We describe an HIV-negative 43-year-old woman presenting with a diffuse ulceronodular eruption and positive serological tests for syphilis consistent with lues maligna. Lues maligna is a severe and rare variant of secondary syphilis characterized by prodromal constitutional symptoms followed by the formation of multiple well-circumscribed nodules with ulceration and crust. This case depicts a particularly rare presentation as lues maligna usually involves HIV-positive men. The clinical presentation of lues maligna can pose a diagnostic challenge, with infections, sarcoidosis, and cutaneous lymphoma as just a few entities in its broad differential diagnosis. However, with a high index of suspicion, clinicians can diagnose and treat this entity earlier and reduce morbidity

Blalock, Travis W

Li, Monica M

Nguyen, Christopher N

Shaw, Fiona M

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UC DavisDermatology Online JournalTitleA rare case of lues maligna in an HIV-negative womanPermalinkhttps://escholarship.org/uc/item/2p99p9zmJournalDermatology Online Journal, 28(5)AuthorsNguyen, Christopher NShaw, Fiona MLi, Monica Met al.Publication Date2022DOI10.5070/D328559250Copyright InformationCopyright 2022 by the author(s).This work is made available under the terms of a Creative Commons Attribution-NonCommercial-NoDerivatives License, available at https://creativecommons.org/licenses/by-nc-nd/4.0/ Peer reviewedeScholarship.org Powered by the California Digital LibraryUniversity of CaliforniaVolume 28 Number 5|September/October 2022| 28(5):16   - 1 - Dermatology Online Journal  ||  Photo Vignette A rare case of lues maligna in an HIV-negative woman Christopher N Nguyen1 MD, Fiona M Shaw2 MD, Monica M Li3 MD, Travis W Blalock2 MD Affiliations: 1School of Medicine, Baylor College of Medicine, Texas, USA, 2Department of Dermatology, Emory School of Medicine, Georgia, USA, 3Department of Medicine, Emory School of Medicine, Georgia, USA Corresponding Author: Christopher N Nguyen, 1 Baylor Plaza, Houston, Texas, 77030, Tel: 713-979-7528, Email: christopher.nguyen42@gmail.com     Keywords: HIV, lues maligna, malignant syphilis, ulceronodular  Introduction Lues maligna, also termed malignant syphilis or ulceronodular syphilis, is a rare and severe form of secondary syphilis first described in 1859 [1]. Most reported cases involve an immunocompromised state, usually HIV, and/or men [2-5]. We present a rarer case of a woman presenting with lues maligna and found to be HIV-negative.  Case Synopsis A 43-year-old woman with a history of type two diabetes mellitus, homelessness, schizophrenia, and polysubstance dependence presented with a diffuse painful and pruritic eruption of one month duration. Although she was not taking any medications for her diabetes, her hemoglobin A1C was within normal limits. A review of systems was negative for systemic symptoms. Physical examination revealed diffuse well-circumscribed erythematous nodules and plaques of varying sizes; some exhibited rolled borders, ulceration, and superficial crusting (Figure 1). Lesions involved the face, neck, chest, abdomen, back, and all extremities, sparing the palms and soles. Palpable inguinal lymphadenopathy was also present. The rapid plasma reagin (RPR) titer was 1:128, and the treponemal immunoglobulin G antibody test was positive. Human immunodeficiency virus (HIV) antigen and antibodies were negative. A skin biopsy revealed epidermal acanthosis with a diffuse dermal infiltrate comprised of plasma cells (Figure 2A). Immunohistochemistry for Treponema pallidum showed abundant spirochetes within the epidermis  Abstract We describe an HIV-negative 43-year-old woman presenting with a diffuse ulceronodular eruption and positive serological tests for syphilis consistent with lues maligna. Lues maligna is a severe and rare variant of secondary syphilis characterized by prodromal constitutional symptoms followed by the formation of multiple well-circumscribed nodules with ulceration and crust. This case depicts a particularly rare presentation as lues maligna usually involves HIV-positive men. The clinical presentation of lues maligna can pose a diagnostic challenge, with infections, sarcoidosis, and cutaneous lymphoma as just a few entities in its broad differential diagnosis. However, with a high index of suspicion, clinicians can diagnose and treat this entity earlier and reduce morbidity. Figure 1. A) Numerous well-circumscribed erythematous flat nodules and plaques of varying sizes exhibiting rolled borders, ulceration, and crust. B) Primary morphology of individual lesions showed a well-defined plaque with rolled borders and central erosion.B AVolume 28 Number 5|September/October 2022| 28(5):16   - 2 - Dermatology Online Journal  ||  Photo Vignette and dermis. Gram, acid-fast bacillus, and Periodic acid–Schiff stains were negative (Figure 2B). A diagnosis of syphilis, specifically lues maligna, was made. The patient was given 2.4 million units of penicillin G benzathine intramuscularly and demonstrated an RPR titer of 1:32 two weeks later. However, clinical improvement of the rash could not be fully assessed as the patient was subsequently lost to follow-up. Subsequent emergency department visits noted absence of rash and continued HIV-negative status one year after presentation.  Case Discussion Clinicians should be aware of this atypical presentation of this common entity. As opposed to the papulosquamous eruption of typical secondary syphillis, lues maligna presents as multiple well-circumscribed papules, papulopustules, or nodules with ulceration and a lamellar or rupioid crust on the trunk and extremities [2]. The skin lesions may be preceded by weeks-to-months of constitutional symptoms such as fevers, arthralgias, and weight loss, although this was not seen in our patient. This clinical presentation can pose a diagnostic challenge, with bacterial, fungal, and mycobacterial infections, as well as sarcoidosis, pityriasis  lichenoides, leukemia cutis, and cutaneous lymphoma among the potential diagnoses [2,6]. Fisher et al. proposed the following criteria to make the diagnosis of lues maligna: congruent gross and microscopic characteristics, positive syphilis serologies, the Jarisch-Herxheimer reaction, and responsive to antiobitic treatment [7]. The Jarisch-Herxheimer reaction is a self-resolving febrile reaction that occurs within the first 24 hours of treatment of spirochetal infections, such as syphillis [8]. Our patient exhibited all of Fisher et al.’s criteria except the Jarisch-Herxheimer reaction, similarly seen in other reported cases [2,9]. The typical histopathological features of syphilis include dermal plasma cell infiltrate and perivascular infiltrate. Vessel obstruction with histologic features of vasculitis may be seen as well [7]. Interestingly, Treponema pallidum organisms are commonly not visualized by silver stains in lues maligna biopsies, but immunohistochemistry has increased sensitivity and specificity [2,9]. Since microscopy of lesions commonly reveal nonspecific findings and often have an absence of organisms with staining, clinical pathologic correlation paired with a low threshold for serologic testing for syphilis is key to prompt diagnosis and management [6]. As seen in our workup, additional histological stains should be used to rule out other infectious etiologies. Clinicians  Figure 2. Pathology images of biopsied abdominal lesion. A) Low power magnification reveals epidermal acanthosis with a diffuse dermal inflammatory infiltrate comprised of numerous plasma cells. H&E, 4×. B) Higher power magnification with immunohistochemistry for Treponema pallidum shows abundant spirochetes stained red (arrows) within the dermis, consistent with a diagnosis of syphilis. H&E, 40×. BA Volume 28 Number 5|September/October 2022| 28(5):16   - 3 - Dermatology Online Journal  ||  Photo Vignette should also be aware of potential false-negative RPR results related to high antibody titers that prevent proper antigen-antibody complex formation and visualization [10]. This reaction is known as the prozone phenomenon and may be seen especially in lues maligna patients as they can have markedly high antibody titers [11]. If suspected, clinicians may request the dilution of the specimen to obtain more accurate results. A review by Sands et al. identified only 14 reported cases of lues maligna prior to 1988 [12]. These were commonly associated with alcoholism, diabetes mellitus, and malnourishment, like our patient [4]. An otherwise healthy woman presenting with lues maligna is exceedingly rare and had not been reported in 50 years prior to Held et al.’s report in 1990 [13]. Of note, our patient may have been more susceptible to syphilis owing to her diabetes, which has been shown to increase risk of infection through dysregulating the immune system [14]. Lues maligna has become more common following the HIV epidemic, though it is still rare. HIV-positive patients are 60 times more likely to develop lues maligna and conversely, lues maligna may also represent the initial manifestation of HIV [2]. With this strong association in mind, HIV status should be tested in all patients with lues maligna.  Fortunately, lues maligna responds well to multiple penicillin regimens with complete resolution of lesions and minimal-to-no scarring [9]. Before treatment, clinicians should caution the patient of the self-limited Jarisch-Herxheimer reaction. Along with fever, this reaction may be associated with worsening of the rash or other systemic symptoms such as chills, headache, and myalgias. Also, HIV-positive patients should continue anti-retroviral therapy during treatment [15]. Response should be monitored with regular clinical examinations and down-trending RPR titers [2]. A repeat HIV test may be warranted for HIV-negative patients with lues maligna that fail to respond to treatment.   Conclusion Herein, we report a rare case of lues maligna in an HIV-negative woman. Clinicians should always consider lues maligna in a patient with HIV or risk factors for HIV presenting with ulcerated nodules. Clinical pathological correlation and serologic tests for syphilis are key to early diagnosis and treatment to reduce patient morbidity. Lastly, it is imperative to test for HIV infection in all lues maligna patients if it has not already been diagnosed.  Potential conflicts of interest The authors declare no conflicts of interest.    References 1. Bazin APE. Lec¸on theorique et clinique sur les syphilides radiquess par le Fournier. Adrian Delahayer, Paris: 1959. 2. Tucker JD, Shah S, Jarell AD, et al. Lues maligna in early HIV infection case report and review of the literature. Sex Transm Dis. 2009;36:512-514. [PMID: 19455078]. 3. Ghanian S, Dalla Costa R, Singer H, Robinson-Bostom L. Extensive lues maligna syphilis in an immunocompromised male. Int J Dermatol. 2022;61:e410-e411. [PMID: 34468018]. 4. Alves J, António AM, Matos D, Coelho R, Cachão P. Malignant lues in an immunocompetent patient. Int J STD AIDS. 2015;26:518-520. [PMID: 25015934]. 5. Dunn C, Applebaum DS. Lues maligna in an immunocompetent male. J Cutan Med. 2019;3:102-104. [DOI: 10.25251/skin.3.2.44]. 6. Mena Lora AJ, Braniecki M, Nasir A, Brito M. The great impostor: Lues maligna in an HIV-infected male. SAGE Open Med Case Rep. 2017;5:2050313X17731050. [PMID: 28955441]. 7. Fisher DA, Chang LW, Tuffanelli DL. Lues maligna. Presentation of a case and a review of the literature. Arch Dermatol. 1969;99:70-73. [PMID: 5761808]. 8. Butler T. The Jarisch-Herxheimer Reaction After Antibiotic Treatment of Spirochetal Infections: A Review of Recent Cases and Our Understanding of Pathogenesis. Am J Trop Med Hyg. 2017;9:46-52. [PMID: 28077740]. 9. Cid PM, Cudós ES, Zamora Vargas FX, Merino MJ, Pinto PH. Pathologically confirmed malignant syphilis using immunohistochemical staining: report of three cases and review of the literature. Sex Transm Dis. 2014;41:94-97. [PMID: 24413487]. 10. Liu LL, Lin LR, Tong ML, et al. Incidence and risk factors for the prozone phenomenon in serologic testing for syphilis in a large cohort. Clin Infect Dis. 2014;59:384-389. [PMID: 24803377]. 11. Watson KM, White JM, Salisbury JR, Creamer D. Lues maligna. Clin Exp Dermatol. 2004;29:625-627. [PMID: 15550139]. 12. 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;20:387-390. [PMID: 7742445]. 13. Held JL, Ross M, Beltrani V Jr, Kohn SR, Grossman ME. Noduloulcerative or "malignant" syphilis occurring in an otherwise healthy woman: report and review of a dramatic Volume 28 Number 5|September/October 2022| 28(5):16   - 4 - Dermatology Online Journal  ||  Photo Vignette dermatosis. Cutis. 1990;45:119-122. [PMID: 2178881]. 14. Berbudi A, Rahmadika N, Tjahjadi AI, Ruslami R. Type two Diabetes and its Impact on the Immune System. Curr Diabetes Rev. 2020;16:442-449. [PMID: 31657690]. 15. Gevorgyan O, Owen BD, Balavenkataraman A, et al. A nodular-ulcerative form of secondary syphilis in AIDS. Proc (Bayl Univ Med Cent). 2017;30:80-82. [PMID: 28127144].  

A rare case of lues maligna in an HIV-negative woman

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