Author's Accepted Manuscript
Extramedullary Hemopoiesis Eleni Orphanidou-Vlachou MBChB, PhD, Chrysa Tziakouri-Shiakalli MD, PhD, Christos Georgiades MD, PhD, FSIR
www.elsevier.com/locate/enganabound
PII: DOI: Reference:
S0887-2171(13)00146-7 http://dx.doi.org/10.1053/j.sult.2013.12.001 YSULT569
To appear in: Semin Ultrasound CT MRI
Cite this article as: Eleni Orphanidou-Vlachou MBChB, PhD, Chrysa Tziakouri-Shiakalli MD, PhD, Christos Georgiades MD, PhD, FSIR, Extramedullary Hemopoiesis, Semin Ultrasound CT MRI , http://dx.doi.org/10.1053/j.sult.2013.12.001 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Extramedullary Hemopoiesis Eleni Orphanidou‐Vlachou1, Chrysa Tziakouri‐Shiakalli2, Christos Georgiades3 1. Eleni Orphanidou‐Vlachou MBChB PhD Radiology Trainee Department of Radiology Nicosia General Hospital Nicosia, Cyprus [email protected] 2. Tziakouri Shiakalli Chrysa MD,PhD Interventional Radiologist Deputy Director Radiology Department Nicosia General Hospital Cyprus Email: kithreas @cytanet.com.cy [email protected] 3. Christos Georgiades MD PhD FSIR Director, Vascular & Interventional Radiology American Medical Center Nicosia, Cyprus [email protected]
Name of Institution where the work reported was done: Nicosia General Hospital, Archbishop Makarios III Hospital Grant support: none Corresponding author: Christos S Georgiades MD PhD FSIR American Medical Center, 215 Spyrou Kyprianou Avenue, 2047 Nicosia, Cyprus (357)‐22‐476777 [email protected] Abstract Various chronic hematological disorders that lead to ineffective hemopoiesis or inadequate bone marrow function (i.e. chronic hemolytic anemias, thalassemia, sickle cell anemia, myelofibrosis of many causes, lymphoma, leukemia) can potentially precipitate extra‐marrow new blood element creation. Extra marrow soft tissue that produces blood elements is called extramedullary hemopoietic tissue and the process extramedullary hemopoiesis (EMH). Sites commonly involved by extramedullary hemopoiesis include the liver, spleen, lymph nodes and most commonly paravertebral regions, although other sites can sometimes be involved. Physicians rarely consider extramedullary hemopoiesis in their differential diagnosis even in cases where it is warranted (diseases of ineffective erythropoiesis). This is likely because of the rarity of the condition and because
imaging findings are non‐specific. We present here a systematic review the imaging findings in extramedullary hemopoiesis. Extramedullary Hemopoiesis Various chronic hematological disorders that lead to ineffective hemopoiesis or inadequate bone marrow function (i.e. chronic hemolytic anemias, thalassemia, sickle cell anemia, myelofibrosis of many causes, lymphoma, leukemia) can potentially precipitate extra‐marrow new blood element creation. Extra marrow soft tissue that produces blood elements is called extramedullary hemopoietic tissue and the process extramedullary hemopoiesis (EMH). The incidence of EMH is highest in chronic hemolytic anemias, especially thalassemia intermedia. The transfusion‐independence in patients with thalassemia intermedia causes greater pressure for the compensatory mechanisms leading to EMH (compared to for example, poly‐transfused thalassemia major patients) (1). There are two sources of EMH, one seen when normal hemopoietic tissue expands outside the bone marrow medulla, through permeative erosions of the inner cortex and a second seen when previously hemopoietic tissues that become normally dormant are reactivated. It should be obvious then that findings can be non‐ specific and mimic other diseases including malignancies. Because EMH masses can mimic neoplasms, tissue biopsy may be required to exclude that diagnosis. These lesions most often are detected incidentally on imaging, but sometimes can present due to
mass effect, such as in the case of spinal cord compression from intraspinal canal lesions (2, 3). Ineffective erythropoiesis also leads to expansion of bone marrow space in the ribs, long bones, vertebral column, skull and characteristically, facial bones and may lead to osteoporosis. The medulla expands, cortical bone thins and cancellous bone is resorbed, leading to bone density loss. Furthermore, premature fusion of the growth plates in tubular bones of the extremities is common in children with thalassemia major (3) resulting in physical growth delays. Sites commonly involved by extramedullary hemopoiesis include the liver, spleen, lymph nodes and most commonly the paravertebral regions. The thymus, heart, breasts, prostate, broad ligaments, kidneys, adrenal glands, pleura, retroperitoneal tissue, skin, peripheral and cranial nerves and the spinal canal may also be involved (2). These sites are thought to be involved in active hematopoiesis in the fetus, and although their activity ceases at birth, the extramedullary hemopoietic vascular connective tissues retain the ability to produce red cells, in cases of chronic ineffective erythropoiesis (1). Head & Neck EMH is rare in the head and neck, but has been reported in the nasopharynx, paranasal sinuses, middle ear, lacrimal fossa, cervical lymph nodes, thyroid gland and paratracheal area (4, 5). EMH can rarely occur in the nasopharynx, causing obstructive sleep apnea (6). T1‐ and T2‐weighted MRI may show a hyperintense mass in the mucosa of the pharynx/nasopharynx, or a diffusely T2‐hyperintense thickening of the nasopharyngeal
mucosa (2). Another rare location for EMH is the paranasal sinuses (7), most commonly the maxillary sinus, where it is usually asymptomatic. It has also been reported in the ethmoid and sphenoid sinuses (4), and may be confused with chronic sinusitis and/or mucoceles. CT imaging reveals a soft tissue mass occupying the paranasal sinuses, which maybe partially calcified, a characteristic of chronicity or a “burnt‐out” lesion. MR imaging demonstrates a mass with variable signal intensity on T1 weighted imaging and a T2‐hyperintense mass with homogeneous contrast enhancement (2, 4). Occasionally and especially in thalassemia major, the marrow of the skull can expand and erode cortical bone (Figs. 1, 2) giving rise to the “hair‐on‐end” appearance. Chest The paravertebral region is a very common site (probably the most common) for extramedullary hemopoietic tissue, and when this happens it presents as large multi‐ lobed, paravertebral thoracic masses. They rarely cause significant symptoms, such as dyspnea, pleural effusion or hemothorax (2). If paraspinal hemopoietic tissues extend into the central canal, neurologic symptoms of spinal cord compression are observed (8). Chest X‐Ray reveals smooth, well demarcated paraspinal masses (2, 8) (Figs. 3, 4, 5). Rib (Figs. 3, 4, 6) or diploic space (Figs. 1, 2) (“hair‐on‐end appearance”) expansion can occur, especially in thalassemia (8). These and other radiological signs of chronic anemia, such as cardiomegaly, and clinical features such as high‐output cardiac failure suggest the diagnosis of EMH (2, 8).
On computed tomography (CT) images, EMH paravertebral masses appear isodense to adjacent muscle, smooth and well marginated and usually do not erode adjacent bone from outside‐in (Figs. 7, 8, 9). Actively hemopoietic masses demonstrate mild homogeneous enhancement post‐contrast (high vascularity), whereas old burnt‐out lesions have inhomogeneous contrast‐enhancement due to iron deposition and fat infiltration (2, 8, 9). These paraspinal masses are characteristic as they involve multiple levels in a bilateral distribution and are nearly symmetric. Very few other diseases can present thusly and therefore, the diagnosis of EMH should be strongly considered in such cases. MR imaging can be useful for further evaluation of paravertebral masses (Figs.10, 11, 12), although findings are non‐specific (2, 8). Fat within the paravertebral masses gives high signal intensity on T1‐ and T2‐weigthed images (2).
Abdomen and Pelvis The commonest sites of EMH in the abdomen are the liver, spleen and lymph nodes, all sites of in‐utero hemopoietic activity. Signs and symptoms include hepatosplenomegaly (Figs. 13, 14, 15) and abdominal discomfort, as well as shortness of breath in the case of massive enlargement (2, 8). Pain can be the presenting symptom if splenic infarction occurs (2). Hepatosplenomegaly can be detected on cross‐sectional imaging (CT, MRI, US) and 99mTc methylene diphosphonate whole body bone scan (2, 8). Usually there are no focal liver or splenic lesions in EMH, but rarely CT can reveal foci of EMH noted as uniformly low‐attenuation lesions with clear margins (Figs. 16, 17). On T1‐ weighted MRI these can be seen as hypointense masses, and slightly hyperintense compared to liver parenchyma on T2‐weighted MRI (Fig. 18) (8). Follow‐up imaging with clinical correlation or image‐guided biopsy is required to confirm the diagnosis of EMH. Multiple involved, enlarged retroperitoneal lymph nodes may also be detected (2). In transfusion‐dependent chronic anemia, multiple transfusions can lead to secondary hemosiderosis and/or hemochromatosis. This is detected as a homogeneous increase in the density of the liver and spleen on CT as a result of iron deposition, and low signal on T1‐ and T2‐weighted MRI (Figs. 18, 19 ) and may complicate the appearance of liver involved by EMH (2, 8). Albeit it rarely, the kidneys may also be involved by EMH, which may present as uniform
enhancing perinephric masses engulfing the kidneys (Fig. 20). The masses do not distort the shape of the kidneys and may present a diagnostic dilemma; difficult to distinguish from renal lymphoma (8). On ultrasonography, they can appear as echogenic masses that replace most of the pelvocalyceal system of the kidneys (10). EMH may also involve the mesentery, and needs to be differentially diagnosed from lymphadenopathy or metastatic disease (8). Presacral pelvic hemopoietic masses are rare, and present as well‐marginated, lobulated masses, with soft tissue density, with or without bony erosion on CT. On T1‐ and T2‐ weighted MR imaging, they appear as well‐encapsulated masses, slightly hyperintense (fatty tissue) or isointense to muscle, with uniform gadolinium enhancement (Figs. 21, 22) (2, 8, 9).
Conclusion Extramedullary hemopoiesis is a reactive/compensatory mechanism of new extra‐ marrow blood element formation as a result of chronically ineffective erythropoiesis. It is usually seen in paraspinal areas, the spleen, liver and lymph nodes, although a spectrum of other anatomical sites has been reported, as described above. The rarity of the disease and the non‐specific findings hinder initial consideration of the diagnosis. Physicians need to be aware of this possibility in order to initiate appropriate diagnostic and treatment interventions. Knowledge of the patients’ clinical history is absolutely essential. A history of a disease/condition resulting in chronically ineffective hemopoiesis should prompt the physician to have a high index of suspicion. The patient’s history, clinical and laboratory findings, together with plain radiography findings of cardiomegaly, rib or diploic space expansion can quickly point the physician in the diagnostic possibility of EMH. There are clearly described imaging findings in plain radiography, computed tomography, magnetic resonance imaging and bone scans, which can establish the diagnosis in the appropriate context. Follow‐up imaging or tissue biopsy may sometimes be required to clarify the differential diagnosis, especially in tumor‐like lesions. Acknowledgments: We would like to thank Dr. Sotiroulla Christou from the Cyrpus Thalassaemia Centre, for her help with identifying patients with relevant findings and their clinical histories.
References 1. Haidar R, Mhaidli H, Taher AT. Paraspinal extramedullary hematopoiesis in patients with thalassemia intermedia. Eur Spine J. 19(6):871‐8, 2010 2. Sohawon D, Lau KK, Lau T, et al. Extra‐medullary haematopoiesis: A pictorial review of its typical and atypical locations. J Med Imaging Radiat Oncol. 56:538‐44, 2012 3. Zhu G, Wu X, Zhang X, et al. Clinical and Imaging Findings in thalassemia patients with extramedullary hematopoiesis. Clin Imaging 36:475‐82, 2012 4. Saito N, Nadgir RN, Flower EN, et al. Clinical and Radiologic Manifestations of Sickle Cell Disease in the Head and Neck. Radiographics. 30(4):1021‐34, 2010 5. Kurtman C, Ozbilgin MK, Andrieu MN, et al. Paratracheal extramedullary hematopoiesis. Int J Hematol. 73(4):492‐5, 2001 6. Kapelushnik J, Shalev H, Schulman H, et al. Upper airway obstruction‐related sleep apnea in a child with thalassemia intermedia. J Pediatr Hematol Oncol. 23(8):525‐6, 2001 7. Bizzoni A, Lombardi D, Maroldi R, et al. Extramedullary hematopoiesis: A rare occurrence in the sinonasal tract. Auris, nasus, larynx. 37(2):233‐7, 2010 8. Georgiades CS, Neyman EG, Francis IR, et al. Typical and Atypical Presentations of Extramedullary Hemopoiesis AJR Am J Roentgenol. 179:1239‐43, 2002 9. Işık Balcı Y, Kaya V, Ateşçi MS. Presacral and intrathoracic extramedullary hematopoiesis: a case report. Clin Imaging. 36(4):406‐8, 2012
10. Kwak H. S., Lee J. Μ. CT findings of extramedullary hematopoiesis in the thorax, liver and kidneys, in a patient with idiopathic myelofibrosis. J Korean Med Sci. 15(4):460‐2, 2000 Legends Figure 1. Lateral skull radiograph of a 40 year‐old man with thalassemia major. Image demonstrates diploic space expansion with “hair‐on‐end appearance” as the marrow expands through the thinned cortex (arrowheads). Figure 2. Mid‐sagittal T1‐w image of a 49‐year old male with a history of thalassemia. Image demonstrates diploic space expansion and cortical thinning (arrowheads). Figure 3. PA chest film of a 55‐year old male with a history of thalassemia intermedia who was transfusion‐independent for many years. The image demonstrates very large paraspinal masses (star and long arrow) and rib expansion (small arrow). Figure 4. AP chest film of a 25 year‐old‐male with thalassemia and known paraspinal extramedullary hemopoiesis. Image shows diffuse expansion of the ribs (arrowheads) and paraspinal soft tissue mass (arrow). Figure 5. PA and lateral chest films of a young female with history of thalassemia and known extramedullary hemopoiesis. Images show bilateral, bulky paraspinal soft tissue
masses (arrowheads) compatible with extramedullary hemopoiesis. Images courtesy Dr Michael B. Sneider, University of Michigan. Figure 6. PA chest film of a 50 year‐old man with thalassemia intermedia who has not required blood transfusions. The image demonstrates marked, bilateral, symmetric rib expansion (arrows). Figure 7. Axial CT through the chest of a 59‐year old man with a history of thalassemia intermedia. The image demonstrates smooth, uniformly dense, well‐marginated paravertebral masses with no bony‐erosion (arrowheads). Figure 8. Axial CT image through the chest of a 49 year‐old male with a history of thalassemia. The image shows paravertebral and juxta‐coastal EMH masses. Marked osteoporosis of the vertebral body and mild rib expansion (arrowheads) is also noted. Figure 9. Axial contrast‐enhanced, CT image through the chest of a young female with a history of thalassemia and known extramedullary hemopoiesis. The image demonstrates uniformly enhancing, hemopoietic masses without bony erosion (arrows). Images courtesy Dr Michael B. Sneider, University of Michigan. Figure 10. T2‐w MR image through the chest of a 52‐year old male with a history of
thalassemia intermedia who has not received blood transfusions. Image demonstrates rib expansion and paravertebral masses (arrowheads) which are slightly hyperintense to muscle. Figure 11. Axial T2‐w MR image through the chest of a 53‐year old male with a history of thalassemia demonstrating homogeneous paravertebral EMH masses (arrows). Figure 12. Axial T2‐w MR image through the chest of a 53‐year old male with a history of thalassemia intermedia, demonstrating large, hyper‐intense heterogeneous paravertebral masses and rib expansion (arrows). Figure 13. Frontal abdominal film and reconstructed CT image of a 59‐year old with a history of thalassemia intermedia. There is marked hepatomegaly (arrows) and splenomegaly (arrowheads) as well as visceral displacement towards the midline. Fig. 14. Coronal T1‐weighted MR image of the abdomen of a 51 year‐old‐female with myelofibrosis and splenomegaly on physical examination demonstrates massive splenomegaly (arrowheads) secondary to infiltration by immature hemopoietic elements. Fig. 15. Posterior and anterior views from a T99m‐MDP bone scan of 54 year‐old‐ female with long standing myelofibrosis who presents with shortness of breath and
abdominal pain. Images show massive hepatomegaly that proved to be due to extramedullary hemopoiesis. Fig. 16. Axial contrast enhanced CT(A) and T1‐w MR (B) images through the liver of a 33 year‐old male with unspecified myeloproliferative disorder presenting with abdominal pain. Patient has a history of splenectomy for severe splenomegaly as well cavernous transformation of the portal vein. Images show an ill‐defined mass (star) in the region of the porta‐hepatis which is iso‐intense to the liver parenchyma on MR. The mass proved to be extramedullary hematopoietic tissue. Fig. 17. Axial CT image through the liver dome of a 40 year‐old‐male with sickle cell disease demonstrates two well‐delineated homogeneously low density lesions (arrow). Ultrasound‐guided percutaneous needle biopsy revealed a polymorphous population of mature and immature hemopoietic cells consistent with extramedullary hemopoiesis. Fig. 18. Axial T1 and T2 w MR images through the liver of a 53 year‐old‐male with weight loss and abdominal pain show a T1‐hypointense, T2‐hyperintense, partially exophytic mass from the left lobe of the liver. Percutaneous biopsy showed the mass to be made of mature and immature hemopoietic cells compatible with extramedullary hemopoiesis. The patient was subsequently diagnosed with myelofibrosis. Fig. 19. Axial, non‐contrast enhanced CT image through the liver of a 40 year‐old‐male
with sickle cell disease and 5‐6 painful crises per year presenting with abdominal pain, shows a dense liver parenchyma consistent with hemosiderosis The patient’s history included multiple transfusions.
Fig. 20. Axial CT 2‐years prior to presentation (top) and at presentation (bottom) of a 56 year‐old‐male with myelofibrosis presenting with flank and abdominal pain. The current CT scan shows bilaterally symmetric perinephric masses with minimal enhancement. Biopsy revealed hemopoietic tissue. Fig. 21. Axial CT (top), axial T1‐w MR (bottom) and mid‐sagittal T2‐w MR (right) images of a 49‐year old male with a history of thalassemia. Images show a uniformly enhancing, presacral mass, with clear margins (arrowheads) and mild bony erosion. Fig. 22. Axial CT image through the pelvis of a 48‐year‐old‐male with a history of hemolytic anemia complicated by myelofibrosis. Image reveals a pre‐sacral, soft tissue mass (arrowhead) without bone destruction. Biopsy demonstrated megakaryocytes, erythroid and myeloid precursors characteristic of extramedullary hematopoiesis. Courtesy Dr. Isaac Francis, University of Michigan
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Extramedullary Hemopoiesis Eleni Orphanidou-Vlachou MBChB, PhD, Chrysa Tziakouri-Shiakalli MD, PhD, Christos Georgiades MD, PhD, FSIR
www.elsevier.com/locate/enganabound
PII: DOI: Reference:
S0887-2171(13)00146-7 http://dx.doi.org/10.1053/j.sult.2013.12.001 YSULT569
To appear in: Semin Ultrasound CT MRI
Cite this article as: Eleni Orphanidou-Vlachou MBChB, PhD, Chrysa Tziakouri-Shiakalli MD, PhD, Christos Georgiades MD, PhD, FSIR, Extramedullary Hemopoiesis, Semin Ultrasound CT MRI , http://dx.doi.org/10.1053/j.sult.2013.12.001 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Extramedullary Hemopoiesis Eleni Orphanidou‐Vlachou1, Chrysa Tziakouri‐Shiakalli2, Christos Georgiades3 1. Eleni Orphanidou‐Vlachou MBChB PhD Radiology Trainee Department of Radiology Nicosia General Hospital Nicosia, Cyprus [email protected] 2. Tziakouri Shiakalli Chrysa MD,PhD Interventional Radiologist Deputy Director Radiology Department Nicosia General Hospital Cyprus Email: kithreas @cytanet.com.cy [email protected] 3. Christos Georgiades MD PhD FSIR Director, Vascular & Interventional Radiology American Medical Center Nicosia, Cyprus [email protected]
Name of Institution where the work reported was done: Nicosia General Hospital, Archbishop Makarios III Hospital Grant support: none Corresponding author: Christos S Georgiades MD PhD FSIR American Medical Center, 215 Spyrou Kyprianou Avenue, 2047 Nicosia, Cyprus (357)‐22‐476777 [email protected] Abstract Various chronic hematological disorders that lead to ineffective hemopoiesis or inadequate bone marrow function (i.e. chronic hemolytic anemias, thalassemia, sickle cell anemia, myelofibrosis of many causes, lymphoma, leukemia) can potentially precipitate extra‐marrow new blood element creation. Extra marrow soft tissue that produces blood elements is called extramedullary hemopoietic tissue and the process extramedullary hemopoiesis (EMH). Sites commonly involved by extramedullary hemopoiesis include the liver, spleen, lymph nodes and most commonly paravertebral regions, although other sites can sometimes be involved. Physicians rarely consider extramedullary hemopoiesis in their differential diagnosis even in cases where it is warranted (diseases of ineffective erythropoiesis). This is likely because of the rarity of the condition and because
imaging findings are non‐specific. We present here a systematic review the imaging findings in extramedullary hemopoiesis. Extramedullary Hemopoiesis Various chronic hematological disorders that lead to ineffective hemopoiesis or inadequate bone marrow function (i.e. chronic hemolytic anemias, thalassemia, sickle cell anemia, myelofibrosis of many causes, lymphoma, leukemia) can potentially precipitate extra‐marrow new blood element creation. Extra marrow soft tissue that produces blood elements is called extramedullary hemopoietic tissue and the process extramedullary hemopoiesis (EMH). The incidence of EMH is highest in chronic hemolytic anemias, especially thalassemia intermedia. The transfusion‐independence in patients with thalassemia intermedia causes greater pressure for the compensatory mechanisms leading to EMH (compared to for example, poly‐transfused thalassemia major patients) (1). There are two sources of EMH, one seen when normal hemopoietic tissue expands outside the bone marrow medulla, through permeative erosions of the inner cortex and a second seen when previously hemopoietic tissues that become normally dormant are reactivated. It should be obvious then that findings can be non‐ specific and mimic other diseases including malignancies. Because EMH masses can mimic neoplasms, tissue biopsy may be required to exclude that diagnosis. These lesions most often are detected incidentally on imaging, but sometimes can present due to
mass effect, such as in the case of spinal cord compression from intraspinal canal lesions (2, 3). Ineffective erythropoiesis also leads to expansion of bone marrow space in the ribs, long bones, vertebral column, skull and characteristically, facial bones and may lead to osteoporosis. The medulla expands, cortical bone thins and cancellous bone is resorbed, leading to bone density loss. Furthermore, premature fusion of the growth plates in tubular bones of the extremities is common in children with thalassemia major (3) resulting in physical growth delays. Sites commonly involved by extramedullary hemopoiesis include the liver, spleen, lymph nodes and most commonly the paravertebral regions. The thymus, heart, breasts, prostate, broad ligaments, kidneys, adrenal glands, pleura, retroperitoneal tissue, skin, peripheral and cranial nerves and the spinal canal may also be involved (2). These sites are thought to be involved in active hematopoiesis in the fetus, and although their activity ceases at birth, the extramedullary hemopoietic vascular connective tissues retain the ability to produce red cells, in cases of chronic ineffective erythropoiesis (1). Head & Neck EMH is rare in the head and neck, but has been reported in the nasopharynx, paranasal sinuses, middle ear, lacrimal fossa, cervical lymph nodes, thyroid gland and paratracheal area (4, 5). EMH can rarely occur in the nasopharynx, causing obstructive sleep apnea (6). T1‐ and T2‐weighted MRI may show a hyperintense mass in the mucosa of the pharynx/nasopharynx, or a diffusely T2‐hyperintense thickening of the nasopharyngeal
mucosa (2). Another rare location for EMH is the paranasal sinuses (7), most commonly the maxillary sinus, where it is usually asymptomatic. It has also been reported in the ethmoid and sphenoid sinuses (4), and may be confused with chronic sinusitis and/or mucoceles. CT imaging reveals a soft tissue mass occupying the paranasal sinuses, which maybe partially calcified, a characteristic of chronicity or a “burnt‐out” lesion. MR imaging demonstrates a mass with variable signal intensity on T1 weighted imaging and a T2‐hyperintense mass with homogeneous contrast enhancement (2, 4). Occasionally and especially in thalassemia major, the marrow of the skull can expand and erode cortical bone (Figs. 1, 2) giving rise to the “hair‐on‐end” appearance. Chest The paravertebral region is a very common site (probably the most common) for extramedullary hemopoietic tissue, and when this happens it presents as large multi‐ lobed, paravertebral thoracic masses. They rarely cause significant symptoms, such as dyspnea, pleural effusion or hemothorax (2). If paraspinal hemopoietic tissues extend into the central canal, neurologic symptoms of spinal cord compression are observed (8). Chest X‐Ray reveals smooth, well demarcated paraspinal masses (2, 8) (Figs. 3, 4, 5). Rib (Figs. 3, 4, 6) or diploic space (Figs. 1, 2) (“hair‐on‐end appearance”) expansion can occur, especially in thalassemia (8). These and other radiological signs of chronic anemia, such as cardiomegaly, and clinical features such as high‐output cardiac failure suggest the diagnosis of EMH (2, 8).
On computed tomography (CT) images, EMH paravertebral masses appear isodense to adjacent muscle, smooth and well marginated and usually do not erode adjacent bone from outside‐in (Figs. 7, 8, 9). Actively hemopoietic masses demonstrate mild homogeneous enhancement post‐contrast (high vascularity), whereas old burnt‐out lesions have inhomogeneous contrast‐enhancement due to iron deposition and fat infiltration (2, 8, 9). These paraspinal masses are characteristic as they involve multiple levels in a bilateral distribution and are nearly symmetric. Very few other diseases can present thusly and therefore, the diagnosis of EMH should be strongly considered in such cases. MR imaging can be useful for further evaluation of paravertebral masses (Figs.10, 11, 12), although findings are non‐specific (2, 8). Fat within the paravertebral masses gives high signal intensity on T1‐ and T2‐weigthed images (2).
Abdomen and Pelvis The commonest sites of EMH in the abdomen are the liver, spleen and lymph nodes, all sites of in‐utero hemopoietic activity. Signs and symptoms include hepatosplenomegaly (Figs. 13, 14, 15) and abdominal discomfort, as well as shortness of breath in the case of massive enlargement (2, 8). Pain can be the presenting symptom if splenic infarction occurs (2). Hepatosplenomegaly can be detected on cross‐sectional imaging (CT, MRI, US) and 99mTc methylene diphosphonate whole body bone scan (2, 8). Usually there are no focal liver or splenic lesions in EMH, but rarely CT can reveal foci of EMH noted as uniformly low‐attenuation lesions with clear margins (Figs. 16, 17). On T1‐ weighted MRI these can be seen as hypointense masses, and slightly hyperintense compared to liver parenchyma on T2‐weighted MRI (Fig. 18) (8). Follow‐up imaging with clinical correlation or image‐guided biopsy is required to confirm the diagnosis of EMH. Multiple involved, enlarged retroperitoneal lymph nodes may also be detected (2). In transfusion‐dependent chronic anemia, multiple transfusions can lead to secondary hemosiderosis and/or hemochromatosis. This is detected as a homogeneous increase in the density of the liver and spleen on CT as a result of iron deposition, and low signal on T1‐ and T2‐weighted MRI (Figs. 18, 19 ) and may complicate the appearance of liver involved by EMH (2, 8). Albeit it rarely, the kidneys may also be involved by EMH, which may present as uniform
enhancing perinephric masses engulfing the kidneys (Fig. 20). The masses do not distort the shape of the kidneys and may present a diagnostic dilemma; difficult to distinguish from renal lymphoma (8). On ultrasonography, they can appear as echogenic masses that replace most of the pelvocalyceal system of the kidneys (10). EMH may also involve the mesentery, and needs to be differentially diagnosed from lymphadenopathy or metastatic disease (8). Presacral pelvic hemopoietic masses are rare, and present as well‐marginated, lobulated masses, with soft tissue density, with or without bony erosion on CT. On T1‐ and T2‐ weighted MR imaging, they appear as well‐encapsulated masses, slightly hyperintense (fatty tissue) or isointense to muscle, with uniform gadolinium enhancement (Figs. 21, 22) (2, 8, 9).
Conclusion Extramedullary hemopoiesis is a reactive/compensatory mechanism of new extra‐ marrow blood element formation as a result of chronically ineffective erythropoiesis. It is usually seen in paraspinal areas, the spleen, liver and lymph nodes, although a spectrum of other anatomical sites has been reported, as described above. The rarity of the disease and the non‐specific findings hinder initial consideration of the diagnosis. Physicians need to be aware of this possibility in order to initiate appropriate diagnostic and treatment interventions. Knowledge of the patients’ clinical history is absolutely essential. A history of a disease/condition resulting in chronically ineffective hemopoiesis should prompt the physician to have a high index of suspicion. The patient’s history, clinical and laboratory findings, together with plain radiography findings of cardiomegaly, rib or diploic space expansion can quickly point the physician in the diagnostic possibility of EMH. There are clearly described imaging findings in plain radiography, computed tomography, magnetic resonance imaging and bone scans, which can establish the diagnosis in the appropriate context. Follow‐up imaging or tissue biopsy may sometimes be required to clarify the differential diagnosis, especially in tumor‐like lesions. Acknowledgments: We would like to thank Dr. Sotiroulla Christou from the Cyrpus Thalassaemia Centre, for her help with identifying patients with relevant findings and their clinical histories.
References 1. Haidar R, Mhaidli H, Taher AT. Paraspinal extramedullary hematopoiesis in patients with thalassemia intermedia. Eur Spine J. 19(6):871‐8, 2010 2. Sohawon D, Lau KK, Lau T, et al. Extra‐medullary haematopoiesis: A pictorial review of its typical and atypical locations. J Med Imaging Radiat Oncol. 56:538‐44, 2012 3. Zhu G, Wu X, Zhang X, et al. Clinical and Imaging Findings in thalassemia patients with extramedullary hematopoiesis. Clin Imaging 36:475‐82, 2012 4. Saito N, Nadgir RN, Flower EN, et al. Clinical and Radiologic Manifestations of Sickle Cell Disease in the Head and Neck. Radiographics. 30(4):1021‐34, 2010 5. Kurtman C, Ozbilgin MK, Andrieu MN, et al. Paratracheal extramedullary hematopoiesis. Int J Hematol. 73(4):492‐5, 2001 6. Kapelushnik J, Shalev H, Schulman H, et al. Upper airway obstruction‐related sleep apnea in a child with thalassemia intermedia. J Pediatr Hematol Oncol. 23(8):525‐6, 2001 7. Bizzoni A, Lombardi D, Maroldi R, et al. Extramedullary hematopoiesis: A rare occurrence in the sinonasal tract. Auris, nasus, larynx. 37(2):233‐7, 2010 8. Georgiades CS, Neyman EG, Francis IR, et al. Typical and Atypical Presentations of Extramedullary Hemopoiesis AJR Am J Roentgenol. 179:1239‐43, 2002 9. Işık Balcı Y, Kaya V, Ateşçi MS. Presacral and intrathoracic extramedullary hematopoiesis: a case report. Clin Imaging. 36(4):406‐8, 2012
10. Kwak H. S., Lee J. Μ. CT findings of extramedullary hematopoiesis in the thorax, liver and kidneys, in a patient with idiopathic myelofibrosis. J Korean Med Sci. 15(4):460‐2, 2000 Legends Figure 1. Lateral skull radiograph of a 40 year‐old man with thalassemia major. Image demonstrates diploic space expansion with “hair‐on‐end appearance” as the marrow expands through the thinned cortex (arrowheads). Figure 2. Mid‐sagittal T1‐w image of a 49‐year old male with a history of thalassemia. Image demonstrates diploic space expansion and cortical thinning (arrowheads). Figure 3. PA chest film of a 55‐year old male with a history of thalassemia intermedia who was transfusion‐independent for many years. The image demonstrates very large paraspinal masses (star and long arrow) and rib expansion (small arrow). Figure 4. AP chest film of a 25 year‐old‐male with thalassemia and known paraspinal extramedullary hemopoiesis. Image shows diffuse expansion of the ribs (arrowheads) and paraspinal soft tissue mass (arrow). Figure 5. PA and lateral chest films of a young female with history of thalassemia and known extramedullary hemopoiesis. Images show bilateral, bulky paraspinal soft tissue
masses (arrowheads) compatible with extramedullary hemopoiesis. Images courtesy Dr Michael B. Sneider, University of Michigan. Figure 6. PA chest film of a 50 year‐old man with thalassemia intermedia who has not required blood transfusions. The image demonstrates marked, bilateral, symmetric rib expansion (arrows). Figure 7. Axial CT through the chest of a 59‐year old man with a history of thalassemia intermedia. The image demonstrates smooth, uniformly dense, well‐marginated paravertebral masses with no bony‐erosion (arrowheads). Figure 8. Axial CT image through the chest of a 49 year‐old male with a history of thalassemia. The image shows paravertebral and juxta‐coastal EMH masses. Marked osteoporosis of the vertebral body and mild rib expansion (arrowheads) is also noted. Figure 9. Axial contrast‐enhanced, CT image through the chest of a young female with a history of thalassemia and known extramedullary hemopoiesis. The image demonstrates uniformly enhancing, hemopoietic masses without bony erosion (arrows). Images courtesy Dr Michael B. Sneider, University of Michigan. Figure 10. T2‐w MR image through the chest of a 52‐year old male with a history of
thalassemia intermedia who has not received blood transfusions. Image demonstrates rib expansion and paravertebral masses (arrowheads) which are slightly hyperintense to muscle. Figure 11. Axial T2‐w MR image through the chest of a 53‐year old male with a history of thalassemia demonstrating homogeneous paravertebral EMH masses (arrows). Figure 12. Axial T2‐w MR image through the chest of a 53‐year old male with a history of thalassemia intermedia, demonstrating large, hyper‐intense heterogeneous paravertebral masses and rib expansion (arrows). Figure 13. Frontal abdominal film and reconstructed CT image of a 59‐year old with a history of thalassemia intermedia. There is marked hepatomegaly (arrows) and splenomegaly (arrowheads) as well as visceral displacement towards the midline. Fig. 14. Coronal T1‐weighted MR image of the abdomen of a 51 year‐old‐female with myelofibrosis and splenomegaly on physical examination demonstrates massive splenomegaly (arrowheads) secondary to infiltration by immature hemopoietic elements. Fig. 15. Posterior and anterior views from a T99m‐MDP bone scan of 54 year‐old‐ female with long standing myelofibrosis who presents with shortness of breath and
abdominal pain. Images show massive hepatomegaly that proved to be due to extramedullary hemopoiesis. Fig. 16. Axial contrast enhanced CT(A) and T1‐w MR (B) images through the liver of a 33 year‐old male with unspecified myeloproliferative disorder presenting with abdominal pain. Patient has a history of splenectomy for severe splenomegaly as well cavernous transformation of the portal vein. Images show an ill‐defined mass (star) in the region of the porta‐hepatis which is iso‐intense to the liver parenchyma on MR. The mass proved to be extramedullary hematopoietic tissue. Fig. 17. Axial CT image through the liver dome of a 40 year‐old‐male with sickle cell disease demonstrates two well‐delineated homogeneously low density lesions (arrow). Ultrasound‐guided percutaneous needle biopsy revealed a polymorphous population of mature and immature hemopoietic cells consistent with extramedullary hemopoiesis. Fig. 18. Axial T1 and T2 w MR images through the liver of a 53 year‐old‐male with weight loss and abdominal pain show a T1‐hypointense, T2‐hyperintense, partially exophytic mass from the left lobe of the liver. Percutaneous biopsy showed the mass to be made of mature and immature hemopoietic cells compatible with extramedullary hemopoiesis. The patient was subsequently diagnosed with myelofibrosis. Fig. 19. Axial, non‐contrast enhanced CT image through the liver of a 40 year‐old‐male
with sickle cell disease and 5‐6 painful crises per year presenting with abdominal pain, shows a dense liver parenchyma consistent with hemosiderosis The patient’s history included multiple transfusions.
Fig. 20. Axial CT 2‐years prior to presentation (top) and at presentation (bottom) of a 56 year‐old‐male with myelofibrosis presenting with flank and abdominal pain. The current CT scan shows bilaterally symmetric perinephric masses with minimal enhancement. Biopsy revealed hemopoietic tissue. Fig. 21. Axial CT (top), axial T1‐w MR (bottom) and mid‐sagittal T2‐w MR (right) images of a 49‐year old male with a history of thalassemia. Images show a uniformly enhancing, presacral mass, with clear margins (arrowheads) and mild bony erosion. Fig. 22. Axial CT image through the pelvis of a 48‐year‐old‐male with a history of hemolytic anemia complicated by myelofibrosis. Image reveals a pre‐sacral, soft tissue mass (arrowhead) without bone destruction. Biopsy demonstrated megakaryocytes, erythroid and myeloid precursors characteristic of extramedullary hematopoiesis. Courtesy Dr. Isaac Francis, University of Michigan
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