürler D, Sayman N, Açıkbaş E, Vural Ç. Lues Maligna in an immunocompetent male: A case report. J Cosmet Dermatol. 2022 Jul;21(7):3160-3162. doi: 10.1111/jocd.15113. Epub 2022 Jun 4. PMID: 35612931.

  14. Margulies S, Patel SP, Motaparthi K. Ulceronecrotic rash in an immunocompetent individual. JAAD Case Rep. 2022 Jul 5;27:29-31. doi: 10.1016/j.jdcr.2022.06.029. PMID: 35990229; PMCID: PMC9389133.

  15. Dev A, Mitra S, Sekar A, Vinay K. Multiple ulceronecrotic nodules: An uncommon presentation. Int J Dermatol. 2023 Aug;62(8):1011-1012. doi: 10.1111/ijd.16496. Epub 2022 Nov 4. PMID: 36331118.

  16. Workowski KA, Bachmann LH, Chan PA, et al. Sexually Transmitted Infections Treatment Guidelines, 2021. MMWR Recomm Rep 2021; 70(No. RR-4):1-187.

  17. CDC. Sexually Transmitted Disease Surveillance 2021. Available at: https://www.cdc.gov/std/statistics/2021/default.htm. Accessed 8/21/2023.

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