Syphilis is an infection caused by Treponema pallidum, a spirochete bacterium that exclusively infects humans.1 Malignant syphilis (MS), also known as syphilis maligna, lues maligna, or rupioid syphilis, is a rare aggressive form of secondary syphilis.1 The term “rupioid” stems from the rupia or “oyster-like” appearance of these lesions, describing well-demarcated plaques with thick, lamellate, and adherent crusts on the surface that resemble an oyster shell.2 In 1859, the French dermatologist Pierre Bazin first used the term malignant to describe a case of secondary syphilis, and in 1896, at the Third International Congress of Dermatology in London, the Danish dermatologist Haslund and German dermatologist Neisser, independently classified MS as a rare, aggressive, ulcerating form of secondary syphilis and not an early form of tertiary syphilis, as had previously been assumed.1,3 It is distinguished from classical secondary syphilis based on a more severe general clinical picture and the presence of pleomorphic and ulceronecrotic skin lesions.4

MS presents as crusted or scaly papules and plaques that can ulcerate or become necrotic.5 The exanthem mainly affects the trunk and limbs, although the face, scalp, mucous membranes, palms, and soles can also be affected. Palpable peripheral lymphadenopathy, fever, and constitutional symptoms are commonly observed in patients with the disease. There have been only a limited number of reports of MS published in medical literature, and most of the reported cases have been in immunocompromised individuals, particularly those infected with human immunodeficiency virus (HIV).6 Syphilis and HIV co-infection can lead to an increased HIV viral load, concomitantly with a decreased CD4+ cell counts, greatly increasing the risk of MS, especially if untreated.7,8 Before the HIV pandemic, MS was extremely rare; between 1900 and 1988, only 14 cases had been published in English language. At present, it is estimated that up to 7% of all syphilis cases in immunocompromised patients meet the criteria for MS, often presenting as the first clinical manifestation of HIV infection.4 However, some reports on MS in immunocompetent individuals have been recently published.9,10 We conducted a systematic review of case reports on MS published between 2014 and 2018 to analyze demographic and risk factors of MS.

In order to review clinical, laboratory, and therapeutic data from patients with documented MS, we searched 2 databases (PubMed and Google Scholar) for literature published between 2014 and 2018, using the following terms: malignant syphilis OR lues maligna OR rupioid syphilis OR ulceronodular syphilis (Fig. 1). Our literature search yielded 39 articles, which were independently reviewed by 2 investigators, and any disagreement was resolved by consensus. We included all studies where the diagnosis was documented by serology or any combination of serology, pathologic findings, and immunostaining. Studies without positive serologic tests were not included. The inclusion criteria for the articles were: (1) case report with one of the aforementioned expressions in the title; (2) article in English; (3) articles published between 2014 and 2018; and (4) contain all the necessary information (gender, age, sexual behavior (heterosexual, bisexual or homosexual), location and description of the lesions, onset, serology and histopathology results, HIV status, immunostaining, treatment and post-treatment reactions, outcome). In total, 36 of the 39 articles were considered relevant and met the inclusion criteria. From those selected articles, we collected a total of 45 cases of MS.2,3,9–39 We extracted the details on each case and recorded it on a spreadsheet Microsoft Excel 2016. We used Microsoft Excel 2016 to produce basic descriptive statistics (frequencies, percentages, and medians) of the data. We did not do any hypothesis testing.

Figure 1.

Search flowchart.

(0.4MB).

We reviewed published case reports on 45 patients with MS, published in 2014-2018. It is well recognized that MS is commonly observed in immunosuppressed patients such as those with HIV infection. The pathogenesis of MS is unknown, but it is generally believed that immunosuppression due to HIV coinfection enables T. pallidum to become more virulent. Notably however, most of the HIV-positive patients had a CD cell count >200 cells/mm3, and thus, they were not deeply immunosuppressed.12 The loss of CD4 T cells that occurs as a result of HIV infection or other conditions4 leads to a greater action of cytotoxic T cells and neutrophils on the skin2 in MS. As a result, MS differs from conventional syphilis that occurs in individuals with intact immune systems. This reasoning is consistent with its occurrence in patients with comorbidities or debilitating disease as a cofactor. Our review revealed that 6 of the 12 HIV-negative patients (50%) had comorbidities such as diabetes mellitus, alcoholism, drug abuse, psoriasis, and hepatitis, which could have affected their immune function. The occurrence of MS in HIV-negative patients with comorbidities raises the possibility of aberrant immune response caused by these systemic conditions triggering a more severe skin manifestation and the possibility of a more virulent strains of Treponema, which already considered by other authors.4,32,38,39

MS is often seen in association with high nontreponemal titers and systemic symptoms.5 To guide the clinical diagnosis, in 1969, Fisher et al., proposed 4 criteria in order to identify this rare variant of syphilis, namely: (1) Comparable gross and microscopic morphology; a high titer serologic test for syphilis; a Jarisch-Herxheimer reactions (JHR); and a dramatic response to antibiotic therapy.40

Diagnosis by skin biopsy in affected patients is challenging because spirochetes are generally sparse in the skin lesions. Skin biopsy is, however, a recommended procedure to exclude other bacterial, fungal, and mycobacterial infections. Data obtained from special staining and dark-field microscopy may be insufficient to make a histologic diagnosis,33,40 but microscopic evaluation may reveal nonspecific inflammatory findings, such as histological patterns of dermal infiltrate with plasma cells and lymphocytes, sometimes granulomatous and vascular damage. Our review revealed that lymphohistiocytic dermal infiltrate with plasma cells was the most commonly reported histological feature.12 Immunohistochemistry is superior to silver stains for detecting spirochetes, but it is not always be available as a routine procedure.33

An increase in the incidence of JHR has been described both in patients with MS and in patients with HIV in general. Yang et al describe a rate of incidence of JHR as high as 34.6% in HIV-infected patients.41 In our review, JHR was reported in only 9 patients (20%), and of these 9 patients, 7 were provided with prophylactic corticosteroids. JHR is a transient immunological phenomenon seen commonly in patients during treatment of secondary syphilis; it manifests with constitutional symptoms such as fever, chills, headache, and myalgia, in addition to exacerbation of existing cutaneous lesions. The reaction usually occurs hours after the administration of an appropriate antibiotic and normally resolves without any intervention within 24 hours. JHR is more severe when the number of pathogens is abundant, consistent with a high-titer serological test being part of MS criteria. It should be managed symptomatically and does not require discontinuation of the appropriate antimicrobial treatment. Corticosteroids have been used to prevent the reaction, but there is no conclusive evidence regarding their benefit.35,42

Currently, there is no specific recommendations for MS treatment. The most commonly used treatment regimen is the same as that used for late latent syphilis (3 consecutive weekly intramuscular injections of benzathine penicillin, 2.4 million units/dose). In case of allergy to penicillin, treatment with ceftriaxone can be used. In resistant cases or relapses, prolonged therapy with high doses of penicillin is suggested.12,25 About 80% of the patients in our review were treated with penicillin, either intramuscularly or intravenously as aqueous solution, and all the patients had a rapid improvement in their condition following antibiotic treatment.

Our review included 45 case reports of MS published from 2014-2018, available on the PubMed and/or Google Scholar databases. Of the patients, 74% were HIV positive. Of the HIV-negative patients, half had a comorbidity such as diabetes mellitus, alcoholism, drug abuse, psoriasis, hepatitis. The majority of cases occurred in men (84%), the median age of presentation is 41 years with the 40-44 years old age group being the most frequently affected. The most frequent cutaneous manifestations were ulceronodular lesions with an adherent crust on the central surface affecting the face, trunk, and limbs. with half of patients with HIV infection having a CD4 cell count in the 200-499 cells/mm3 range. The majority of patients were treated with benzathine penicillin G or aqueous penicillin G, and all patients experienced a rapid clinical improvement following antibiotic therapy. JHR was reported in 20% of patients, despite the majority of them having been given prophylactic corticosteroids. In the face of the increased number of cases of this rare form of syphilis regardless of the immune status, dermatologists and general practitioners should be attentive to the occurrence of MS in order to allow early diagnosis and treatment, hence reducing their morbidity.

The authors declare no conflicts of interest.