Thymoma associated with pancytopenia and hypogammaglobulinemia

Thymoma

Associated

with Pancytopenia

and Hypogammaglobulinemia* Report of a Case and Review of the Literature BERTRAM

H.

G. ROGERS,

M.D., JOSE R.

MANALIGOD,

M.D. and WILLIAM

V. BLAZEK,

M.D.t

Chicago, Illinois In the patient here described a thymoma, hematopoietic insufficiency, hypogammaglobulinemia and antinuclear antibodies were present. The association of hypogammaglobulinemia and positive antinuclear antibodies with thymoma is cited as evidence of autoimmune disease. The reported cases of thymic tumor and hematopoietic insufficiency are reviewed.

T

of thymic tumor with hematopoietic insufficiency has been recognized with increasing frequency during recent years. The most recent comprehensive review was published by Dreyfus et al. in 1963 [ 71. Although the mechanism(s) involved are uncertain, it seems probable that there is a causal relationship between the two; removal of the tumor has resulted in amelioration or apparent cure of the hematologic deficit in fifteen of the sixty-one reported cases. This case concerns a patient who had a thymoma, pancytopenia, hypogammaglobulinemia and features of autoimmune disease. Because of the great interest in thymic function and especially in the relationship of the thymus to the development of immune mechanisms, we have reviewed the data in all the recorded cases of thymic tumor with hematopoietic insufficiency, looking for evidence of immunologic dysfunction.

included a recent hospitalization for similar complaints. During this hospitalization a bone marrow aspirate showed “fatty marrow.” A roentgenogram of the chest showed a mediastinal tumor. There was no recent history of antibiotic or drug ingestion, other than a daily vitamin tablet, and no known exposure to benzene-containing compounds, cleaning solution or radiation. The patient had had a 30 pound weight loss over the three years prior to her admission. Physical examination revealed an elderly woman with generalized petechial and ecchymotic hemorrhages. The pulse was 84, blood pressure 95 mm. Hg systolic and 55 mm. Hg diastolic, temperature 100.8”~., and respirations 28 per minute. There were two flame-shaped hemorrhages in the left fundus. There was a necrotic ulcerating lesion in the right tonsilar area with associated firm, tender, enlarged anterior cervical lymph nodes. The lungs were clear. No abdominal organomegaly or masses were found. No muscle weakness could be demonstrated. Rectal examination revealed black feces which were strongly positive for blood.

HE ASSOCIATION

The hematocrit was 24 per cent, the hemoglobin 7.4 gm. per cent; the red blood cells were 2.79 million per cu. mm. and the white blood cells 2,450 cells of 32 per cent per cu. mm., with a differential neutrophils, 65 per cent lymphocytes and 3 per cent monocytes. The platelet count was 2,400 per cu. mm. The bleeding time test gave no end point at fortythree minutes. The clotting time was twelve minutes

CASE REPORT This sixty year old housewife of Italian extraction (R.C. No. 545124) presented with petechial hemorrhages of three months’ duration, and sore throat and gingival bleeding of about two weeks’ duration. She had noted hematuria on the day of admission. There was no family history of hematologic or immunologic diseases. The patient’s past history

with poor retraction. The prothrombin time was 79 per cent of the control. The direct and indirect

* From the Department of Medicine and the Department of Pathology, The University of Illinois Research and Educational Hospitals, Chicago, Illinois 60612. Requests for reprints should be addressed to Bertram H. G. Rogers, M.D., 180 East Delaware Place, Chicago, Illinois 60611. Manuscript received December 12, 1966. t Present address: Glen View, Illinois. 154

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test was negative.

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was A, Rh

et nl.

155

l‘estosterone therapy was discontinued on the fifteenth hospital day. By the eighteenth day the dosage of prednisone had been reduced gradually to 45 mg. per day. The patient was maintained on this dose for one month. On the fiftieth hospital day, and thirty-eight days after removal of the tumor, the patient had not shown any hematologic response. The dose of prednisone was then increased to its former level of 2 mg. per kg. (115 mg. per day). There was no change in the pancytopenia during the three weeks at this dosage level.

monocytes and 1 per cent band forms. ‘The white blood cell count remained abnormally low and the differential showed up to 90 per cent lymphocytes. Five weeks after surgery the white blood cell count was 1,700 per cu. mm., with a differential of 90 per cent lymphocytes, 8 per cent monocytes and 2 per cent neutrophils. The platelet count remained low. A Cushingoid appearance and diabetes developed; the latter was controlled with diet and tolbutamide administration. After ten weeks of hospitalization, the patient was discharged to be followed in the hematology clinic. She was readmitted to the hospital five clays later because of a cough productive of bloody and purulent sputum. On readmission the white blood cell count was 2,400 per cu. mm. The hematocrit was 18 per cent. Her temperature rose to 104’F. She became hypotensive and died on the day of admission. A culture of the lung autospy showed many Escherichia coli, a few micrococci (coagulase-negative), geotrichum, Pseudomonas aeruginosa and Klebsiella. The specimen obtained from the anterior mediastinum at the time of thoracotomy consisted of thymic tissue, deformed near one edge by an intrathymic tumor. The entire specimen measured 10 by 4 by 2 cm. and weighed 49 gm. The tumor mass was discrete and spherical and measured 4.5 by 3.5 by 2 cm. On cut section it had a fibrous capsule 2 to 3 mm. in thickness. The more central portions of the tumor were soft and lobulated by deep clefts. In other areas! lobules were separated by dense fibrous septums. Histologically, the tumor was divided into lobules by dense bands of fibrous tissue. The lobules predominantly contained densely packed epithelial cells with scanty and poorly defined cytoplasm and spindle shaped, hyperchromatic nuclei with prominent nucleoli (Fig. 1). Occasionally, the nuclei were larger, ovoid and pale staining (Fig. 2). Rare mitotic figures were present. Scattered among the spindle cells were few lymphocytes. A pseudoacinar or cribriform pattern was evident in some areas (Fig. 3). Spaces were lined by epithelial cells and contained few lymphocytes and fluid. Frequently, the spaces also showed the cross section of thin endothelial rings as described by Castleman [Z] (Fig. 4). Hassall’s corpuscles and germinal centers were not seen. The tumor was classified as a spindle cell thymoma. The intact thymus was replaced by abundant fat and only focal collections of lymphocytes were seen. At autopsy, the area of thymomectomy was firm and fibrous. The mediastinum was not abnormally shifted. There was no evidence of the thymus gland or of residual tumor on histologic examination of the mediastinal soft tissues.

The day after surgery the patient’s white blood cell count was 2,800 per cu. mm., with 30 per cent neutrophils, 68 per cent lymphocytes, 1 per cent

Histologically, the bone marrow was markedly hypocellular and replaced by abundant fat. There was a scattering of small groups of hemocytoblasts and

positive.

Three

bone

marrow

aspirations

were

performed as well as a Turkel biopsy. In all instances the marrow was markedly hypocellular. Marrow supporting cells, occasional plasma cells and lymphocytes were seen. Fecal urobilinogen was within normal limits at 80 Erhlich units per 100 gm. The fasting blood sugar was 122 mg. per cent. The blood urea nitrogen, creatinine, uric acid and total bilirubin values were within normal limits. Roentgenographic examination of the chest revealed a mass in the right anterior mediastinum. On fluoroscopic examination the mass was not pulsatile nor did it move with deglutition. Serum protein electrophoresis revealed marked hypogammaglobulinemia. The serum total proteins were 6.0 gm. per cent. The distribution was 65.8 per cent albumin, 4.1 per cent alphar, 11.4 per cent alphas, 10.7 per cent beta and 8.1 per cent gamma globulin. Three subsequent determinations gave similar results. The speckled-antigen qualitative test for antinuclear antibodies was positive. A lupus erythematosus preparation was negative. The Kahn and Wassermann tests were negative as was the Jolly electrical stimulation test for myasthenia gravis. An intermediate purified protein derivative and histoplasmin skin tests were applied on the third hospital day and found to be negative on the fifth hospital day. Beginning on the second hospital day the patient was given prednisone, 2 mg. per kilo per day, and testosterone propionate, 150 mg. per day. After an infusion of 2 units of fresh blood the hematuria and gingival bleeding ceased but petechial and ecchymotic hemorrhages persisted throughout the patient’s hospitalization. During her illness she required blood transfusions every two weeks to keep her hemoglobin between 9 and 10 gm. per cent. The tonsillitis responded promptly to oral penicillin therapy. On the twelfth hospital day the patient was taken to surgery and the entire mediastinal tumor was successfully removed. Recovery from the thoracotomy was uneventful. The tumor was found to be a well encapsulated, benign, spindle cell thymoma.

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FIG. 2. Large plump epithelioid cells such as these were noted in only a few scattered areas of the tumor.

FIG. 1. Densely packed spindle shaped epithelial cells, the most prominent cell type seen in the thymoma.

myelocytes. Normoblasts were absent but cells that could be classified as polychromatophil erythroblasts were present. Plasma cells and megakaryocytes were rare. Occasional small lymphocytes were present, some of which appeared in fairly large clumps. The spleen weighed 150 gm. The white pulp was diminished. The red pulp was markedly congested. No germinal centers or plasma cells were seen. Lymph nodes taken from the mediastinum and elsewhere contained decreased numbers of lymphocytes. Germinal centers were absent. Clumps The lungs showed bilateral pneumonitis. There of bacteria were visible within the alveoli. appeared to be a weak polymorphonucIear response. REVIEW We and

were

literature. are

able

hematopoietic These

summarized

given

to searching

OI; THE LITERATURE to find

sixty

cases

insufficiency cases, herein.

along Special

for evidence

of thymoma in

with

the our

attention

et al.

world case, was

of immunologic

dysfunction. CAsE 1. A walnut sized spindle cell thymoma was found at autopsy in a sixty-two year old woman who had had pernicious anemia for two years before death [3]. CASE 2. This sixty-seven year old man had refractory anemia and a mediastinal tumor. Between the eighteenth and nineteenth transfusion his blood type apparentIy changed from B to AB. After three years of illness, he was still receiving transfusions and the tumor had not been removed [4]. A twenty year old man presented with a CASE 3. mediastinal tumor that disappeared following x-ray therapy. Four weeks later anemia and neutropenia were noted. After additional radiation therapy, the

anemia and leukopenia became progressively worse and the patient died of an apparently overwhelming infection. At autopsy it was found that the entire thymic tumor had been converted to dense fibrotic tissue and liquefied necrotic material [5]. CASE 4. This f&y-six year old man had a locally invasive thymoma associated with rapidly progressive and fatal pancytopenia. The tumor was composed chiefly of fibrous tissue, with scattered areas of epithelial cells [6]. CASE 5. This fifty-eight year old woman had suffered from refractory anemia and mediastinal tumor for seventeen months before she died. At autopsy the tumor was found to be a lymphoepithelial thymoma [71. CASE 6. In this fifty-eight year old woman refractory anemia developed two years after a mediastinal mass was found. Radiation therapy to the tumor was without hematologic effect, removal of a spindle cell thymoma resulted in apparent cure. Reticulocytosis appeared within a week after surgery. The Kline test, which had been 3+ to 4+, eventually became negative after thymomectomy. The patient died of hemochromatosis one year after surgery [a]. CASE 7. A forty-seven year old man with refractory anemia was cured by removal of a thymoma [Q]. CASE 8. A forty-eight year old man had myasthenia gravis. Later refractory anemia developed. Numerous lymphoid cells in the bone marrow disappeared after removal of a lymphoepithelial thymoma. The anemia responded to both thymomectomy and splenectomy but was followed in each case by relapse. Two years after treatment with ACTH the patient was well, without myasthenia gravis, and taking no medications [ 701. AMERICAN

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FIG. 3. The pseudoacinar or cribriform pattern of spindle cells seen in some sections of tumor. CASE 3. A sixty-two year old woman had x-ray evidence of a mediastinal tumor two years before the onset of refractory anemia. Numerous lymphoid cells in the bone marrow disappeared after removal of a lymphoepithelial thymoma. The mild response of the anemia was accentuated by ACTH therapy but relapse followed. After splenectomy, the administration of ACTH was required to maintain normal erythropoiesis [ 701. CASE 10. A mediastinal mass was found in a forty-four year old woman three years before the onset of refractory anemia. Bone marrow erythroblastopenia and large multinucleated cells were suggestive of Reed-Sternberg cells. An acquired hemolytic anemia developed (Coombs’ test was positive), which was cured by splenectomy (Coombs’ test became negative). A thymic tumor composed primarily of spindle cells was removed without effect on the refractory anemia and the patient died six years later of cardiac failure, agammaglobulinemia, diabetes and sepsis. A diagnosis of Hodgkin’s disease could never be substantiated [ 77,721. CASE 11. A forty-five year old woman had refractory anemia, high serum globulin levels and a spindle cell thymoma. There was no initial response to thymomectomy or to the administration of steroids but four years after surgery her transfusion requirements diminished gradually and erythropoiesis was re-established [ 77, 721. CASE 12. This sixty-two year refractory anemia and myasthenia of a spindle cell thymoma resulted but the patient died of myocarditis the operation [ 731.

old woman had gravis. Removal in reticulocytosis, three weeks after

CAKE 13. In this seventy-six year old woman with refractory anemia, diabetes mellitus and myasthenia thrombocytopenia developed just prior to gravis, VOL.

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FIG. 4. _Ahigh power view showing an endothelial ring. death. found

At

autopsy

a

lymphocytic

thymoma

was

[ 741.

CASE 14. This fifty-three year old man had hypoplastic erythroblastic anemia and thrombocytopenia. There was a transient remission after transfusions. The patient died of an apparent intracranial hemorrhage. At autopsy a cystic thymoma was found [ 751. CASE 15. This woman had myasthenia gravis and severe erythroblastic hypoplasia. Following carotid denervation one year later and without further hematologic treatment the anemia subsided. Eleven years later an anterior mediastinal calcified tumor, thought to be a thymoma, was discovered [ 761. CASE 16. This seventy-seven year old man had “pure” red cell anemia, hypogammaglobulinemia, leukopenia, diarrhea and skin infections associated with a spindle cell thymoma. He died twenty hours after thymomectomy. Autopsy revealed increased numbers of lymphocytes in the bone marrow. The tumor was seen on roentgenograms two years prior to the onset of anemia [ 771. CASE 17. In this sixty-eight year old man, refractory anemia did not respond either to removal of a spindle cell thymoma or to splenectomy. He did respond to androgen therapy and was only slightly anemic one year after it was discontinued. The initial bone marrow examination revealed that twothirds of the leukocytes were lymphocytes whereas a repeat examination during remission disclosed normocellular marrow [ 78-271. CASE 18. In this fifty-eight year old man roentgenograms disclosed a mediastinal mass six years before the onset of refractory anemia, mild thrombocytopenia and lymphocytosis. However, there was no benefit following removal of a spindle cell thymoma. Three months before his death sternal bone marrow examination disclosed marked hypocellu-

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laxity with no normoblasts. Small lymphoid cells were present [ 78,20,27]. CASE 19. In this forty-five year old woman with a four year history of an anterior mediastinal mass, erythroblastic hypoplastic anemia and thrombocytopenia developed. The bone marrow showed large mononuclear cells suggestive of Hodgkin’s disease. She derived no benefit from nitrogen mustard therapy. Leukopenia appeared and a Coombs’ test was positive. Her transfusion requirements decreased after the removal of an enlarged spleen showing lymphoid hyperplasia, hemosiderosis and erythrophagocytosis. Six months after splenectomy a spindle cell thymoma was removed. Again there was less frequent need for transfusions. Six months after thymomectomy the Coombs’ test was only weakly positive and subsequently it became negative. Diabetes mellitus and agammaglobulinemia developed before death. Autopsy disclosed erythroid aplasia, atrophied adrenal glands and hemochromatosis, pituitary acidophile hyperplasia. There was no evidence of Hodgkin’s disease [22]. CAKE 20. A sixty-three year old woman with refractory erythroblastopenia was found to have a mediastinal tumor. The anemia became more severe and six months after its onset she died of bronchopneumonia. Autopsy revealed a benign lymphoepithelial thymoma [23]. CASE 21. In this fifty year old woman with hypertension, a history of myocardial infarction and diabetes mellitus, a mediastinal mass was found four years before the onset of erythroblastic hypoplastic anemia. Eight months after the onset of the anemia she suffered a stroke and died. A lymphocytic thymoma was found at autopsy [24]. CASE 22. In this seventy-three year old woman with pancytopenia, elevated gamma globulin levels and nodular goiter, autopsy examination revealed a spindle cell thymoma and a bone marrow which contained moderate numbers of plasma cells and many lymphocytes [25]. CASE 23. In this fifty-seven year old woman a spindle cell thymoma was removed two years before the onset of refractory anemia. A bone marrow biopsy specimen showed 43 per cent lymphocytes in addition to erythroblastopenia. Four years after the onset of anemia she was being maintained with transfusions. During this time a carcinoma of the breast had been removed [26]. CASE 24. A sixty-four year old woman had refractory anemia which was not relieved by removal of a spindle cell thymoma. No suppression of eythropoiesis was demonstrated when an infusion of the filtered suspension of the tumor was given to a dog [26]. C~sx 25. A seventy year old woman with a mediastinal mass and anemia was given x-ray therapy for

et al.

suspected lymphoma. Leukopenia and thrombocytopenia soon appeared. Autopsy revealed a lymphoepithelial thymoma [27]. CASE 26. In this seventy-eight year old woman with erythroblastic hypoplastic anemia, autopsy disclosed a benign lymphoepithelial thymoma. A low grade scirrhous carcinoma of the breast was also present [27]. This sixty-eight year old man had CASE 27. received 2,020 r to the skin for seborrheic dermatitis over a four year period. Pancytopenia with relative lymphocytosis and generalized hypoplastic bone marrow was associated with a mediastinal mass which proved to be a spindle cell thymoma at autopsy [28]. CASE 28. This fifty-eight year old man had a locally invasive lymphocytic thymoma which had been resected three times during the eighteen years before the development of hypoplastic erythroblastic anemia and mild thrombocytopenia. The anemia was refractory and the patient died of serum hepatitis [29]. CASE 29. In this sixty-four year old woman, hypoplastic erythroblastic anemia was apparently cured by removal of a lymphoepithelial thymoma. A few “abnormal” lymphoid cells were seen in the bone marrow prior to surgery. Three weeks postopertively erythroid activity was normal and the lymphoid cells were no longer evident [29]. CASE 30. In a seventy-three year old woman with “pure” red cell anemia, there was no improvement following thymomectomy [30]. CASE 31. This seventy-one year old woman had refractory anemia which did not respond to thymomectomy. Six weeks postoperatively she showed a good hematologic response to the administration of prednisone. Two months after apparent cure staphylococcal septicemia developed and the patient died. Samples of her plasma given as injections to normal rats did not inhibit erythropoiesis [37]. CAKE 32. In this seventy year old woman a mediastinal mass was found three years before her death. Anemia developed shortly before death. Examination of the bone marrow disclosed marked erythroblastic hypoplasia and many small dense lymphoid cells. The patient died of bronchiectasis and urinary tract infection. A mixed thymoma composed of lymphocytes and spindle cells was found at autopsy [32]. CASE 33. This sixty-six year old woman had erythroblastic hypoplasia and spindle cell thymoma. She died six months after thymomectomy without remission [33]. CASE 34. This forty-eight year old woman had erythroblastic hypoplasia associated with a mediastinal mass which was unresponsive to radiation AMERICAN

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therapy. One year later leukopenia and thrombocytopenia appeared; she died two years later of a respiratory tract infection. Autopsy revealed a spindle cell thymoma [34]. CASE 35. This fifty-eight year old woman had refractory anemia, thrombocytopenia and a mediastinal mass. There was no response to radiation therapy of the mass but the anemia responded rapidly to prednisolone therapy. Six months later, this patient died of pneumonia. At autopsy a cystic hemorrhagic mass circumscribed by fibrous tissue was found [34]. CASE 36. A fifty-five year old woman had erythroblastic hypoplasia and a large anterior mediastinal mass. Bilateral pleural effusions developed but responded to radiation therapy of the tumor which shrunk. In two and a half years of follow-up the frequency of transfusions had been reduced by treatment with prednisolone [34]. CASE 37. This fifty-one year old woman had “pure” red cell anemia, lymphoepithelial thymoma and elevated serum globulin levels. After thymomectomy there was a brief response to adrenocorticosteroid therapy but she died shortly thereafter of pneumonia [35]. CASE 38. This sixty-five year old man had a mediastinal tumor ten years before the onset of erythroblastic anemia. The anemia responded to steroid therapy initially and then recurred. A lymphoepithelial thymoma was removed but there was no response until corticoids were given. Sixteen months after all medications were discontinued the patient had a normal blood count. Prior to surgery he had a chronic polymorphonuclear leukocytosis. Bone marrow was richly cellular, 80 per cent of the cells being of the granulocytic series. After steroid therapy the polymorphonuclear leukocytosis resolved. After thymomectomy the bone marrow became normal and 50 per cent peripheral lymphocytosis and hypergammaglobulinemia were eventually noted [36]. CASE 39. This seventy-four year old man had erythroblastic hypoplasia and spindle cell thymoma. Thymomectomy was performed but there was no response; the patient died of a stroke fourteen days after the operation [37]. CASE 40. In this thirty-three year old woman with a three year history of myasthenia gravis diarrhea developed and she was found to have medullary erythroblastopenia, hypergammaglobulinemia and a large mediastinal tumor. She died within a short time and a large locally invasive and metastatic lymphocytic thymoma was found at autopsy [38]. CASE 41. In a summary of 138 cases of thymornay there is a brief description of a previously unreported case of erythropoietic hypoplasia and spindle cell thymoma. The anemia in this case did not diminish after thymomectomy [ZO]. VOL.

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CASE 42. This seventy;seven year old man had “pure” red cell anemia, positive direct and indirect Coombs’ tests, positive lupus erythematosus preparations, diabetes mellitus and spindle cell thymoma. Two years after the onset of anemia the thymoma was removed. Postoperatively the anemia remained refractory but reactions to the Coombs’ and lupus erythematosus tests became negative. The patient died one year after surgery in congestive heart failure [39]. CASE 43. A thymoma composed of reticulum cells and lymphocytes was removed from a fifty-three year old woman five years before the onset of erythroblastopenia. The anemia was refractory to steroid therapy until splenectomy was performed. Steroid therapy was continued postoperatively, the hemoglobin level became stabilized and no further transfusions were required. The patient died a few months later of staphylococcal pneumonia. Autopsy disclosed active marrow with erythropoiesis [do]. CASE 44. A seventy-six year old man was known to have a mediastinal tumor for five years before the development of erythroblastic aplasia. Bone marrow function returned to normal during steroid treatment, but the anemia recurred after the administration of steroids was discontinued so it was reinstituted. At the time of writing this patient was doing well and the tumor had not been removed [47]. CASE 45. A forty-one year old man with aplastic anemia was treated with ACTH without improvement and soon died. At autopsy a nonencapsulated, lobulated, fatty thymoma was found. Microscopically, the tumor was composed primarily of fat cells [42]. CASE 46. A forty-two year old woman had erythroblastic hypoplastic anemia, hypogammaglobulinemia and mediastinal tumor. Neutropenia developed and she died of pneumonia. Autopsy disclosed a lymphoepithelial thymoma [42]. CASE 47. A seventy-four year old woman had “pure” red cell anemia, moderate hypergammaglobulinemia and a large mediastinal mass thought to be a thymoma. The anemia was refractory. Surgery was refused. She died one year after the diagnosis of her disease. Permission to perform an autopsy was not obtained [43]. CASE 48. A fifty-six year old woman was known to have a mediastinal mass for thirteen years. A spindle cell thymoma was removed and two months later erythroblastic hypoplasia developed which was refractory to steroid therapy. The Coombs’ test became weakly positive. Splenectomy was performed. Infustion of 175 ml. of plasma from a patient with secondary polycythemia did not produce a reticulocytosis. Injections of somatotropin, exchange transfusion and injections of fresh plasma had no effect upon the anemia. The patient finally responded to very large doses of steroid hormones and at the

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time of her last report was receiving small daily doses. Injections of the patient’s plasma given to bled rats did not inhibit active erythropoiesis. The Coombs’ test became negative. Antinuclear antibodies were demonstrated by immunofluorescence. The rate of formation of antipolio and antitetanus antibodies was found to be normal. During the anemic period after thymomectomy the bone marrow showed increased small lymphocytes to 23 per cent [I]. CASE 49. This fifty-eight year old woman was apparently cured of “pure” red cell anemia by the removal of a lymphocytic thymoma [a]. CASE 50. A sixty-nine year old man with lymphoepithelial thymoma had an associated intermittent “pure” red cell anemia. At age fifty diarrhea and marked anemia developed which remitted spontaneously after six months. At age fifty-six an asymptomatic lymphoepithelial thymoma was removed. At age fifty-eight he again had diarrhea, erythroblastic aplasia and a slightly positive Coombs’ test. Three years later the anemia disappeared after ACTH therapy. At age sixty-five “pure” red cell anemia and diarrhea recurred. Bone marrow showed small dark atypical lymphocytes. At age sixty-seven he had a spontaneous remission that lasted until death two years later which was due to bronchopneumonia. Postmortem examination of the bone marrow was within normal limits. During the patient’s life the anemic periods were correlated closely with diarrhea and on several occasions malabsorption was found [45]. CASE 51. A fifty-three year old woman had a refractory erythroblastic hypoplasia, compensated mitral insufficiency, positive Coombs’ test and elevated serum globulin levels. The serum globulin levels diminished with steroid therapy. The patient died of serum hepatitis without showing any diminution in the anemia. At autopsy a spindle cell thymoma was found [&I. CASE 52. In this fifty-nine year old woman with a history of myasthenia gravis which regressed spontaneously four to six years after her menopause, “pure” red cell anemia developed in association with a lymphocytic thymoma. Five months after thymomectomy she had a rapid response to corticoid therapy and at the time of the last report she was being maintained on small doses and her hemoglobin level was normal. After thymomectomy and prior to the administration of steroids, the bone marrow had shown erythroblastic aplasia and lymphocytes had increased to 20 per cent. Antinuclear antibodies were demonstrated by immunofluorescence and complement fixation [47]. CASE 53. In this sixty-eight year old woman erythroblastic hypoplasia developed four years after the onset of myasthenia gravis. A spindle cell thy-

et al.

moma was removed. The anemia was unresponsive to therapy with prednisone, testosterone and pyridoxine. Diabetes mellitus, hepatomegaly and thrombocytopenia developed and the patient died four years after the onset of the anemia [48]. CASE 54. In this seventy-three year old woman refractory anemia developed nine months after a large mass in the lower right side of the chest was found on roentgenograms. The mass was unresponsive to radiation. Diabetes mellitus, hepatomegaly and elevated serum globulin levels were noted. Bone marrow showed almost complete absence of red cell precursors. A large spindle cell thymoma was removed but the patient died on the second postoperative day [48]. CASE 55. This forty-five year old man had a bullous skin eruption thought to be pemphigus vulgaris two years before the onset of erythroblastic aplasia associated with a calcified mass in the anterior superior mediastinum. The anemia responded to prednisone therapy and transfusions but recurred four months later. Fluoxymesterone was given with apparent benefit. Lupus erythematosus tests were consistently positive. Two and a half years after the onset of the anemia an encapsulated cystic epithelial thymoma was removed. Postoperatively the patient has required varying amounts of prednisone, androgens and occasional blood transfusions to maintain his hemoglobin level. He has been working daily and doing reasonably well. Although antinuclear antibodies have been found consistently there are no other manifestations to suggest systemic lupus erythematosus [49,50]. CASE 56. A sixty-two year old woman had an asymptomatic lymphocytic thymoma removed. It recurred five years later and was excised again. Two years after the second excision, refractory erythroblastic aplastic anemia developed suddenly. Bone marrow showed numerous lymphocytes. One year after the onset of anemia, the thymoma recurred during the patient’s terminal illness [57]. CASE 57. A forty-seven year old man with myasthenia gravis and pancytopenia died four hours after his admission to the hospital. At autopsy a benign lymphoepithelial thymoma and marked reduction of bone marrow erythroid elements were found [52]. CASE 58. In this sixty-seven year old man a thymoma had been proved by biopsy ten years before the onset of a “pure” red cell anemia which responded to the administration of hematinics, including steroids. However, he suffered a relapse after discontinuing medications on his own. The anemia became refractory. Hypogammaglobulinemia (500 mg. per cent) was found. Thrombocytopenia and neutropenia appeared. He died of hemorrhage. AMERICAN

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Autopsy revealed spindle cell thymoma and bone marrow with hardly any cells except lymphocytes [53]. CASE 59. This seventy-five year old woman was found to have a slowly growing anterior mediastinal mass eight years before the onset of refractory anemia and thrombocytopenia. Bone marrow showed erythroblastic aplasia and plentiful small dark lymphocytes. A benign encapsulated spindle cell thymoma was removed. Despite postoperative treatment with steroids and testosterone repeated transfusions were required. Two and a half years after the onset of anemia the patient died with a terminal hemorrhagic diathesis [27 j. CASE 60. A fifty-eight year old man had had a known mediastinal mass for eight years before the development of refractory erythroblastic hypoplasia and thrombocytopenia. Small dark lymphoid cells were noted in the bone marrow. He did not benefit from the removal of a spindle cell thymoma. Pancytopenia developed shortly before his death three years later [27]. CASE 61. A sixty year old woman presented with pancytopenia and hypogammaglobulinemia. Removal of a spindle cell thymoma and treatment with steroids and testosterone had no beneficial effect. Antinuclear antibodies were demonstrated. Diabetes developed and the patient’s condition deteriorated progressively and she died about three months after the onset of anemia. The clinical features of this Clinical Features. syndrome are related for the most part to the patient’s hematologic status. The most common symptoms are those of an insidiously developing anemia. Hemorrhagic manifestations secondary to thrombocytopenia may be the first symptoms. Most of these thymomas were not invasive and were asymptomatic. They are usually found incidentally on a routine roentgenogram of the chest. Locally invasive thymomas are more apt to produce signs and symptoms such as cough, pain, pleural effusion or the superior vena caval syndrome. Lymphadenopathy, hepatomegaly and splenomegaly are not prominent features. Age, Sex and Incidence. Of the sixty-one patients reported in this series, the ages of fiftyeight are known. The youngest was twenty and the oldest seventy-eight years of age. The average age was sixty. Twenty-eight patients were fifty-eight years of age or younger and thirty were fifty-nine years of age or older. The sex of sixty of the sixty-one patients is known. Of these forty were female and twenty male. The significance of female sex predominance is not clear but it corresponds to the increased incidence of VOL.

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autoimmune disease among females. The occurrence of hematopoietic insufficiency with thymic abnormality is relatively rare. However, it is probably not as uncommon as was once thought since fifty-six of the sixty-one cases tabulated here have been recorded since 1953. The Anemia. The most typical combination in this syndrome is a benign thymoma of the spindle cell variety associated with a pure red cell anemia or erythroblastic hypoplasia. The anemia may be combined with thrombocytopenia, neutropenia or both. There is no recorded case in which neutropenia or thrombocytopenia occurred before the anemia. It appears, then, that the pathologic process is more detrimental to erythropoiesis than to myelopoiesis or megakaryopoiesis. Thirty-nine of the sixty-one cases were of the pure red cell type. In seven instances there was associated thromboyctopenia (Cases 13, 14, 18, 28,35,53 and 59). Neutropenia in addition to the anemia was noted in four cases (Cases 3, 16, 19 and 46). Six patients presented with pancytopenia (Cases 22, 25, 27, 45, 57 and 61). In three pancytopenia developed later (Cases 4, 34 and 58). In one of the patients who presented with anemia and thrombocytopenia pancytopenia subsequently developed (Case 60). Manifestations of Autoimmune Disease. In twenty-six of the sixty-one cases findings were those usually considered manifestations of autoimmune disease. Eight patients had myasthenia gravis (Cases 8, 12, 13, 15, 40, 52, 53 and 57). It has been shown that some patients with myasthenia gravis have circulating autoantibodies to muscle [54]. Serum proteins were determined in thirty-two patients. Thirteen had increased levels of serum globulins and four had hypergammaglobulinemia (Cases 22,38,40 and 47). Six had marked hypogammaglobulinemia (Cases 10, 16, 19, 46, 58 and 61). These patients would be classified as “acquired” hypogammaglobulinemia. having Ten per cent of the cases of hematopoietic insufficiency and thymic abnormality have been associated with hypogammaglobulinemia. There is increasing evidence that adult “acquired” hypogammaglobulinemia is genetically determined [55-591; perhaps the anemia in the patients described herein will eventually be found to have a similar pattern. A positive Coombs’ test was noted in six cases (Cases 10, 19, 42, 48, 50 and 51). It became

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negative in three of these after removal of the thymoma. Antinuclear antibodies were found in four cases (Cases 48, 52, 55 and 61). Positive lupus erythematosus preparations were obtained in two (Cases 42 and 55); a false-positive serologic reaction in one (Case 6), and malabsorption was noted in one (Case 50). Bone Marrow Lymphocytes. In classic aplastic anemia the majority of nucleated cells obtained at sternal puncture are lymphocytes which may comprise 60 to 100 per cent of the nucleated cells. Bone marrow lymphocytosis is also seen in association with “pure” red cell anemia. In this series increased lymphocytes were found in the bone marrow in sixteen cases of anemia. Ten of these were of the pure red cell type. Bone marrow lymphocytosis appears during periods of marrow depression and disappears from the marrow with remission. The reason for the accumulation of lymphocytes in the marrow is not known. In this series surgical or autopsy specimens were obtained in fifty-six of the sixty-one cases (specimens were not obtained in Cases 2, 15, 36, 44 and 47). Three were simply described as thymomas without histologic details (Cases 7, 30 and 31). The spindle cell thymoma was the most common type of tumor found, it was present in twenty-five instances. The next most common type was the lymphoepithelioma (mixed type) of which fourteen were found. Seven were of the lymphocytic variety. Two were of the epithelial type. One was a thymolipoma (Case 45). One was described as composed chiefly of fibrous tissue with scattered areas of epithelial cells (Case 4). One was cystic (Case 14). Two had postradiation changes that did not allow identification of the cellular type (Cases 3 and 35). The great majority of the thymomas associated with hematopoietic insufficiency have been benign, although a few have been invasive (Cases 4, 40 and 56). Treatment. The treatment of this syndrome has been entirely empirical. Thymomectomy alone and thymomectomy with other forms of therapy have been most successful. Of the sixtyone cases reviewed, the thymic tumor was removed in thirty-five. Seven of these patients were eventually well, i.e., maintained a normal hemoglobin and had a normal bone marrow without supporting medication. Eight of the patients were considered improved but not cured. Twelve were thought to be unimproved.

et al.

Of the seven patients considered cured, four required no treatment except removal of the thymic tumor (Cases 6, 7, 29 and 49). In these cases there appeared to be a direct cause and effect relationship between the tumor and the anemia. In order to effect a cure two patients required additional treatment with corticoids (Cases 31 and 38). One patient had splenectomy in addition to thymomectomy and steroid therapy (Case 8). Of the eight patients who improved after thymomectomy, three required adrenal cortical steroid therapy (Cases 11, 37 and 52); one required splenectomy and steroids therapy (Case 9) ; one improved after thymomectomy but died three weeks postoperatively of myocarditis (Case 12) ; one responded to testosterone therapy after thymomectomy, splenectomy and steroid therapy had been unsuccessful (Case 17) ; and one improved on prednisone and fluoxymesterone therapy after thymomectomy (Case 55). The twelve patients who did not improve were given various forms of therapy in addition to thymomectomy, including steroids, splenectomy, androgens, vitamin Bi2, iron, cobaltous chloride, folic acid, liver extract, transfusions, radiation of the tumor and other measures. In six cases the thymic tumor was excised before the onset of the anemia (Cases 23, 28,43, 48, 50 and 56). Two patients died during the postoperative period (Cases 16 and 54). All seven cases in which the patients were considered cured were of the “pure” red cell type. Seven of the eight patients who showed improvement with thymomectomy and various other forms of therapy also had “pure” red cell anemias. One patient in this group had thrombocytopenia and leukopenia. This patient showed an initial response to removal of the thymoma but had a relapse soon afterwards. Of the patients who did not respond to thymomectomy and additional therapy, one had complicating hemolytic anemia (Case lo), one had pancytopenia (Case 61) and three had thrombocytopenia (Cases l&59 and 60). The other seven patients who did not improve had “pure” red cell anemia. Of the six patients in whom the thymoma was removed before the onset of the anemia, one responded after steroid therapy and splenectomy (Case 43), and one responded after splenectomy and large doses of steroids (Case 48). In another the anemia seemed to appear, remit and reappear spontaneously, although steroids were AMERICAN

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given during relapse (Case SO). Another

did not improve despite therapy with steroids, radiation of the tumor and hematinics in addition to the thymomectomy (Case 28). One patient did not respond to the administration of steroids or other medications (Case 23). In one case the thymoma recurred and was excised again before the onset of the anemia (Case 56). All six cases of anemia which occurred after thymomectomy were of the “pure” red cell type. Five of the six cases of hypogammaglobulinemia were associated with spindle cell thymomas (Cases 10, 16, 19, 58 and 61). There was no correlation between the cellular type of tumor and the hematologic manifestations. The response to thymomectomy or other forms of therapy did not correlate with the cellular type of tumor. In addition to thymomectomy, blood transfusions, steroids, androgens and radiation of the tumor all have been of help in stimulating erythropoiesis. Several patients responded to various forms of therapy prior to removal of the thymic tumor (Cases 14, 35, 36, 44, 55 and 58).

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REFERENCES

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