Cyclic Autoimmune Hemolytic Anemia as a Presenting Manifestation of Splenic Hodgkin ’s Disease

MAGNUS BJORKHOLM. MD,’ GORAN HOLM, MD,t AND KARL MERK, MD’

The case report of a 52-year-old woman with an eight-year history of cyclic autoimmune hemolytic anemia and progressive splenic enlargement is presented. At laparotomy the enlarged spleen and splenic hilar lymph nodes showed lymphocyte-predominant Hodgkin’s disease. No specific antitumor treatment was given and three years following splenectomy the patient is in excellent health and has not experienced any new hemolytic episodes. The patient illustrates the association between Hodgkin’s disease and autoimmune hemolytic anemia as well as the extreme variation in the clinical picture of the disease.

Cancer 49:1702-1704, 1982.

NEMIA is a common manifestation of Hodgkin’s A disease (HD) . A mild to moderate anemia is found in 25-50% of the patients when first e~arn ined .~ . ’ The major defect is usually insufficient erythrocyte pro- duction, even in cases without apparent bone marrow i n v ~ l v e m e n t . ~ ~ ~ However, shortened erythrocyte survival can also be seen, particularly in advanced Erythrocyte destruction in the spleen may be increased even in the absence of splenic tumor involvement and can be treated successfully by splenectomy.’

Overt autoimmune hemolytic anemia is rare in HD but common in B-cell lymphoproliferative disease^.^.^ W e report a patient with an eight-year history of cyclic Coombs’-positive autoimmune anemia in whom spleno- megaly eventually developed. Exploratory laparotomy with splenectomy revealed Stage IIs+ A HD. No spe- cific antitumor treatment was given. Three years fol- lowing splenectomy the patient is in excellent health with no signs of autoimmune hemolytic anemia or HD.

Case Report

The patient, a previously healthy 41 -year-old housewife, was seen in 1970 with pallor and fatigue. Her mother died at the age of 70 from histiocytic lymphoma.

The patient’s illness started one week before admission; for a few days she complained of pyrexia and a sore throat. She was in a good nutritional state but showed marked pallor and slight icterus. There was no abdominal masses and no enlarged

From the *Department of Medicine, Danderyd’s Hospital, Dan- deryd, Sweden; and the TDepartment of Clinical Immunology, Hud- dinge Hospital, Huddinge, Stockholm, Sweden.

Address for reprints: Magnus Bjorkholm, MD, Department of Medicine, Danderyd‘s Hospital, S-182 88 Danderyd, Sweden.

Accepted for publication February 16, 198 1.

lymph nodes. Laboratory investigation revealed: hemoglobin 62 g/liter; reticulocytes 47%; platelets 117 X 109/liter; leu- kocyte count 7.8 X 109/liter with a normal differential count; erythrocyte sedimentation rate 95 mm/l hour and serum bil- irubin 42 pmol/liter (normal range, 3.4-2 l pmol/liter) with 10 pmol/liter unconjugated. The results of direct and indirect Coombs’ tests were negative. Serum iron was 8.2 pmol/liter (normal range, 14.0-32.0 pmollliter). A bone marrow aspirate showed marked normoblastic hyperplasia, abundant mega- caryocytes, and subnormal iron stores. Iron injections were given. The patient eventually recovered with normalization of blood counts.

One year later she entered a new severe episode of hemolytic anemia with a negative direct Coombs’ test. Again no specific treatment was given and the hemolysis remitted sponta- neously. In May 1972 after an upper respiratory tract infection a Coombs’-positive hemolytic crisis developed. The spleen was now palpable 2 cm below the left costal margin. Corticosteroid treatment induced a prompt clinical remission with normali- zation of laboratory tests, including a negative Coombs’ test. During the years 1973-1976 six new episodes of autoimmune hemolytic anemia were documented and easily controlled with corticosteroids. However, progressive splenomegaly and a need for continuous corticosteroid treatment to control hemolysis necessitated that the patient be referred to the hematology unit at the Seraphimer Hospital in 1978.

On examination the spleen was grossly enlarged (7 cm below the left costal margin). The patient was on prednisolone (10 mg/day). The Hb was 103 g/liter; leukocyte count 38.8 X lo9/ liter; platelets 176 X 109/liter; reticulocytes 2.4%; serum bil- irubin 23 pmol/liter; and haptoglobin 0.3 g/liter (normal range, 0.3- 1.6 g/liter). Glucose-6-phosphatase reactivity, os- motic fragility, and Ham’s test were normal. Sternal bone marrow showed pronounced erythropoietic and myelopoietic hyperplasia with a normal leukocyte alkaline phosphatase score. Blood volume (‘3’I-albumin) was 4.5 liters (normal range, 4.8-5.8 liters) and total Hb 419.5 g (normal range, 530-650 g). Serum electrophoresis revealed a haptoglobin

0008-543X/82/0415/1702 $0.65 0 American Cancer Society

1702

No. 8 AUTOIMMUNE ANEMIA IN H D - Bjorkholm et al. 1703

FIG. 1. High-power view of a section of the spleen showing a Sternberg-Reed cell surrounded by lymphocytes and a few eosinophils. The his- topathology is consistent with Hodgkin's disease, lymphocyte predominant ( H & E, X700).

value alf 0.25 g/liter but was otherwise normal. A direct Coombs' test was negative.

Later the direct antiglobulin test of the patient's washed erythrocytes became strongly positive. The cells were coated with IgG and C3b. N o cold agglutinins were identified. The patient's blood group was 0 Rh+. Test for autoantibodies against nuclear, thyroid, smooth-muscle and kidney antigens, and mitochondria were negative. No cryoglobulins were found.

Erythrocyte survival was studied using autologous "Cr- chromate-labeled erythrocytes suspended in autologous plasma before injections. External measurements gave a spleen-liver ratio of 3.2 (normal, 1.5). The mean survival time of eryth- rocytes was 38 days.

Radiologic examinations of the chest and gastrointestinal tract showed no abnormalities. An abdominal radiogram con- firmed 1.he splenic enlargement. Liver radiographs and scans showed no abnormalities; a bipedal lymphangiography was the same.

The patient's purified blood lymphocytes had a moderately decreased in vitro reponse to stimulation with mitogens (Con- canavalrn A and pokeweed mitogen) and antigen (PPD). The spontanleous lymphocyte D N A synthesis was not i n ~ r e a s e d . ~

These investigations indicated an increased erythrocyte de- struction in the spleen. Splenectomy was performed in January 1979; the spleen was enlarged (1050 g). Abnormal splenic hilar lymph nodes were found. A nodular pattern of tumor infiltration was observed on the surface of the spleen. Mi- croscopy showed diffuse infiltration of lymphoctes with very few neutrophilic granulocytes and plasmocytes. There were occasional eosinophilic granulocytes and Reed-Sternberg cells; the picture was of lymphocyte-predominant HD (Fig 1). Biop- sies of the splenic hilar lymph nodes also revealed lymphocyte- predominant HD. Biopsies from para-aortic nodes and the liver were normal. The pathologic stage was therefore IIs+ A. Because all tumor mass seemed to be removed no specific treatment was given.

After operation the patient recovered; the anemia was cor-

rected and the antiglobulin reaction became negative. For a period the patient was on salicylates to treat postsplenectomy thrombocythemia. Now, almost three years following sple- nectomy, she remains in excellent health without medication.

Discussion

Anemia is often a prominent feature of H D at di- agnosis and in almost all cases during the course of the disease.6*8.'0 A shortened erythrocyte survival is caused mainly by increased sequestration in the spleen but other mechanisms can contribute, particularly in gen- eralized disease.I4 Adult autoimmune hemolytic anemia of warm type is frequently associated with malignancy, in particular chronic lymphocytic leukemia and non- Hodgkin's lymphoma^.^*'^ However, overt hemolysis with a positive Coombs' test is uncommon in HD. Eisner et u I . ~ observed a positive Coombs' test in five of 210 HD patients (2.7%). In none of these patients, however, did the discovery of a positive antiglobulin reaction or overt hemolysis antedate the diagnosis of lymphoma. Severe hemolysis long before the appearance of other manifestations of H D rarely has been f ~ u n d . ~ - " * ' ~ * ' ~ Bowdler and Glick' described a patient with a three- year interval between the onset of autoimmune hemo- lytic anemia and the first H D manifestation. The pa- tient underwent splenectomy early because of increased erythrocyte destruction in the enlarged spleen; micro- scopic examination of the spleen did not show any signs of lymphoma

The history of our patient had some features of par- ticular interest. When referred to our unit she had an eight-year history of cyclic autoimmune hemolytic anemia with progressive enlargement of the spleen.

1704 CANCER April I5 1982 Vol. 49

Though most hemolytic episodes were associated with upper respiratory tract infections, the underlying dis- ease was not revealed until exploratory laparotomy with splenectomy was performed. The histology of the en- larged spleen and splenic hilar lymph nodes was HD of lymphocyte-predominance type. Because no further hemolytic episodes have appeared during a three-year period following splenectomy without further tumor treatment, a linkage between the autoimmune hemo- lytic anemia and HD seems very likely. The decision not to give radiotherapy was further supported by the finding of preserved T-cell functions in witro, which is intimately associated with a good prognosis in HD.’

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