: Professor G Narsimulu, Prof and Head, Department of Rheumatology, Nizam's Institute of Medical Sciences, Panjagutta, Hyderabad 500 082, Andhra Pradesh, India. Email: firstname.lastname@example.org
One of the rare causes of secondary vasculitides is malignancy. Hematological malignancies produce secondary vasculitis more frequently than solid malignancies. Here in we report a case of acute myeloid leukemia presenting with anti-neutrophil cytoplasmic antibody-positive vasculitis. This case highlights the importance of looking for underlying malignancies, especially leukemias in patients presenting with features of systemic vasculitides.
Systemic vasculitides can be divided into primary and secondary. Primary systemic vasculitides are heterogeneous multisystem disorders of unknown aetiology characterized by inflammation and necrosis of small, medium or large-sized blood vessels.1 Secondary vasculitides can occur due to infections, allergy, rheumatologic and/or autoimmune diseases, drugs or rarely malignancies. Hematological malignancies produce secondary vasculitis more frequently than solid malignancies.2 The common hematologic malignancies associated with secondary vasculitis include myelodysplastic syndrome, lymphomas, and hairy cell leukemia. Most of the time they are anti-neutrophil cytoplasmic antibody (ANCA)-negative.2 Herein we report a case of acute myeloid leukemia presenting with ANCA-positive secondary vasculitis.
A 38-year-old woman presented to us with history of irregular fever and polyarthritis of 2 months duration. She also had erythematous, maculopapular skin lesions over both legs associated with pruritus. Ten days prior to presentation, similar lesions also appeared in the trunk and upper limbs. She was a known asthmatic for the last year, for which she was using salbutamol inhalers as and when needed. There was no history of using leukotriene antagonists for the bronchial asthma.
On examination, she had mild pallor. Erythematous maculopapular lesions were seen on the legs, thighs, back as well as on the neck (Fig. 1). Musculoskeletal examination revealed mild tenderness of left ankle, wrist and metacarpophalangeal joints. There was no bony tenderness, lymphadenopathy, or bleeding tendencies. She also had tingling and impaired sensation on the ulnar aspect of the left forearm and medial two fingers. In view of the history of bronchial asthma, cutaneous lesions, and ulnar neuropathy, an initial diagnostic possibility of Churg-Strauss syndrome was considered.
On investigation, she had anemia with hemoglobin (Hb) 8.7 g/dL. The total leucocyte count was 5.9 × 109/L with a differential count showing neutrophils 63%, lymphocytes 27%, monocytes 4% and eosinophils 1% and atypical cells 5%. Her platelet count was 23 × 10 (E9)/L (ref. range 150–400 × 10 (E9)/L)3 and the erythrocyte sedimentation rate (ESR) was 88 mm/h. The peripheral smear showed normal count and normal differential with 5% atypical cells. Complete urine analysis was normal. Her antinuclear antibody (ANA) test was negative, ANCA by indirect immunofluroscence was positive, showing a perinuclear pattern (pANCA); antimyeloperoxidase antibody (MPO) was positive at 3.0 (> 1.1 positive). Antiproteinase 3 (PR3) was negative. Serology for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV), and human immunodeficiency virus (HIV) were negative. Her serum was negative for cryoglobulins. Serum immunoglobulin E (IgE) was within normal limits (200 IU/mL). Blood and urine culture were sterile and the chest X-ray was normal. Her renal function and liver function tests were within normal limits.
A skin biopsy was done from a lesion on the trunk. The histopathological section showed skin tissue with normal epidermis. Lymphomononuclear infiltrates were seen around the blood vessels in the dermis. Two vessels also showed neutrophilic infiltrates. Immunofluroscence was negative. The features were consistent with leukocytoclastic vasculitis. In view of the anemia and the atypical cells reported in the peripheral smear, a bone marrow aspiration biopsy was done. The peripheral blood and marrow cytological features were suggestive of acute myeloblastic leukemia with maturation (AML-M2 type). She was started on prednisolone 0.5 mg/kg in view of her joint symptoms and vasculitic rash, to which she responded very well. She was subsequently transferred to medical oncology for the treatment of AML.
The patient presented with certain features (prolonged fever, weight loss, arthritis, cutaneous purpura, ulnar neuropathy and history of bronchial asthma) which initially made us consider the clinical possibility of a systemic small vessel vasculitis. ANCA by indirect immunofluroscence and anti-MPO by enzyme-linked immunosorbent assay (ELISA) were found to be positive. A deep skin biopsy revealed leukocytoclastic vasculitis. The unexplained anemia with prolonged pyrexia and atypical cells in the peripheral smear were the reasons for doing a bone marrow biopsy which clenched the diagnosis. Apart from anemia she did not have any other features to suggest leukemia at the time of presentation.
The association between malignancies and vasculitis is rare. The reported frequency is 2.3%–8.0% of patients.3,4 The vasculitides that have been described in relation to malignancy are leukocytoclastic vasculitis (45%), polyarteritis nodosa (36.7%), Wegener's granulomatosis, microscopic polyangitis, and Henoch–Schönlein purpura.2 The most common clinical vasculitic manifestation is cutaneous vasculitis without systemic involvement.
The relation between the two conditions is interesting. Vasculitis may appear after the onset of malignancy, at the time of diagnosis of the malignancy, or it may precede the neoplasm. What actually predisposes to vasculitis in malignancies is not very clear. In the setting of malignancy, it is believed that persistent antigen stimulation from the tumour results in T-cell activation or immune complex formation and deposition. Other mechanisms of vasculitis associated with malignancy are polyclonal activation of B lymphocytes, monoclonal immunoglobulin activity, antibodies directed toward endothelial antigens, direct effect of the malignancy on the vascular wall, or adverse reactions to anticancer treatment.5,6 In one study, infections, drug reactions, or cryoglobulins were found to be responsible for 39% of patients who developed cutaneous vasculitis during the course of hematological malignancies.7
The relationship between malignancy and vasculitis is bidirectional. Cancer appears more like a vasculitis-triggering factor.2 The malignancy rate in patients with small vessel vasculitis has also been found to be higher than that of a normal age-matched general population.8 The outcome of the two diseases are not strictly chronologically parallel.
In a study of 65 malignancies associated with vasculitides, Fein etal. found hematologic (myelodysplastic syndrome [32.3%], lymphomas [29.2%], chronic lymphocytic leukemia [6.2%]) and solid tumours (36.9%) as the important causes.2 Acute myeloid leukemia was not found to be a cause of vasculitis in this cohort. However, there are few reports of an association between acute myeloid leukemia and vaculitis in the literature. Bourantas etal. described three patients presenting with skin vasculitis as the initial clinical manifestation in whom a diagnosis of acute myelomonocytic leukemia was subsequently established by peripheral blood smear and bone marrow aspirate examinations.9
In the studies by Longley etal.,10 Greer etal.,11 and Beylot etal.12 describing 25 patients with either lympho- or myeloproliferative diseases associated with cutaneous vasculitis, only five patients had acute myelogenous leukemia (4 patients had acute myelogenous leukemia that was not further specified and one patient had acute myeloblastic leukemia). In general, vasculitides associated with malignancy have poor response to conventional therapy directed against the vasculitides.
Case reports and small series have found ANCA-positive and ANCA-negative vasculitis associated with hematological malignancies.7 Hamidou etal. studied the prevalence of ANCA and rheumatic manifestations in chronic hematological malignancies and found that in a group of lymphoid malignancies (n = 140) six patients were ANCA-positive with perinuclear pattern in four cases, atypical pattern in one and cytoplasmic pattern in one. Two sera had anti-MPO specificity, and others had no known specificity; none had anti-proteinase 3 (PR3) specificity. No correlation was shown between vasculitis and the activity of the hematological disorder, transfusion frequency, treatments or infectious events. They found no relationship between vasculitis, ANCA or cytogenetic abnormalities.13
It was Savige etal. who first investigated ANCA in hematological malignancies. In a study of 25 patients, one patient with AML secondary to myelodysplastic syndrome had pANCA without any known specificity on ELISA.14 ANCA probably occurs secondary to immune dysregulation in myelodysplastic syndromes and lymphoproliferative conditions and they are not necessarily associated with the presence of vasculitis.14
Skin involvement in acute myeloid leukemia includes three types of lesions: non-specific, leukemic cutis, and granulocytic sarcoma.15,16 Non-leukemic skin vasculitis in patients with acute myeloid leukemia has rarely been reported. In vasculitides, the basic histopathologic characteristic is inflammatory changes in vessel walls. The inflammatory infiltrate can be predominantly neutrophilic (usually accompanied by leukocytoclasis), lymphocytic, or granulomatous. Necrotizing changes (usually of fibrinoid type) of the vessel wall may be present or absent. The differential diagnoses in our case include leukemia cutis, drug eruptions, and various infectious processes. However, the skin biopsy of our patient did not show any evidence of leukemic infiltrates. There was no history of any new drug intake and the lesions also were not suggestive of drug rash. There was also no evidence of skin infections.
Cutaneous vasculitis may follow, accompany or precede hematologic malignancy. The present case highlights the importance of looking for underlying malignancies, especially leukemias in patients presenting with features of systemic vasculitides.