September 2015

A 59-year-old female with rash and possible plasma cell dyscrasia

Christine James, DO and Patrick Bacaj, MD

Overview

A 59-year-old woman with a past medical history of diabetes, hypertension, fatigue, and multinodular goiter presented to her primary care physician with generalized malaise, weakness, and a diffuse macular rash. The rash began on the forehead and spread down to her arms, per the patient. She also reported a 15 to 20 pound unintentional weight loss over five months time and drenching night sweats. No lymphadenopathy was found on examination. Routine bloodwork revealed anemia, and serum electrophoresis was ordered (Figure 1). Immunotyping revealed no monoclonal proteins. The patient underwent a bone marrow biopsy, which showed a mild polyclonal plasmacytosis (8%). An HIV test was negative.

Figure 1. Capillary electrophoresis revealed a polyclonal gammopathy. Subsequent immunotyping revealed no monoclonal proteins in the expanded gamma region.

Gross Description

A skin biopsy of the rash showed a diffuse dermal plasmacytic infiltrate extending into the subcutis (Figure 2A-B). However, kappa and lambda in situ hybridization demonstrated no monoclonal restriction (Figure 3A-B). This supported the serum electrophoresis finding of a polygammopathy.

Figure 2. A. Skin punch biopsy showing dense inflammatory infiltrate at 20x. B. Plasmacytoid infiltrate at 400x.
Figure 3: A. Kappa ISH. B. Lambda ISH. Note the polyclonal nature of the infiltrate.

The Hematology-Oncology service suspected multicentric Castleman disease and requested an HHV-8 stain, which was negative. A treponemal antibody stain was done because of other laboratory findings, which revealed rare organisms.

Figure 4: Treponemal antibody stain at 1000x (oil-immersion).

Diagnosis

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Discussion

Syphilis is a sexually transmitted infection caused by the Gram-negative spirochete Treponema pallidum, subspecies pallidum. The motile, helical bacterium is 6-15 μm long and 0.14-0.2 μm wide. 1 The organism has humans as its only natural reservoir and cannot live for more than a few hours outside the host due to metabolic requirements. The spirochete has an innate ability to evade the host’s immune system as it lacks an abundance of recognizable antigens on its cell surface.1

Treponema pallidum is a fastidious organism and cannot be cultured in the laboratory setting. 2 Instead, the organism can be identified in tissue utilizing dark field microscopy, Warthin-Starry stains and treponemal antibody stains. The Venereal Disease Research Laboratory (VDRL), Rapid Plasma Reagin (RPR), and Toludine Red Unheated Serum Test (TRUST) are considered non-treponemal assays and are used for screening. 2,3 These assays rely on antibodies to a non-specific cardiolipin-cholesterol-lecithin antigen on the spirochete’s surface to generate a semi-quantitative result. 2 These tests may not flag as positive until three weeks after the initial infection due to slow IgM antibody production. Because of the sluggish immune response, dark field microscopy may be used for diagnosis during the acute onset of symptoms. 1 In addition, patients with HIV co-infection may have false negative results depending on their level of immunosuppression.2 Non-treponemal tests require confirmation using a specific treponemal test. These confirmatory tests include fluorescent treponemal antibody absorption assays (FTA-ABS), Treponema pallidum particle agglutination tests (TP-PA), microhemagglutination tests for antibodies to T. pallidum (MHA-TP), and T. pallidumenzyme immunoassays (TP-EIA). 2,3 These assays, while more specific than the screens, generate only a qualitative result. In some laboratories, enzyme immunoassays have become the preferred screening test. 2 No rapid point-of-care test has yet been approved by the FDA, though some are commercially available.2

Primary syphilis classically presents with a firm, painless, non-pruritic skin ulcer known as a chancre. This site is the initial invasion site of the bacterium. 3Chancres generally appear 3-90 days after initial exposure, and may persist for 3-6 weeks without treatment. Of note, 40-85% of women and 20-65% of men report no initial chancre formation after being diagnosed with syphilis, as detection may be difficult in the genital region. 3 The presence of multiple lesions should not exclude the diagnosis, as multiple lesions are common when associated with HIV co-infection. 3 The differential diagnosis for primary syphilis includes genital herpes and the chancroid caused by Haemophilus ducreyi. 4

Secondary syphilis presents as a diffuse, symmetric rash that can involve the palms of the hands and soles of the feet. The rash may be macular, papular, or nodular but will not be vesicular. 4 Condyloma lata result when the mucous membranes are involved. 3 Secondary syphilis typically develops 6-8 weeks after chancre appearance. 3 The rash remains infectious, and biopsy will reveal the spirochete’s presence. 3 Lymphadenopathy is common but not required for diagnosis. Epitrochlear node enlargement is highly suggestive of this disease process. 4 Secondary syphilis may also be manifested by fever, malaise, weight loss, “moth eaten” alopecia, uveitis, and headache. 3,4 Without treatment, the rash and other symptoms will resolve after 3-6 weeks, but may recur in up to 25% of patients. Secondary syphilis may be followed by latent syphilis, in which the patient remains serologically positive but does not exhibit any symptoms of the disease. 3 Latent syphilis may last for years before reactivating to secondary syphilis or progressing to the tertiary stage.

Tertiary syphilis may manifest in three ways: gummatous syphilis, neurosyphilis, or cardiovascular syphilis. The patient is no longer infectious at this stage, which may be 3-15 years after the primary event. Gummas are soft, tumor-like masses of inflammation that typically involve the skin, bone, and liver. Neurosyphilis may present early as syphilitic meningitis or late as meningovascular syphilis or as general paresis, which includes tabes dorsalis, dementia, and Argyll Robertson pupil response. Cardiovascular syphilis generally presents as an aortic aneurysm or ascending aortitis, historically described as a “tree-barking” aorta. 3          

Syphilis incidence rates have been low in recent history, but outbreaks are increasing, particularly in homosexual males. 5 Syphilis cases reached an all time low in 2000 due to a CDC eradication initiative began in 1999. 5 However, the rate of primary and secondary syphilis increased over 15% between 2006 and 2007. 3Between 2005 and 2013, the number of reported cases of primary and secondary syphilis almost doubled. 6 The CDC issued a new initiative in 2010 called the Syphilis Elimination Effort (SEE) with the goal of again decreasing the reported cases of primary and secondary syphilis. 5 A CDC report for 2010 identified 87% of new primary and secondary syphilis cases were in men. 5 Among women, African Americans were found to be affected 21 times more than Caucasians. 5

Co-infection with HIV is now common due to the shared high-risk sexual behavior associated with each. 1 Chancres facilitate HIV virus acquisition. 5 T. pallidumalso stimulates certain cytokines, which in turn increase HIV replication and leads to higher viral load and lower CD4 counts. 1 HIV-positive patients are also at higher risk of developing neurosyphilis. 3 Any person diagnosed with syphilis should be tested for HIV and any newly diagnosed HIV patient should be tested for syphilis. 1,5 Overall, because syphilis is “The Great Imitator” it should be considered in all questionable clinical presentations.

In this case, the patient’s demographics are atypical as she is a middle-aged Caucasian female with no evidence of HIV infection or other immunosuppression. No high-risk behaviors were identified during the patient’s office visit.

References

  1. Kent ME, Romanelli F. Reexamining syphilis: An update on epidemiology, clinical manifestations, and management. Ann Pharmacother. 2008;42(2):226-236. doi: 10.1345/aph.1K086 [doi].
  2. Hicks C. Diagnostic testing for syphilis. http://www.uptodate.com/contents/diagnostic-testing-for-syphilis?source=search_result&search=syphilis&selectedTitle=2%7E150. Updated May 16, 2015.
  3. Mattei PL, Beachkofsky TM, Gilson RT, Wisco OJ. Syphilis: A reemerging infection. Immunodeficiency. 2012;100:5.
  4. Hicks C, Sparling PF. Pathogenesis, clinical manifestations, and treatment of early syphilis. http://www.uptodate.com/contents/pathogenesis-clinical-manifestations-and-treatment-of-early-syphilis?source=search_result&search=syphilis&selectedTitle=1%7E150. Updated December 19, 2014.
  5. Shockman S, Buescher LS, Stone SP. Syphilis in the united states. Clin Dermatol. 2014;32(2):213-218.
  6. Patton ME, Su JR, Nelson R, Weinstock H, Centers for Disease Control and Prevention (CDC). Primary and secondary syphilis—United states, 2005–2013. MMWR Morb Mortal Wkly Rep. 2014;63(18):402-406.