Cutaneous Vasculitis as the Initial Manifestation in Acute Myelomonocytic Leukemia

Methods

Three patients, 2 women and 1 man, were hospitalized with symptoms of skin lesions affecting primarily the lower extremities. They had complete physical examinations; routine laboratory tests; urinalysis; blood and urine cultures; chest roentgenograms; tuberculin skin tests; and immunology tests, including rheumatoid factor, antinuclear antibodies, antibodies to extractable nuclear antigens, antineutrophil cytoplasmic antibodies, cryoglobulins, and complement levels (C₃, C₄). In addition, skin biopsy specimens, blood smears, and bone marrow aspirates were obtained from all patients.

Patient 1

A 30-year-old man, with Down syndrome, was hospitalized on June 1990 because of skin rash and low-grade fever. In November 1989, he had low-grade fever and skin rash affecting primarily the lower extremities. His past medical history was unremarkable. His temperature was 37.8 °C, and he had necrotic skin lesions affecting the lower extremities Figure 1 and forearms. Other test results were negative. The laboratory evaluation showed the following: hemoglobin, 102 g/L; leukocyte count, 6.5 × 10⁹/L; and platelet count, 30 × 10⁹/L. Other laboratory and immunologic test results were negative or within normal limits.

A skin biopsy specimen was obtained, and histologic examination showed a moderately intense inflammatory infiltrate predominantly around capillaries and small vessels of the dermis (Figure 2). The infiltrate consisted mainly of neutrophils, many eosinophils, and a few mononuclear cells. Swelling of endothelial cells and fibrinoid degeneration of vascular walls were also observed. The diagnosis was consistent with leukocytoclastic vasculitis (Figure 2). Test results from peripheral blood smear and bone marrow examinations showed acute myelomonocytic leukemia. Chemotherapy with idarubicin and cytosine arabinoside was started; the patient had a complete clinical remission, and the skin lesions disappeared.

Patient 2

A 30-year-old woman was hospitalized with symptoms of skin rash, arthralgias, and myalgias that occurred 2 months earlier. Peripheral blood smear and bone marrow examinations showed acute myelomonocytic leukemia. A skin biopsy specimen showed a histologic picture compatible with leukocytoclastic vasculitis. She was treated with idarubicin and cytosine arabinoside; she had a complete clinical response, and the skin lesions resolved.

Patient 3

A 29-year-old woman was hospitalized with symptoms of skin rash and nonproductive cough. The skin biopsy specimen showed a typical histologic pattern of leukocytoclastic vasculitis. Peripheral blood smear and bone marrow examinations showed acute myelomonocytic leukemia. She was treated successfully with idarubicin, cytosine arabinoside, and prednisone.

Discussion

Small-vessel vasculitis involving predominantly the skin belongs to the hypersensitivity group of vasculitides. It can be a distinct clinicopathologic syndrome or can be associated with many diverse processes, such as infectious, autoimmune diseases, cryoglobulinemia, neoplastic diseases, drug-induced conditions, or other nosologic entities. Clinically, the cutaneous lesions are mainly characterized by palpable purpura and maculopapular eruptions. Other dermatologic manifestations include urticarial and petechial lesions and ulcers. The lesions have a histopathologic characteristic of necrotizing leukocytoclastic inflammation affecting primarily post-capillary venules and, less frequently, capillaries and arterioles, usually within the superficial dermis [1, 2].

Patients with malignant neoplasia may have symptoms related to the tumor itself or its metastases or may have symptoms and signs related to a paraneoplastic disorder, such as polymyalgia rheumatica, dermatomyositis, and vasculitis [14, 15]. Cutaneous and systemic vasculitis can be associated with malignant disorders. They may appear before the discovery of the neoplasia, simultaneously, or after its diagnosis [8-11]; however, none of these possibilities seems to make the prognosis worse.

Among malignant diseases, a statistically significant association between cutaneous vasculitis and lympho- or myeloproliferative malignancies was noted, when compared with solid tumors [10]; the reason for this association is unknown. Hairy cell leukemia seems to correlate more frequently with vasculitis and especially with the polyarteritis nodosa type of vasculitis [6, 7]. Other hematologic malignancies associated with paraneoplastic cutaneous vasculitis include chronic lymphocytic leukemias, B- or T-cell lymphomas, Hodgkin disease, multiple myeloma, and chronic or acute myelogenous leukemias.

We have described three patients who were hospitalized because of cutaneous vasculitis. The patients did not have polyarteritis nodosa, Wegener granulomatosis, mixed cryoglobulinemia, systemic lupus erythematosus, or other connective tissue disorders. None of our patients had septicemia or tuberculosis, and none was taking medication, such as antibiotics or diuretics, that are known to cause hypersensitive vasculitis.

Skin biopsy specimens from affected areas showed leukocytoclastic vasculitis. In all of our patients, cutaneous vasculitis preceded the diagnosis of acute myelomonocytic leukemia by an interval ranging from 2 to 8 months. We found that all patients had acute myelomonocytic leukemia and that cutaneous vasculitis was the initial manifestation of the disorder.

Paraneoplastic small-vessel vasculitis associated with acute myelogenous leukemia has been rarely reported. After reviewing the literature by Longley and colleagues [9], Greer and colleagues [10], and Beylot and colleagues [11] describing 25 patients with either lympho- or myeloproliferative diseases associated with cutaneous vasculitis or arthritis (or both), only 5 patients had acute myelogenous leukemia (4 patients had acute myelogenous leukemia that was not further specified and 1 patient had acute myeloblastic leukemia). Another patient had granulocytic sarcoma.

The specific immunologic or inflammatory events mediating vasculitis in these patients remain speculative, and several possible pathogenic mechanisms have been postulated. Tumor-associated antigens may play a key role in mediating vascular damage, either directly or indirectly through 1) formation of immune complexes of tumor-associated antigens/antibodies [16]; 2) a direct vascular lesion by antibodies directed against leukemic cells cross-reacting with endothelial cells [17]; and 3) a direct effect of leukemic cells on the vascular wall [18]. However, conclusive data are lacking because abnormal levels of immunoglobulins affecting humoral immunity or circulating immune complexes, abnormal activation of complement, or abnormal use of complement components was identified neither in our patients nor in patients described in the literature [10]. Also, abnormal levels of cells involved in cell-mediated immunity were not found in our patients.

Paraneoplastic vasculitides are usually restricted to the skin, but systemic involvement may be also found in some patients [8-11]. The prognosis of systemic vasculitis was very poor until the introduction of cyclophosphamide therapy [19, 20]. Patients with paraneoplastic vasculitis do not necessarily have a bad prognosis. Specific treatment of the underlying disease with or without steroids may yield an excellent response [8]. In two of our patients, skin lesions disappeared after the first cycle of chemotherapy, although in the third patient, they disappeared after introduction of corticosteroids. In contrast, other investigators have reported that oral corticosteroids or chemotherapy for the underlying disorder inconsistently affected the clinical course of cutaneous vasculitis, and recurrence of skin vasculitis was not prevented. The course of vasculitis appeared to lessen in severity as bone marrow function deteriorated [10, 11].

Our results suggest that patients with acute myelomonocytic leukemia can present with skin vasculitis as the initial manifestation. Patients with unexplainable or persistent small-vessel vasculitic syndromes should be studied carefully because of the possibility of vasculitis caused by a malignant disorder.