Ann Hematol (1992) 65:196-198
Annals of
Hematology 9 Springer-Verlag 1992
Clinicopathologic conference* Mediastinal extramedullary hematopoiesis as first manifestation of hereditary spherocytosis A. Pulsoni 1, G. Ferrazza t, F. Malagnino 1, L. Maurillo ~, E. Pescarmona 2, A. Picardi 1, E . A . Rendina 3, and S. AmadorP Departments of 1 Hematology, 2 Histopathology, 3 Thoracic-Surgery, University "La Sapienza", Rome, Italy Received June 25, 1992/Accepted July 31, 1992
Presentation of case A 60-year-old m a n was first seen in April 1991. One month earlier he had complained of fatigue and palpitations: he looked pale. The only relevant finding was a bilateral paravertebral thoracic mass on the chest film (Fig. 1). A total body CT scan confirmed the presence of 2 solid round masses located symmetrically in the paravertebral space at the level of the 8 - 9 t h thoracic vertebrae; image enhancement was low with iodized contrast medium. No enlarged lymph nodes were observed. The spleen was enlarged 2 cm below the costal margin. Nuclear magnetic resonance imaging of the thoracic vertebral region yielded better definition of the two lesions (Fig. 2). The right and left lesions were 1.5• cm and 2.2x4.4 cm in size, respectively. They were hypodense; contrast enhancement with gadolinium was minimal. No relationship was observed between the two lesions and either the spinal cord or the 8th and 9th vertebral foramina, which were normal. The proximal vertebral bodies were also normal. These data suggested the presence of extramedullary hematopoietic tissue and the patient was referred to our department. At admission the patient was asymptomatic and in good general condition. No abnormalities were observed at physical examination, except for a mild splenomegaly. Laboratory blood tests: hemoglobin 15.9 g/dl, red blood cells 5.14• hematocrit 41.9%, mean red cell volume 81 fl, white blood cell count 11.8 x 109/I with a normal differential count, platelet count 331• reticulocyte count 231.3 x 109/1. Total bilirubin was 0.8 mg /dl; one m o n t h earlier it had been 2.6 mg/dl with an un* Clinicopathologic conference held at the Section of Hematology, Department of Human Biopathology, University "La Sapienza" of Rome. Departments of Hematology, Histopathology and Thoracic Surgery participated jointly in this conference. R. Bieger is the editor of this feature Correspondence to: Dr. Alessandro Pulsoni, Hematology - University "La Sapienza", Via Benevento 6, 1-00161 Roma, Italia
conjugated fraction of 2.1 mg/dl. No erythrocyte autoantibodies were detected by the direct and indirect Coombs tests. The blood film contained about 30~ spherocytes. The acidified-glycerol lysis test revealed a markedly increased erythrocyte osmotic fragility (AGLT-50 = 30 seconds; normal values > 30 minutes). Glucose-6phosphate dehydrogenase and pyruvate kinase activities were both increased in relation to the degree of reticulocytosis. The bone marrow aspirate and biopsy showed a hypercellular bone marrow with erythroblastic hyperplasia. Similar studies of the patient's two children revealed a normal pattern for the girl and increased erythrocyte osmotic fragility for the boy.
Fig. 1. Lateral chest film showing paravertebral masses overlying the dorsal spine
197
Fig. 2. MRI: midthoracic scan showing bilateral paravertebral masses
These data suggested a diagnosis of hereditary spherocytosis (HS), although the familial history was negative and the patient's parents had died of apparently unrelated causes.
been described in splenectomized patients with hereditary spherocytosis. One case is very similar to our patient [2]. Extramedullary hematopoiesis is considered to be a compensatory mechanism in chronic hemolytic disease. In hereditary spherocytosis a prolonged period of stimulation is presumably needed to produce detectable lesions, as indicated by the advanced age at diagnosis. Spenectomy can probably prevent the process by reducing hemolysis. The lesions are usually asymptomatic and compression of the proximal structures has not been described. The preference of extramedullary hematopoietic tissue for the intrathoracic region is not clearly understood; a possible explanation is that negative pressure at that site could facilitate the extrusion of hyperplastic hematopoietic tissue from vertebral marrow. The fact that the extramedullary hematopoietic tissue contains not only erythroid precursors but also myeloid cells and megakaryocytes is understandable because these cells originate from a common progenitor but subsequently develop in the presence of different growth factors. In fact, in vitro bone marrow culture experiments have shown that, in order to grow, erythroid colonies require the presence of both erythropoietin and certain growth factors that interact with the undifferentiated progenitors which are capable of inducing a trilineage expansion [10]. The incidence of extramedullary hematopoiesis is reportedly lower among patients with hereditary spherocytosis today than in the past. This is probably due to earlier diagnosis and subsequent splenectomy of patients with hereditary spherocytosis.
Differential Diagnosis Clinical diagnosis Dr. A. Pulson# Bilateral paravertebral masses must be differentiated from lung tumors, neurogenic tumors, lymphomas, aneurysms and mesenchymal tumors. The regular round shape with definite limits excluded the possibility of a lung tumor. Neurogenic tumors are usually monolateral, although the radiographic image can be very similar to that described for this patient. The localization in the paravertebral space, the absence of enlarged lymph nodes at physical examination and on the CT scan, and the normal bone marrow biopsy did not support a clinical diagnosis of lymphoma. The image on the CT scan after the contrast injection as well as the MR image clearly eliminated the possibility of a vascular origin of the lesions. The hypothesis of hematopoietic heretotopic tissue was then considered; however other kinds of lesion requiring specific treatment can only be excluded by biopsy. The combination of heterotopic hematopoietic tissue and hereditary spherocytosis is rare. A review of literature, using the M E D L I N E database, revealed only three well-documented cases of exreamedullary hematopoiesis in the last 10 years [2, 3, 12]. More cases were described before 1960 [1, 4, 5, 7, 8, 9]. The most frequent presentation is that of bilateral paravertebral retropleural masses located in the inferior mediastinum. Diagnosis of extramedullary hematopoiesis usually occurs in the fifth-seventh decade. The thoracic masses are asymptomatic. Extramedullary hematopoiesis has never
Hereditary spherocytosis with mediastinal localization of heterotopic hematopoietic tissue in a non-splenectomized adult patient. Dr. E . A . Rendina: At the time of referral to the Thoracic Surgery Department, the patient was in excellent general condition with neither signs nor symptoms of either mediastinal compression or infiltration. Posterior mediastinal tumors in the adult are usually neurogenic in nature. The radiological appearance of a posterior mediastinal neurinoma is very similar to that of extramedullary hematopoietic tissue; however, the latter is characterized by a lower tissue density on CT and MR scans and the typical bilateral occurrence. The lesions were clearly benign in appearance and the suspicion of a hematopoietic origin indicated a noninvasive approach. After carefull evaluation, simple biopsy was preferred over a more aggressive approach as the first step of treatment. However, transparietal needle biopsy was excluded because of the risk of uncontrolled endopleural bleeding. Our choice for an optimum diagnostic procedure with minimal surgical trauma and discomfort to the patient was a bilateral thoracoscopy under general anesthesia. Thoracoscopy was first performed on the left side, where the lesion was larger. A soft, purple mass was visible in the subpleural space and multiple biopsies were taken. After insertion of a chest tube into the left pleural
198
Addendum To reduce hemolysis and the associated erythrogenic stimulus, the patient then underwent splenectomy. The spleen was enlarged (15 x 17 x 4 cm, 485 g). Gross examination revealed two subcapsular infarcts. Histologically, there was marked congestion in the red pulp with no evidence o f myeloid metaplasia.
References
Fig. 3. Tumor Histology. Extramedullary hemopoietic tissue characterized by prominent erythroblastic hyperplasia. Some megakaryocytes are also present (arrows). (H/E, x 100)
space, the same procedure was carried out on the right side. The patient was discharged f r o m hospital on the second post-operative day. Dr. E. Pescarmona: Histologically, the lesion was composed o f hematopoietic tissue characterized by erythroblastic hyperplasia. Myeloid precursors and megakaryocytes were also present. Mature adipose tissue represented 10-20~ o f the lesion (Fig. 3). The pathological differential diagnosis was mediastinal extra-medullary h e m a t o poiesis or myelolipoma. The latter, which is c o m p o s e d o f mature fat cells and n o r m a l b o n e m a r r o w elements, is usually located in the adrenal glands and the retroperiton e u m and is almost always unilateral. To our knowledge, myelolipoma is not associated with hematological disorders and has never been described in the mediastinum, in contrast to extramedullary hematopoiesis [6, 11]. Thus, a diagnosis o f extramedullary hematopoiesis of the mediastinum was made.
Pathological diagnosis Mediastinal extramedullary hematopoiesis. spherocytosis.
Hereditary
1. Ask-Upmark E (1945) Tumor simulating intrathoracic heterotopia of bone marrow. Acta Radiol 26:425-440 2. Bastion Y, Coiffier B, Felman P, Assouline D, Tigaud JD, Espinouse D, Bryon PA (1990) Massive mediastinal extramedullary hematopoiesis in hereditary spherocytosis: A case report. Am J Hematol 35:263-265 3. Borgies P, Ferrant A, Leners N, Michaux JL, Bol A, Michel C, Cogneau M, Sokal G (1989) Diagnosis of heterotopic bone marrow in the mediastinum using 52Fe and positron emission tomography. Eur J Nucl Med 15:761-763 4. Coventry WD, La Bree RH (1960) Heterotopia of bone marrow simulating mediastinal tumor: a manifestation of chronic hemolytic anemia in adults. Ann Intern Med 53: 1042-1052. 5. Dawson BE (1931) Hume lectures on haemolytic icterus. Br Med J 1:963-966 6. Fowler MR, Williams GB, Alba JM, Byrd CR (1982) Extraadrenal myelolipomas compared with extramedullary hematopoietic tumors: a case of presacral myelolipoma. Am J Surg Pathol 6:363-374 7. Gleave HH (1936) Paravertebral heterotopia of bone marrow in a case of acholuric jaundice. J Pathol Bacteriol 42:538-539 8. Hanford RB, Schneider GF, MacCarthy JD (1960) Massive thoracic extramedullary hemopoiesis. New Engl J Med 263: 120-123 9. Hartfall SJ, Stewart M J, (1933) Massive paravertebral heterotopia of bone marrow in a case of acholuric jaundice. J Pathol Bacteriol 37:455-459 10. Metcalf D (1984) The hemopoietic colony stimulating factors. New York Elsevier 11. Noble MJ, Montague DK, Levin HS (1982) Myelolipoma. An Unusual surgical lesion of the adrenal gland. Cancer 49: 952-958 12. Petit JJ, Estany C (1987) Case report: mediastinal extramedullary erythropoiesis in hereditary spherocytosis. Clin Lab Haematol 9:327-332
Annals of
Hematology 9 Springer-Verlag 1992
Clinicopathologic conference* Mediastinal extramedullary hematopoiesis as first manifestation of hereditary spherocytosis A. Pulsoni 1, G. Ferrazza t, F. Malagnino 1, L. Maurillo ~, E. Pescarmona 2, A. Picardi 1, E . A . Rendina 3, and S. AmadorP Departments of 1 Hematology, 2 Histopathology, 3 Thoracic-Surgery, University "La Sapienza", Rome, Italy Received June 25, 1992/Accepted July 31, 1992
Presentation of case A 60-year-old m a n was first seen in April 1991. One month earlier he had complained of fatigue and palpitations: he looked pale. The only relevant finding was a bilateral paravertebral thoracic mass on the chest film (Fig. 1). A total body CT scan confirmed the presence of 2 solid round masses located symmetrically in the paravertebral space at the level of the 8 - 9 t h thoracic vertebrae; image enhancement was low with iodized contrast medium. No enlarged lymph nodes were observed. The spleen was enlarged 2 cm below the costal margin. Nuclear magnetic resonance imaging of the thoracic vertebral region yielded better definition of the two lesions (Fig. 2). The right and left lesions were 1.5• cm and 2.2x4.4 cm in size, respectively. They were hypodense; contrast enhancement with gadolinium was minimal. No relationship was observed between the two lesions and either the spinal cord or the 8th and 9th vertebral foramina, which were normal. The proximal vertebral bodies were also normal. These data suggested the presence of extramedullary hematopoietic tissue and the patient was referred to our department. At admission the patient was asymptomatic and in good general condition. No abnormalities were observed at physical examination, except for a mild splenomegaly. Laboratory blood tests: hemoglobin 15.9 g/dl, red blood cells 5.14• hematocrit 41.9%, mean red cell volume 81 fl, white blood cell count 11.8 x 109/I with a normal differential count, platelet count 331• reticulocyte count 231.3 x 109/1. Total bilirubin was 0.8 mg /dl; one m o n t h earlier it had been 2.6 mg/dl with an un* Clinicopathologic conference held at the Section of Hematology, Department of Human Biopathology, University "La Sapienza" of Rome. Departments of Hematology, Histopathology and Thoracic Surgery participated jointly in this conference. R. Bieger is the editor of this feature Correspondence to: Dr. Alessandro Pulsoni, Hematology - University "La Sapienza", Via Benevento 6, 1-00161 Roma, Italia
conjugated fraction of 2.1 mg/dl. No erythrocyte autoantibodies were detected by the direct and indirect Coombs tests. The blood film contained about 30~ spherocytes. The acidified-glycerol lysis test revealed a markedly increased erythrocyte osmotic fragility (AGLT-50 = 30 seconds; normal values > 30 minutes). Glucose-6phosphate dehydrogenase and pyruvate kinase activities were both increased in relation to the degree of reticulocytosis. The bone marrow aspirate and biopsy showed a hypercellular bone marrow with erythroblastic hyperplasia. Similar studies of the patient's two children revealed a normal pattern for the girl and increased erythrocyte osmotic fragility for the boy.
Fig. 1. Lateral chest film showing paravertebral masses overlying the dorsal spine
197
Fig. 2. MRI: midthoracic scan showing bilateral paravertebral masses
These data suggested a diagnosis of hereditary spherocytosis (HS), although the familial history was negative and the patient's parents had died of apparently unrelated causes.
been described in splenectomized patients with hereditary spherocytosis. One case is very similar to our patient [2]. Extramedullary hematopoiesis is considered to be a compensatory mechanism in chronic hemolytic disease. In hereditary spherocytosis a prolonged period of stimulation is presumably needed to produce detectable lesions, as indicated by the advanced age at diagnosis. Spenectomy can probably prevent the process by reducing hemolysis. The lesions are usually asymptomatic and compression of the proximal structures has not been described. The preference of extramedullary hematopoietic tissue for the intrathoracic region is not clearly understood; a possible explanation is that negative pressure at that site could facilitate the extrusion of hyperplastic hematopoietic tissue from vertebral marrow. The fact that the extramedullary hematopoietic tissue contains not only erythroid precursors but also myeloid cells and megakaryocytes is understandable because these cells originate from a common progenitor but subsequently develop in the presence of different growth factors. In fact, in vitro bone marrow culture experiments have shown that, in order to grow, erythroid colonies require the presence of both erythropoietin and certain growth factors that interact with the undifferentiated progenitors which are capable of inducing a trilineage expansion [10]. The incidence of extramedullary hematopoiesis is reportedly lower among patients with hereditary spherocytosis today than in the past. This is probably due to earlier diagnosis and subsequent splenectomy of patients with hereditary spherocytosis.
Differential Diagnosis Clinical diagnosis Dr. A. Pulson# Bilateral paravertebral masses must be differentiated from lung tumors, neurogenic tumors, lymphomas, aneurysms and mesenchymal tumors. The regular round shape with definite limits excluded the possibility of a lung tumor. Neurogenic tumors are usually monolateral, although the radiographic image can be very similar to that described for this patient. The localization in the paravertebral space, the absence of enlarged lymph nodes at physical examination and on the CT scan, and the normal bone marrow biopsy did not support a clinical diagnosis of lymphoma. The image on the CT scan after the contrast injection as well as the MR image clearly eliminated the possibility of a vascular origin of the lesions. The hypothesis of hematopoietic heretotopic tissue was then considered; however other kinds of lesion requiring specific treatment can only be excluded by biopsy. The combination of heterotopic hematopoietic tissue and hereditary spherocytosis is rare. A review of literature, using the M E D L I N E database, revealed only three well-documented cases of exreamedullary hematopoiesis in the last 10 years [2, 3, 12]. More cases were described before 1960 [1, 4, 5, 7, 8, 9]. The most frequent presentation is that of bilateral paravertebral retropleural masses located in the inferior mediastinum. Diagnosis of extramedullary hematopoiesis usually occurs in the fifth-seventh decade. The thoracic masses are asymptomatic. Extramedullary hematopoiesis has never
Hereditary spherocytosis with mediastinal localization of heterotopic hematopoietic tissue in a non-splenectomized adult patient. Dr. E . A . Rendina: At the time of referral to the Thoracic Surgery Department, the patient was in excellent general condition with neither signs nor symptoms of either mediastinal compression or infiltration. Posterior mediastinal tumors in the adult are usually neurogenic in nature. The radiological appearance of a posterior mediastinal neurinoma is very similar to that of extramedullary hematopoietic tissue; however, the latter is characterized by a lower tissue density on CT and MR scans and the typical bilateral occurrence. The lesions were clearly benign in appearance and the suspicion of a hematopoietic origin indicated a noninvasive approach. After carefull evaluation, simple biopsy was preferred over a more aggressive approach as the first step of treatment. However, transparietal needle biopsy was excluded because of the risk of uncontrolled endopleural bleeding. Our choice for an optimum diagnostic procedure with minimal surgical trauma and discomfort to the patient was a bilateral thoracoscopy under general anesthesia. Thoracoscopy was first performed on the left side, where the lesion was larger. A soft, purple mass was visible in the subpleural space and multiple biopsies were taken. After insertion of a chest tube into the left pleural
198
Addendum To reduce hemolysis and the associated erythrogenic stimulus, the patient then underwent splenectomy. The spleen was enlarged (15 x 17 x 4 cm, 485 g). Gross examination revealed two subcapsular infarcts. Histologically, there was marked congestion in the red pulp with no evidence o f myeloid metaplasia.
References
Fig. 3. Tumor Histology. Extramedullary hemopoietic tissue characterized by prominent erythroblastic hyperplasia. Some megakaryocytes are also present (arrows). (H/E, x 100)
space, the same procedure was carried out on the right side. The patient was discharged f r o m hospital on the second post-operative day. Dr. E. Pescarmona: Histologically, the lesion was composed o f hematopoietic tissue characterized by erythroblastic hyperplasia. Myeloid precursors and megakaryocytes were also present. Mature adipose tissue represented 10-20~ o f the lesion (Fig. 3). The pathological differential diagnosis was mediastinal extra-medullary h e m a t o poiesis or myelolipoma. The latter, which is c o m p o s e d o f mature fat cells and n o r m a l b o n e m a r r o w elements, is usually located in the adrenal glands and the retroperiton e u m and is almost always unilateral. To our knowledge, myelolipoma is not associated with hematological disorders and has never been described in the mediastinum, in contrast to extramedullary hematopoiesis [6, 11]. Thus, a diagnosis o f extramedullary hematopoiesis of the mediastinum was made.
Pathological diagnosis Mediastinal extramedullary hematopoiesis. spherocytosis.
Hereditary
1. Ask-Upmark E (1945) Tumor simulating intrathoracic heterotopia of bone marrow. Acta Radiol 26:425-440 2. Bastion Y, Coiffier B, Felman P, Assouline D, Tigaud JD, Espinouse D, Bryon PA (1990) Massive mediastinal extramedullary hematopoiesis in hereditary spherocytosis: A case report. Am J Hematol 35:263-265 3. Borgies P, Ferrant A, Leners N, Michaux JL, Bol A, Michel C, Cogneau M, Sokal G (1989) Diagnosis of heterotopic bone marrow in the mediastinum using 52Fe and positron emission tomography. Eur J Nucl Med 15:761-763 4. Coventry WD, La Bree RH (1960) Heterotopia of bone marrow simulating mediastinal tumor: a manifestation of chronic hemolytic anemia in adults. Ann Intern Med 53: 1042-1052. 5. Dawson BE (1931) Hume lectures on haemolytic icterus. Br Med J 1:963-966 6. Fowler MR, Williams GB, Alba JM, Byrd CR (1982) Extraadrenal myelolipomas compared with extramedullary hematopoietic tumors: a case of presacral myelolipoma. Am J Surg Pathol 6:363-374 7. Gleave HH (1936) Paravertebral heterotopia of bone marrow in a case of acholuric jaundice. J Pathol Bacteriol 42:538-539 8. Hanford RB, Schneider GF, MacCarthy JD (1960) Massive thoracic extramedullary hemopoiesis. New Engl J Med 263: 120-123 9. Hartfall SJ, Stewart M J, (1933) Massive paravertebral heterotopia of bone marrow in a case of acholuric jaundice. J Pathol Bacteriol 37:455-459 10. Metcalf D (1984) The hemopoietic colony stimulating factors. New York Elsevier 11. Noble MJ, Montague DK, Levin HS (1982) Myelolipoma. An Unusual surgical lesion of the adrenal gland. Cancer 49: 952-958 12. Petit JJ, Estany C (1987) Case report: mediastinal extramedullary erythropoiesis in hereditary spherocytosis. Clin Lab Haematol 9:327-332
