Nodular Erythema Elevatum Diutinum Mimicking Kaposi's Sarcoma in a Human Immunodeficiency Virus Infected Patient.

Erythema elevatum diutinum (EED) has been emerging as a specific Human Immunodeficiency Virus (HIV) associated dermatosis in recent times. It is an extremely rare chronic disease of unknown origin and part of the spectrum of leukocytoclastic vasculitis. We describe a case of EED simulating Kaposi's sarcoma in a 52-year-old HIV infected female patient with no previous opportunistic infections and CD4+ count of 164/mm(3). Therapy with oral dapsone (100 mg/day) for two weeks resulted in resolution of some lesions.

What was known?

There is a relationship between EED and HIV infection.

Introduction

Erythema elevatum diutinum (EED) is a chronic and rare dermatosis that is considered to be a variant of leukocytoclastic vasculitis. Clinically, it is characterized by symmetrical, persistent nodules, and plaques over the extensor aspects of both upper and lower extremities with a predilection for the joints particularly hands, feet, elbows, and knees. The condition was first described by Hutchinson and Bury in the 1880s, and the condition was later named in 1894 by Radcliffe-Crocker and Williams.[1] There have been several recent reports of the disease in association with Human Immunodeficiency Virus (HIV).[2345678]

The nodular lesions are rare variants and such lesions develop most often in HIV positive patients and they are confused with Kaposi's sarcoma and bacillary angiomatosis.[910] Cutaneous biopsy is mandatory in all cases to differentiate EED from these clinical simulators. Early lesions of EED show leukocytoclastic vasculitis with fibrinoid necrosis of the vessel walls with abundant neutrophilic dust and late lesions show most frequent fibrosis and areas of granulation tissue with no proliferation of spindle cells.

We report a case of nodular EED in a HIV infected woman, who has been on anti-retroviral therapy (ART) for the past seven years.

Case Report

A 52-year-old married HIV infected woman, who had been on ART for the last seven years (Zidovudine + Lamivudine + Nevirapine), was referred for evaluation of skin lesions that had appeared nine months ago. There was no history of any opportunistic infection before the onset of skin nodules. Except arthralgia and mild constitutional symptoms, her general condition was fairly good and all her vitals were within normal limits. On examination, there were multiple, dusky red, large nodules and plaques over the feet, ankles, soles, shins, knees, and elbows. Majority of the lesions were non tender and symmetrically distributed [Figures 1 and 2]. Few nodules over the soles were painful and ruptured with sero-sanguinous discharge. Some nodules over the shins healed with hyperpigmented macules. Inguinal lymph nodes on both sides were palpable and firm in consistency. There were no lesions elsewhere over the body and no mucosal lesions were present. Systemic examination disclosed no abnormalities. On ophthalmologic examination, there were no lesions in the eyes. Clinically, Kaposi's sarcoma or bacillary angiomatosis was suspected and the case was evaluated.

Figure 1

Multiple, dusky red, large nodules and plaques on the legs

Figure 2

Multiple, yellowish nodules on right elbow

Laboratory tests disclosed the following values: Hemoglobin, 10.4 gm/dl; total leukocyte count, 3600 cells/mm3; total red blood cell count, 2.70 million/mm3; erythrocyte sedimentation rate, 80 mm/1st hour; reticulocyte count, 2.5%; packed cell volume, 29.4%; mean corpuscular volume, 108.9 fL; mean corpuscular hemoglobin, 38.5 pg; platelet count, 3, 21,000/mm3, differential count – 59% neutrophils, 32% lymphocytes, 7% eosinophils, 2% monocytes; serum glutamic oxalotransferase (SGOT), 48u/L; serum glutamic phosphotransferase (SGPT), 96 u/L; serum alkaline phosphatase, 102 Iu/L; CD4+ count, 164/mm3; HIV RNA PCR (viral load), 666 IU/ml. Peripheral smear revealed macrocytic normochromic erythropoiesis and negative for immature cells. Mantoux test, serological tests for syphilis (VDRL, TPHA), hepatitis B and C, and anti-nuclear antibodies (ANA) were negative. Chest radiography and abdominal echography were normal. Two biopsies from nodule and plaque lesions were taken. Both specimens showed areas of ribbon-like thickening of collagen and areas with infiltrates of neutrophils and abundant neutrophilic nuclear dust. Few of the vessels showed features of vasculitis with fibrin in their walls. No proliferation of spindle cells was seen. Also, no vascular proliferation was observed [Figures 3 and 4]. Based on histopathology, a diagnosis of EED was arrived at and the patient's blood was sent for estimation of serum IgA level which was 11.3 g/l (normal, 0.7-4). The patient was treated with oral dapsone 100 mg/day. After two weeks period, majority of the lesions resolved. But the patient developed hypersensitivity reaction to dapsone and the drug was withdrawn. After four weeks, colchicine 0.5 mg twice daily was given in place of dapsone. The response was slow and smaller lesions regressed, while larger lesions are in the process of regression. As the patient has low CD4+ count inspite of being on ART since seven years, she was referred to the nearest ART–plus centre for second line therapy. The second line therapy (atazanavir-based) was started in the month of November 2012.

Figure 3

Ribbon like thickening of collagen and several interstitially scattered neutrophils and few eosinophils (H and E, ×100)

Figure 4

Neutrophils and neutrophilic nuclear dust, few eosinophils surrounding affected blood vessels with surrounding ribbon like collagen (H and E, ×400)

Discussion

EED is a rare, chronic vasculitis of unknown etiology that promotes tissue fibrosis. It is mediated by immune complexes (Arthus type reaction) and has been associated with auto immune, neoplastic and infectious processes.[1] In addition, EED has been associated with hypergammaglobulinemia, IgA monoclonal gammopathies,[11] as well as with myelodysplasia, pyoderma gangrenosum, and relapsing polychondritis.

The nodular variant of EED is even rarer, but it evolves most often in HIV-positive individuals. The nodular lesions closely resemble Kaposi's sarcoma and bacillary angiomatosis and careful histopathological examination would differentiate these conditions from one another.[10] A thorough literature search revealed an association of 20-25 cases of EED with HIV disease.[234567891012] To the best of our knowledge, our case is the first case of nodular EED simulating Kaposi's sarcoma associated with HIV infection in Indian literature. It is now recognized as one of the defined reactive dermatosis associated with HIV.[1] In majority of cases including ours, EED lesions were seen in patients with low CD4+ counts (<200). But, in some cases, EED was reported as a first clinical manifestation of HIV infection.[4] Recently, a case of erosive and bullous EED in HIV-positive patient was also reported.[2] A rare case of EED with polyclonal gamma-globulinemia with HIV-2 infection was also reported in 1996.[12]

The association of EED with HIV infection is not clearly known, but it may be due to either HIV-related antigen-antibody complexes directly damaging the small blood vessels or the HIV-induced immunosuppressed state allowing other infectious agents to serve as an antigenic stimulus.[4610] In addition, EED has been associated with IgA hypergammopathy,[11] which is also a common finding in the HIV infection.[3] Since, in our case also IgA levels were elevated, we presume that IgA hypergammopathy may act as a trigger and promote chronic vasculitis with HIV background.

Although dapsone is the drug of choice, it is not very effective in older fibrotic nodular lesions in HIV-related EED. Intralesional and topical steroids, colchicine, chloroquine, tetracycline, and niacinamide also may be tried.[12] The course of the EED is chronic and benign and the lesions persist for a long time. Systemic complications are rare.

Disseminated skin nodules in HIV-infected patients may belong to a wide spectrum of tumours, ranging from the common appearance of Kaposi's sarcoma, bacillary angiomatosis, xanthomas, lymphomas to the very rare occurrence of benign nodular EED. Our case raises the necessity of histopathological confirmation for all cases of suspected Kaposi's sarcoma and other tumours in patients with HIV background.

What is new?

Nodular EED can be considered as a new cutaneous marker of HIV infection.