Erythroblastic Hypoplasia Associated with Thymic Tumor and

ERYTHROBLASTIC HYPOPLASIA ASSOCIATED WITH THYMIC TUMOR AND MYASTHENIA GRAVIS

REPORT OF A CASE

JACK G. WEINBAUM, M.D., AND ROBERT F. THOMPSON, M.D.

St. Joseph's Mercy Hospital, Ann Arbor, Michigan

Erythroblastic hypoplasia is a rare form of aplastic anemia characterized by an almost complete lack of erythrocyte progenitors in the bone marrow witliout depression of the granulocytic series or megakaryocytes. Severe anemia of this type has been reported in patients with thymic tumors with and without myasthenia gravis.5, 6'8> 14,19

In 1928 Matras and Priesel14 reported a thymic tumor found at autopsy in a 62-year-old woman who had a 3-year history of marked anemia, believed during life to be pernicious anemia. The tumor was the size of a walnut and consisted of epithelioid cells and cells resembling lymphocytes. There is nothing in the history suggesting that the patient had had myasthenia gravis. Davidsohn,6 in a clinico-pathologic conference published in 1941, reported the case of a 58-year-old white woman with severe anemia and a mediastinal mass visible by fluoroscopy. The initial blood count was 1.6 million red blood cells and 7200 white blood cells per cu. mm. No reticulocytes were present. Sternal puncture showed a depression or hypoplasia of the erythropoietic elements of the marrow. After numerous transfusions of whole blood, the patient died 19 months after her first hospital admission. At autopsy a firm, globular, encapsulated mass 4.5 by 4.5 by 4.0 cm. was found in the upper mediastinum on the right side close to the right border of the trachea and of the aorta. On section, the surfaces were dark brown and lobulated. The histologic diagnosis of the tumor was lymphoepithe-lioma of the thymus,<In~I945 Humphreys and Southworth8 reported the occurrence of aplastic'anemia terminated by removal of a mediastinal tumor in a 58-year-jjJd-'woman without myasthenia gravis. The blood count was 1 million red bloo"cTcells per cu. mm., hemoglobin 1.5 Gm. per 100 ml.; no reticulocytes were found. The platelet and leukocyte counts were normal. A sternal marrow biopsy was reported as showing mild hypoplasia. The patient's anemia was apparently related to her tumor, inasmuch as after removal of the tumor, the blood showed a sharp reticulocytosis with return of the erythrocyte count to normal. Ten months after operation she died. Autopsy showed widespread hemochromatosis and lobar pneumonia, but no evidence of reappearance of the original tumor. There had been no postoperative recurrence of the anemia. The tumor removed at surgery was encapsulated and contained both lymphocytes and reticulum cells. I t was thought by A. P. Stout to be of thymic origin. Ross and associates19

Received for publication January 27, 1955; accepted, March 4, 1955. Dr. Weinbaum was Associate Pathologist and Dr. Thompson is Resident in the De

partment of Medicine, St. Joseph's Mercy Hospital. Dr. Weinbaum's present address is Terre Haute Medical Laboratory, 206-210 Rose Dispensary Building, Terre Haute, Indiana.

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762 WEINBATJM AND THOMPSON Vol. 25

in 1954 reported the simultaneous occurrence of a benign thymoma and refractory anemia in 2 adult female patients, the anemia in both being associated with a marked decrease of erythropoietic activity in the bone marrow. The authors also had personal knowledge4 of 2 additional cases, which they described, of refractory anemia that did show some improvement following resection of the thymoma. One was a 48-year-old male with myasthenia gravis. They also refer to a report by Chediak and associates^ concerning a 47-year-old man who had a severe anemia and complete aplasia of the erythropoietic elements of the bone marrow. Following the removal of a thymoma which was demonstrated radiographically, the patient's blood findings returned to normal.

Our patient was an elderly woman with myasthenia gravis, thymoma, erythroblastic hypoplasia of the bone marrow, and diabetes mellitus.

KEPORT OF CASE

Clinical data. A 76-year-old debilitated white woman entered this hospital on March 6, 1951. She had been known to have, diabetes mellitus since 1940. In 1943 slight loss of weight, polyphagia, polydipsia, slurred speech, drooping eyelids and generalized muscular weakness were noted. Easy muscular fatigue was demonstrated by a modified Jolly test. Laboratory examinations revealed a normal hemogram, hyperglycemia and glycosuria. A 70-mm. photofluorogram of the chest was interpreted as normal. Daily oral rations of prostigmine were necessary to maintain muscle strength.

Progressive weakness developed in 1947 despite dietary control of her diabetes and oral rations of prostigmine. Her red blood cell count was 1.S2 million per cu. mm.; hemoglobin concentration, 38 per cent. A significant hematologic response occurred after 3 months of oral administration of liver extract, iron and vitamins. A presumptive diagnosis of pernicious anemia was made, and the treatment was continued.

At an unknown date, she discontinued all antianemic medication. No prostigmine had been taken for at least 2 weeks prior to transfer to the hospital from a convalescent home in March 1951.

Physical findings. The patient had a gray-yellow pallor but no icterus. Minimal slurring of speech and bilateral ptosis of the eyelids were noted. The tongue showed no atrophy of the mucosa. Frequent premature ventricular beats were heard. Her nutritional status was good.

Laboratory findings. Initially there were 900,000 erythrocytes and 8900 leukocytes per cu. mm. of blood and 3.4 Gm. of hemoglobin per 100 ml. It was thought that the platelets in a blood smear were increased. The red blood cells showed slight anisocytosis and marked poikilocytosis. The differential white blood count was normal. After a transfusion of 500 ml. of whole blood, the hematocrit reading was 14 per cent and there was 1 per cent reticulocytes.

Hospital course. Since she had responded to previous treatment for pernicious anemia, she was given 15 Mg. of vitamin Bi2 intramuscularly daily for 13 days. There was no reticulocyte response. The hyperglycemia persisted despite carbohydrate restriction and increasing amounts of protamine zinc insulin. On March 15, 1951, her oral temperature was 104 F., the white blood count was 30,000 per cu. mm., and there was evidence of bronchopneumonia in the right lower lobe, confirmed by an x-ray film. In this film an "unidentified shadow in the right infrahilar region . . . [possibly] a thymoma" was noted (Fig. 1). The pneumonia responded to procaine penicillin-G and Chloramphenicol. There was, however, no hematologic improvement following intramuscular injection of liver extract and oral intake of folic acid, iron and multiple vitamins. The sternal marrow was cellular but erythrocyte progenitors were depressed .(Fig. 2). The few nucleated red cells present were young forms with basophilic cytoplasm and were in various stages of degeneration. Scattered


July 1955 ERYTHROBLASTIC HYPOPLASIA 763

pyknotic nuclei were present whose cellular origin could not be identified. The granulocytic series was well represented and megakaryocytes were present in normal numbers.

Blood transfusions were discontinued after a total of 2500 ml., at the request of the family. On May 16, 1951, the hemoglobin was 2.6 Gm. per 100 ml. of blood. A peripheral blood smear on the same day failed to show significant thrombocytopenia. Immediately prior to death on May 19, 1951, a few small petechiae were noted on the trunk and extremities.

POSTMORTEM EXAMINATION

Gross findings. Distributed over the trunk were purpuric lesions 1 to 3 mm. in diameter. Of greatest interest was an apparently well-encapsulated, moderately firm tumor in the anterior mediastinum, overlying the aorta, superior vena cava and right atrium (Fig. 3). I t measured 7 by 5 by 4 cm. and weighed 28 Gm. The cut surface was milky white and there was only a faint suggestion of lobulation. Scattered throughout were cystic spaces varying from 1 to 5 mm. in diameter. The spleen weighed 150 Gm., the pancreas 100 Gm., and the liver 1200 Gm. These organs were not grossly abnormal. The bone marrow was brown and soft.

Microscopic findings. Sections were prepared from representative material fixed in formalin and were stained with hematoxylin and eosin.

The mediastinal neoplasm was markedly cellular, being composed predominantly of small cells indistinguishable from, and generally recognized as, lymphocytes. Occurring singly and in small groups were larger cells referred to as epithelial cells or epithelial reticulum, with vesicular nuclei and abundant pink-staining cytoplasm. In several of the groups an occasional cell had a distinct cell border; the surrounding cells, sometimes separated by a small space, were concentrically arranged (Fig. 2). The cysts seen grossly contained pink-staining precipitated material, groups of lymphocytes, and peculiarly detached small blood vessels, and were lined with a single flattened layer of cells. They appeared to be related to unusually thick hyalinized trabeculae. Despite the gross appearance, the neoplasm extended through the capsule into adipose tissue in several areas; and in these areas alone, well-formed Hassall's corpuscles were found (Fig. 3). Infiltration was limited to the area about the tumor as additional sections through anterior and superior mediastinal fat showed only normally involuted thymus.

Sections of bone marrow from a rib and vertebral body were striking. The bone marrow was hyperplastic, consisting almost exclusively of cells of the granulocytic series. The usual small groups of erythrocytic progenitors with their dark-staining nuclei such as are seen in normal bone marrow were absent (Fig. 4). In addition, in contrast to the bone marrow examined 3 weeks previously, megakaryocytes were markedly reduced in number.

There were no lymphorrhages in sections of psoas muscle and diaphragm. Anatomic diagnoses. Erythroblastopenic anemia. Thymic tumor (thymoma)

associated with myasthenia gravis (clinically). Terminal thrombocytopenia. Hemorrhages in brain, skin, pleura and epicardium. Hemopericardium. Degenerative fatty infiltration of myocardium. Chronic atrophic gastritis. Hemosiderosis of spleen, liver, mucosa of small intestine and bone marrow. Diabetes mellitus



(clinical). Partially hyalinized islets of Langerhans. Generalized arteriosclerosis. Arteriosclerotic nephropathy. Endometrial polyps.

COMMENT

In 1917 Bell2 noted that the thymic tumors occurring in myasthenia gravis seemed to form a distinct group unlike other thymic tumors. He called them thymomas, wliich he defined as tumors, benign or malignant, probably derived from the thymic epithelium and usually identifiable by the epithelial reticulum and lymphocytes. Castleman and Norris3 described 3 histologic types of thymomas based upon the proportion of epithelial elements or lymphocytes. Thymomas were found in 10 of 35 cases of myasthenia gravis which they studied. Most of these tumors showed nearly equal amounts of epithelial cells and lymphocytes. In reviewing all thymic tumors at Massachusetts General Hospital, they were able to find only one case not associated with myasthenia gravis in wliich the lesion resembled tumors found in their 10 cases of myasthenia gravis. According to Seybold and associates,20 a thymoma is a specific tumor of the thymus that is characterized by the presence of both thymic epithelial cells and thymocyte cells in varying proportions. They found the incidence of thymomas in patients with myasthenia gravis at the Mayo Clinic to be only 15 per cent. However, only 75 per cent of the patients with tumors fitting their definition of thymoma had clinical evidence of myasthenia gravis. I t is clear that not all patients with thymomas have myasthenia gravis at the time the neoplasm is discovered. Castleman and Norris3 mention 5 cases in which there was definite x-ray and clinical evidence of a mediastinal tumor years before the onset of symptoms of myasthenia gravis.

Seventy-five per cent of the 45 thymomas reported by Seybold and co-workers20

had a distinct fibrous capsule. The others had broken through the capsule to invade adjacent structures, and 2 had spread to parietal and visceral pleural surfaces as nodular implants. They were unable to separate, on histologic grounds, those tumors that were invasive or spread by implantation from those that were completely encapsulated.

Wu23 objected to the use of the term "thymoma." He pointed out that it was first used by Grandhomme in 1900 to include all malignant tumors of the thymus, by Ewing as a synonym for lymphosarcoma of the thymus, by Brown to mean primary "carcinoma" of the thymus, and by Margolis to designate all types of growth derived from the thymic parenchyma. He suggested instead the more descriptive term, lymphoepithelioma. Lowenhaupt,11 in her classification of thymic tumors, used both terms. She regarded a thymoma as possibly a mature variant of a lymphoepithelioma, as suggested by the extent of the lymphocytic infiltration in thymomas.

Despite the confusing terminology, it is evident, as Bell2 pointed out in 1917, that thymic tumors associated with myasthenia gravis are of a definite type. They are relatively benign. Local infiltration and implantation do occur but distant metastases are not found. With a few exceptions, thymic tumors associated with myasthenia gravis consist principally of lymphocytes and epithelial cells in



FIG. 1 (upper). Roentgenogram showing shadow in the right infrahilar region. FIG. 2 (lower). Section of tumor showing group of epithelial cells and surrounding

lymphocytes. Developing Hassall's corpuscles. Hematoxylin and eosin.



varying proportions. The tumor in our case is in this group. It should be emphasized that neoplasms of the thymus are not demonstrated in the majority of cases of myasthenia gravis. Their incidence in reported cases varies from 15 to 28 per cent.

Noyes16 stated that the most frequent departure from the normal blood picture in myasthenia gravis is polycythemia, although he does say that often patients suffering from this disease are anemic. He cited no examples of either condition. The anemia in our patient may have been due to one of the drugs taken during her many illnesses, although there is no evidence to support this view. However when this case is grouped with the similar cases in the literature, it is of interest to entertain the possibility of a relationship between the anemia and the thymic tumor associated with myasthenia gravis.

Only a few instances have been reported in adults of anemia which was refractory to all hematinic agents and which showed hematologic pictures similar to that of our patient but with no thymic tumors.1,7> 9 ' 1 0 , 1 2 , 1 3 , 1 5 The patients were usually middle-aged. An occasional patient had splenomegaly. The peripheral blood demonstrated anemia of no constant red cell type; white blood cell and platelet counts were normal. Reticulocytes were either scarce or absent. Terminal thrombocytopenia occasionally occurred. Bone marrow aspirates and autopsy specimens constantly revealed aplasia or severe hypoplasia of erythropoietic elements, occasionally abnormal normoblasts, and normal granulopoiesis and thrombocyte formation. Abnormal platelet formation was found terminally in one case. Achlorhydria was not a constant finding. Multiple blood transfusions were required to sustain life although temporary remissions of the anemia occurred.

Various names have been applied to the hematologic picture, including aregen-erative anemia, atypical aplastic anemia, true aplastic anemia, true red cell aplastic anemia, chronic erythrocytic aplasia, aplastic anemia without agranulocytosis and thrombocytopenia, and erythroblastopenic anemia.

Anemia of similar type is found occasionally in early infancy and has been called congenital hypoplastic anemia.22 It, too, is characterized by a depression of erythropoiesis with normal myelopoiesis and platelet formation. The cause is unknown, but with multiple transfusions to sustain life, the bone marrow eventually functions adequately.

Except for the presence of myasthenia gravis, our case is similar to those of Matras and Priesel14 and of Humphreys and Southworth.8 Although the bone marrow pictures are not specifically described in either of these cases, the peripheral blood findings suggest long-standing isolated erythroblastic hypoplasia, a rare phenomenon in adults. In the former case, as in ours, for many years the patient was thought to have pernicious anemia. In both instances, that diagnosis might have been changed had the bone marrow been examined during life. The very low red blood cell count and the absence of reticulocytes in Humphreys and Southworth's8 case suggest the presence of erythroblastic hypoplasia of the marrow. Mediastinal tumors of similar gross and histologic types were present in the 3 cases. In 3 of the 4 cases reported by Ross and associates19 and in the


FIG. 3 (upper). Lymphocytes extending through the capsule of the tumor into adipose tissue. Well-developed Hassall's corpuscle in lower right. Hematoxylin and eosin.

FIG. 4 (lower). Section of bone marrow removed at autopsy approximatelv 3 hours after death. Nucleated red blood cells are absent. Hematoxylin and eosin. X 700.

767


768 WEINBAUM AND THOMPSON Y61. 25

case reported by Chediak and co-workers5 the bone marrow is stated specifically to show erythroblastic hypoplasia or aplasia associated with normal granulocytic and megakaryocyte elements. In the fourth case, 1 of the 2 cases of Chalmers and Boheimer,4 the marrow contained no erythroblasts prior to removal of a thymoma and the postoperative administration of ACTH. In the 6 cases in which a thymoma was surgically removed, the anemia was cured in 2,6 ' 8 improved in 2,4 and unaffected in 2.19

Classical aplastic anemia associated with other types of thymic pathology has been reported.17,I8>21 Wintrobe mentions myasthenia gravis with aplastic anemia in a patient with an enlarged thymus.21 Opsahl17 in 1939 reported aplastic anemia in a 56-year-old man who had a mediastinal tumor, histologically diagnosed as a thymic carcinoma, which infiltrated the lungs and was adherent to the great vessels. There were no metastases. This patient had leukopenia and thrombocytopenia in addition to the anemia. There were few nucleated red cells or white cells and no megakaryocytes in the bone marrow. In Radojevic and Hahn's18

report, the patient, a 20-year-old male with pancytopenia and generalized hypoplasia of the bone marrow, was found to have a cystic fibrous tumor of the thymus gland at autopsy. I t is of interest that in the more common classical types of aplastic anemia, the thymic lesion varied. On the other hand, all the cases in the group with only erythroblastic hypoplasia of the bone marrow had similar thymic neoplasms.

SUMMARY

A 76-year-old woman had myasthenia gravis associated with a thymoma, diabetes mellitus and erythroblastic hypoplasia of the bone marrow. In the literature only 8 other instances could be found in which a primary thymic neoplasm was associated with severe anemia of similar type. Only one of the previously reported cases had myasthenia gravis, although all of the cases had a thymic tumor of the general type associated with that disorder. In 4 of these patients the defect of red blood cell production was either cured or improved by the removal of the thymic tumor. The occurrence of a relatively rare form of anemia in adults with thymic tumors in 9 patients suggests a relationship between certain thymic tumors and erythroblastic hypoplasia of the bone marrow.

R E F E R E N C E S

1. BEGEMANN, H . : Uber eine isolierte aplastische Aniimie mit vollstiindigem Fehlen der Erythroblas ten (Erythroblastophthise). Klin. Wchnschr., 24-25: 850-853, 1947.

2. B E L L , E . T . : Tumors of the thymus in myasthenia gravis. J . Nerv. & Ment . Dis . , 45: 130-143, 1917.

3. CASTLEMAN, B. , AND NOKKIS , E , H . : The pathology of the thymus in myasthenia gravis. Medicine, 28: 27-58, 1949.

4. CHALMERS, J . N . M. , AND BOHEIMER, K. : Personal communication to J . F . Ross and associates.19

5. CHEDIAK, A. B. , F H S T E , R., AND ROSALES, G. V.: Timoma y anemia aplastica. Arch. Hosp. univ. (Habana), 5: 27-39, 1953.

6. DAVIDSOHN, I . : Hemochromatosis, thymoma, severe anemia and endocardit is in a woman. Illinois M. J. , 80: 427-432, 1941.

7. F O Y , H. , AND K O N D I , A.: A case of true red-cell aplastic anaemia successfully t rea ted with riboflavin. J . Pa th . & Bact. , 65: 559-564, 1953.

8. HUMPHREYS, G. H. , I I , AND SOUTHWORTH, H . : Aplastic anemia terminated by removal of mediastinal tumor. Am. J. M. S c , 210: 501-510, 1945.



9. K A R K , R. M. : TWO cases of aplastic anaemia; one with secondary haemochromatosis following 290 transfusions in 9 years, the other with secondary carcinoma of the stomach. Guy's Hosp. Rep. , 87: 343-353, 1937.

10. KAZNELSON, P . : Zur Ents tehung der Blutplattchen. Verhandl. deutsch.; Gesellsch. inn. Med., 34: 557-559, 1922.

11. LOWENHAUPT, E . : Tumors of the thymus in relation to the thymic epithelial anlage. Cancer, 1: 547-562, 1948.

12. MACFARLANE, J . W., AND C U R R I E , J . P . : Idiopathic aplastic anemia. Edinburgh M. J. , 50: 171-176, 1943.

13. MACKEY, R. : Unusual case of aplastic anaemia with organ changes resembling haemochromatosis. M. J. Australia, 1: 172-173, 1942.

14. MATRAS, A., AND P R I E S E L , A.: Ueber einige Gewiichse des Thymus. Beitr. pa th . Anat. , 80: 270-306, 1928.

15. M I L L S , E . S.: Idiopathic aplastic anemia or aleukia hemorrhagica. Am. J . M. S c , 181: 521-533, 1931.

16. N O Y E S , A. P . : Case of myasthenia gravis with certain unusual features. Rhode Island M. J. , 13: 52-59, 1930.

17. OI 'SAHL, R. : Thymus—Karcinom og aplastik anemi. Nord. med., 2: 1835-1836, 1939. 18. RADOJEVIC, S., AND H A H N , A.: Berinflusst der Thymus die Zahl der Granulozyten?

Strahlentherapie, 53: 90-101, 1935. 19. Ross , J . F . , F I N C H , S. C , STREET, R. B. , J R . , AND STRIEDER, J . W.: The simultaneous

occurrence of benign thymoma and refractory anemia. Blood, 9: 935-952, 1954. 20. SEYBOLD, W. D. , M C D O N A L D , J . R., CLAGETT, O. T. , AND GOOD, C. A.: Tumors of the

thymus. J . Thoracic Surg., 20: 195-215, 1950. 21. WINTROBE, M. M. : Clinical Hematology-. Ed . 3. Philadelphia: Lea & Febiger, 1951,

p . 533. 22. WINTROBE, M. M. : Clinical Hematology. Ed . 3. Philadelphia: Lea & Febiger, 1951,

p . 559. 23. Wu, T . T . : Lymphoepithelioma of the thymus. J . P a t h . & Bact . , 41 : 351-366, 1935.


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Erythroblastic Hypoplasia Associated with Thymic Tumor and