American Journal of Hematology 22:295-300 (1986)

Paravertebral Extramedullary Hematopoiesis Associated With Improvement of Anemia in Congenital Dyserythropoietic Anemia Type II Gilles Lugassy, Joseph Michaeli, Noam Harats, Eugene Libson, and Eliezer A. Rachmilewitz

Departments of Hematology (G. L, J. M., E.A. R.), Internal Medicine (N. H.), and Radiology (E. L.), Hadassah University Hospital, Jerusalem, Israel

Thoracic masses resulting from extramedullary hematopoiesis developed in two sis- ters of Moroccan origin with congenital dyserythropoietic anemia type I1 (HEMPAS). In one patient, the diagnosis of extramedullary hematopoiesis was confirmed histolog- ically. The appearance of extramedullary foci of hematopoiesis mimicking mediastinal tumors has not been previously described in HEMPAS. These masses result from persistent erythropoietic stimulation associated with chronic hemolytic anemia. In both patients, detection of the asymptomatic masses was preceded by normalization of hemoglobin levels. Thus unexpected correction of a chronic refractory anemia associated with the appearance of mediastinal masses might be the heralding manifes- tation of an effective extramedullary hemopoiesis.

Key words: HEMPAS, thoracic masses, erythropoietic stimulus

INTRODUCTION

Congenital dyserythropoietic anemia (CDA) is the term applied to a group of hereditary refractory anemias characterized by chronic hemolysis, ineffective eryth- ropoiesis, erythrocyte membrane abnormalities, and multinuclearity [ 13. The etiology of these anemias is obscure. Three main types of CDA can be distinguished. CDA type I1 or hereditary erythroblastic multinuclearity associated with a positive acidified serum test (HEMPAS) is the most common form. HEMPAS has been described in Israel among patients of Moroccan origin [2]. We describe three siblings with HEMPAS. In two sisters, after 30 years of follow-up, large mediastinal masses developed as a result of extramedullary hematopoiesis.

CASE REPORTS Case No. 1

A 57-year-old Jewish woman of Moroccan origin was admitted to the Hematol- ogy Department in 1982 for evaluation of a mediastinal mass revealed by a routine

Received for publication September 16, 1985; accepted December 14, 1985

Address reprint requests to Dr. Gilles Lugassy, Department of Hematology, Hadassah University Hospital, POB 12000, Jerusalem, Israel 91120.

0 1986 Alan R. Liss. Inc.

2% Case Report: Lugassy et a1

chest X-ray. In 1948, at the age of 21, she was first hospitalized elsewhere because of jaundice and anemia, with a hemoglobin of 8.8 g%. Other details are not available. In 1969, she was admitted to our department because of unexplained jaundice. Physical examination revealed slight conjunctival icterus and mild splenomegaly . The hemoglobin level was 11.2 g % . Other hematological findings and laboratory data are summarized in Table I. The peripheral blood smear showed marked poikylocytosis and anisocytosis. Common causes of hemolytic anemia such as thalassemia or red cell enzyme deficiencies were excluded, and the patient was considered to have a chronic hemolytic anemia of unknown origin. From 1969 until 1982, she did not seek medical advice. In 1982, the patient was again admitted to our department for evaluation of a mediastinal mass discovered on a routine chest X-ray.

On physical examination, conjunctival icterus and moderate hepatomegaly were noted; the spleen was not enlarged. Pertinent laboratory findings were a mild nor- mocytic, normochromic anemia with normal reticulocyte count, an elevated indirect bilirubin level, low cholesterol and vitamin E levels, and normal hemoglobin electro- phoresis and red cell enzymes (Table I). A bone marrow aspiration showed a marked erythroid hyperplasia with numerous binucleated and multinucleated normoblasts. Severe nuclear abnormalities were present, including pyknosis and karyorrhexis. Ferrohnetic studies demonstrated ineffective erythropoiesis and a shortened RBC survival. Red cell agglutination with anti-i and the Ham test were positive (Table I). The chest X-ray (Fig. 1) showed polycyclic bilateral masses in the paravertebral region. The patient refused any further investigation of these asymptomatic masses and was discharged with a diagnosis of CDA type I1 (HEMPAS) complicated by probable paravertebral extramedullary hematopoiesis. At a recent follow-up, the masses were unchanged and the patient remained asymptomatic.

Case No. 2

A 51-year-old woman, the sister of the previous patient, was admitted in 1960 to the Department of Medicine in our institution because of a urinary tract infection. Physical examination showed mild jaundice and a moderately enlarged spleen palpa-

TABLE I. Laboratorv Values

Patient 1 Patient 2 Patient 3 Measure N values 1948 1969 1982 1960 1984 1978

Hemoglobin (g/dl) 14 + 2.0 8.8 11.2 10.7 8.2 13.0 10.4 Hematocrit (%) 41 & 5 28 33 31 26 41 29 MCV (fl) 84 & 7 102 90 92 100 102 Reticulocytes (%) < I 0.3 0.3 0.6 0.4 1.1 Ind. bilirubin (mmol/liter) < 17 40 53 45 62 40 Cholesterol (mrnol/liter) 4.5 * 7.3 3.2 3.5 3.7 4.07 Vitamin E (mg%) >0.5 0.4 0.4 0.45 SI/IBC (pg%) 156 138 175/240 226/268 137/58 RBC survival (days) 26 13 17

Iron utilization ( W ) > 70 28 25

Sucrose test Ham test + "With one control.

Plasma 59Fe clearance (min) 60-120 25 20

Agglutination with anti-i + + + - - -

a + -

Case Report: Paravertebral Extramedullary Hematopoiesis 297

Fig. 1 . Lateral chest X-ray of patient No. 1. Note large paraspinal mass in the midthoracic region.

ble 2 cm below the costal margin. Laboratory studies revealed a normocytic, normo- chromic anemia with normal reticulocyte, leukocyte, and platelet counts, low levels of cholesterol and vitamin E and an indirect bilirubin of 45 mmol/liter. Hemoglobin electrophoresis and enzymatic activity of the red blood cells were normal (Table I). From 1960 until 1984, the patient received blood once only, during pregnancy. In March, 1984, she began to complain of left scapular pain. A chest X-ray revealed the presence of thoracic masses. On physical examination, jaundice and moderate hepa- tosplenomegaly were present. The hemoglobin level was 13.0 g/dl and the reticulo- cyte count 0.4%. Other hematological and laboratory data were comparable to the previous findings in this patient (Table I). The bone marrow showed numerous binucleated and multinucleated normoblasts and a mild proliferation of lymphocytes and plasma cells. The dyserythropoietic changes in the bone marrow, the chronic hemolytic anemia with ineffective erythropoiesis, and the family history of dysery- thropoietic anemia were compatible with the diagnosis of CDA type 11, or HEMPAS. Chest X-ray and spine tomography revealed several cystic masses in the posterior mediastinum, from the first to the sixth thoracic vertebrae. A chest CT scan showed these masses to be contiguous to the vertebral bodies (Fig. 2). A fine-needle aspiration biopsy of one of the masses was performed, and the cytology showed a proliferation of normoblasts without multinuclearity (Fig. 3) and megakaryocytes, thus identifying the mass as hematopoietic tissue.

Case No. 3 A 50-year-old man, the brother of the two previosuly described patients, was

hospitalized in the Department of Medicine in April, 1978, because of primary hypothyroidism. In light of the family history of chronic hemolytic anemia, specific laboratory tests were performed (Table I) and demonstrated a chronic hemolytic

298 Case Report: Lugassy et al

Fig. 2. CT scan of patient No. 2 through the region of the upper abdomen clearly shows bilateral paraspinal masses.

Fig. 3. Patient No. 2 . Photomicrograph of bone marrow ( X 1,200) shows typical dyserythropoietic changes (left) and normal erythroid morphology in the extramedullary hematopoietic mass (right; x 1,024).

Case Report: Paravertebral Extramedullary Hematopoiesis 299

process with ineffective erythropoiesis and severe characteristic dyserythropoietic changes in the peripheral blood and the bone marrow. Positive agglutination with anti-i and a positive Ham test confirmed the diagnosis of HEMPAS, but in contrast to his sisters no paravertebral masses could be demonstrated by radiological studies.

DISCUSSION

Although rare, HEMPAS is encountered in Israel particularly among Jewish families of Moroccan or Kurdish origin. Efrati and Berrebi [2] described HEMPAS in seven such families. The authors emphasized the presence in all these patients of Gaucher-like cells, the lack of association with more common causes of hemolytic anemia (ie, thalassemia) , and an occasional favorable response to splenectomy . Eldor et a1 [3] described three siblings from a Kurdish family with aberrant CDA and thalassemic features.

Our three patients of Moroccan origin presented with the typical hematological and serological features of HEMPAS (Table I). Thoracic masses of extramedullary hematopoiesis as found in the two sisters have not been previously described in HEMPAS. By virtue of their location, extramedullary foci may occasionally cause deleterious side effects [4]. In addition, hemopoiesis in such extramedullary foci is usually ineffective. In our patients, not only were the masses asymptomatic, and their appearance associated with remission of the anemia, but the morphology of the red cell precursors was normal (Fig. 3), whereas a simultaneous bone marrow was still consistent with HEMPAS. Although this discrepancy remains unexplained, it seems likely that the appearance of these masses accounted for the correction of the patients’ anemia.

HEMPAS patients usually do not have spontaneous remissions [ 1,2]. This was also demonstrated by our third patient, who lacked identifiable hemopoietic foci and had a persistent, stable anemia.

Extramedullary hematopoiesis is a rare phenomenon occurring only in a few chronic hematological diseases. It constitutes a compensatory mechanism for a pro- longed hemolytic anemia or bone marrow replacement. Usually, extramedullary hematopoiesis is found as microscopic foci. Less frequently, the ectopic marrow forms macroscopic masses, the paravertebral region being the most common site [5-71. Thalassemia intermedia is the most frequently encountered clinical condition featuring macroscopic masses of extramedullary hematopoiesis [8]. In this disease, the anemia is usually mild, and blood transfusions are seldom required. Hence the erythropoietic stimulus due to the chronic hemolysis is not depressed by repeated transfusions. Furthermore, since the life expectancy of these patients is relatively longer than in thalassemia major, the long-term erythropoietic stimulus may lead to the formation of large masses of hematopoietic tissue.

Similarly, the prolonged clinical course of two of our patients (34 and 23 years, respectively), who received no blood transfusions, enabled the development of large mediastinal tumors.

Several other theories have been proposed to explain the presence of the ectopic marrow foci in the epidural space. One possible explanation is that these masses result from stimulation of small embryonic rests of extramedullary hematopoiesis [4,6]. Another mechanism that could best explain the paravertebral location is direct exten- sion in the epidural space from the marrow cavity itself [7].

300 Case Report: Lugassy et al

In most cases when paravertebral masses have been described in association with chronic hemolytic diseases, it has been emphasized that major diagnostic surgical procedures are unnecessary or even hazardous (81. The appearance of such masses is usually not accompanied by spontaneous correction of the anemia. Consideration of other possible causes for an intrathoracic mass might therefore arise. However, our patients demonstrate that paradoxically such masses can appear with correction of the anemia. They also demonstrate that such masses might not be associated with any adverse effects.

ACKNOWLEDGMENTS

his helpful remarks and assistance in preparation of this manuscript. We are indebted to Dr. J. Spivak from the Johns Hopkins Medical Institute for

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