Marrow outside marrow: imaging of extramedullary haematopoiesis

Clinical Radiology xxx (xxxx) xxx

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Marrow outside marrow: imaging of extramedullary haematopoiesis S. Malla a, A. Razik a, C.J. Das a, *, P. Naranje a, D. Kandasamy a, R. Kumar b a b

Department of Radiology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India Department of Nuclear Medicine, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India

art icl e i nformat ion Article history: Received 24 May 2019 Accepted 13 December 2019

Extramedullary haematopoiesis (EMH) refers to the formation of non-neoplastic blood cell lines outside the bone marrow and is a common incidental finding when patients with haematological disorders are imaged. EMH presenting as mass (tumefactive EMH) has long been a radiological conundrum as it resembles neoplasms. Several imaging findings have been described in EMH, and these vary depending on the activity of the underlying haematopoiesis. The older lesions are easier to diagnose as they often demonstrate characteristic findings such as haemosiderin and fat deposition. In comparison, the newer, actively haematopoietic lesions often mimic neoplasms. Molecular imaging, particularly 99mTc labelled sulphur colloid scintigraphy, may be helpful in such cases. Although imaging is extremely useful in detecting and characterising EMH, imaging alone is often non-diagnostic as no single mass shows all the typical findings. Hence, a judgement based on the clinical background, combination of imaging findings, and slow interval growth may be more appropriate and practical in making the correct diagnosis. In every case, an effort has to be made in providing an imaging-based diagnosis as it may prevent a potentially risky biopsy. When confident differentiation is not possible, biopsy has to be resorted to. This article describes the causes, pathophysiology, and theories underlying the genesis of EMH, followed by the general and location-specific imaging findings. The purpose is to provide a thorough understanding of the condition as well as enable the clinical radiologist in making an imaging-based diagnosis whenever possible and identify the situations where biopsy has to be performed. Ó 2020 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

Introduction Extramedullary haematopoiesis (EMH) is a common incidental finding when patients with haemolytic anaemia or myelofibrosis are imaged for other purposes. In most cases, EMH is microscopic and manifests as hepatosplenomegaly; however, sometimes it may form

tumefactive masses, in which case distinction from other tumours and pathologies may be difficult. Several imaging features have been described in tumefactive EMH, which may suggest the diagnosis; however, no single finding is diagnostic of the condition. The presence of any predisposing haematological condition is the most important factor, which raises the suspicion of EMH. In such patients, a combination of imaging findings and the presence of

* Guarantor and correspondent: C. J. Das, Department of Radiology, All India Institute of Medical Sciences, New Delhi, 110029, India. Tel.: +91 011 26593628. E-mail address: [email protected] (C.J. Das). https://doi.org/10.1016/j.crad.2019.12.016 0009-9260/Ó 2020 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.

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relative stability on serial imaging helps in establishing the diagnosis. In most cases, as in the thoracic paravertebral location (the commonest site of tumefactive EMH), an imaging-based diagnosis may prevent sampling, which could be catastrophic in view of the increased risk for haemorrhage. Hence, it is important for radiologists to provide a confident diagnosis whenever possible. This article outlines the causes, pathophysiology, and genesis of EMH, followed by a detailed description of the general as well as location-specific imaging findings.

Materials and methods A literature search was performed on PubMed, Scopus, and Google Scholar with the keyword “extramedullary haematopoiesis” to look for peer-reviewed original and review articles concerning the topic. The departmental database was reviewed for cases of EMH that were detected or worked-up with imaging. The images of patients with haemolytic anaemia and myelofibrosis who underwent imaging for other purposes were also reviewed retrospectively for evidence of EMH. In cases where the imaging diagnosis was not certain, confirmation was made by reviewing the final histopathological reports. Prior ethical approval was sought from the institutional ethics committee for the usage of the images, all of which were anonymised.

Normal haematopoiesis Haematopoiesis occurs in several waves.1 The initial wave, called primitive haematopoiesis, occurs in the extraembryonic yolk sac on day 17, prior to the genesis of circulation.2,3 The yolk sac mesoderm transforms into haemangioblasts, which give rise to endothelial cells and primitive haematopoietic stem cells (pHSC). These pHSC occur in clusters adherent to the endothelium, called blood islands; however, they possess only limited differentiation potential. The pHSC are transient and are replaced by a second wave of definitive haematopoiesis in the yolk sac by around day 20. These definitive haematopoietic stem cells (dHSC) sequentially acquire full multilineage differentiation potential. Soon after, circulation is established and the first hepatic colonisation by the dHSC occurs around day 23. Beginning on day 27, a third wave of definitive haematopoiesis occurs from transformation of the haemangiogenic endothelium in the aortaegonademesonephros region.4 The multilineage dHSC undertake the second hepatic colonisation around day 30 and subsequently proliferate and differentiate within the liver. Once the liver takes over haematopoiesis, the role of yolk sac and the arterial clusters diminish over the next few weeks. The haematopoietic cell population in the liver maximises in the early second trimester and declines towards the end of gestation. The spleen is also colonised and contributes to haematopoiesis, although to a lesser extent than the liver. The colonisation of bone marrow occurs in the 11th week and haematopoiesis begins in mesodermal structures

called primary logettes5; however, the liver continues to be the major source of blood cells in the fetus until birth, after which the bone marrow takes over as the predominant site of haematopoiesis. The evolution of haematopoiesis in the human fetus is summarised in Fig 1. Bone marrow is of two types: red bone marrow, which actively contributes to haematopoiesis, and yellow bone marrow, which is predominantly fat. At birth, all the marrow is red. In a child, red marrow or the active marrow occupies all the flat bones and almost all of the long bones. In comparison, adult red bone marrow is restricted to the flat bones and the epimetaphyseal region of long bones.6

Causes of extramedullary haematopoiesis Extramedullary haematopoiesis (EMH) refers to the formation of non-neoplastic blood cell lines outside the bone marrow as a compensatory mechanism to inadequate blood cell production or marrow replacement.7,8 EMH may be active or passive. Active EMH refers to the normal EMH existent in fetuses and may also occur as a normal immune response to infection in adults. Passive EMH mostly occurs in response to decreased marrow haematopoiesis resulting from iron-deficiency anaemia or ineffective erythropoiesis as in haemoglobinopathies (sickle cell disease and thalassemia) and megaloblastic anaemias. Marrow infiltrative or myelophthisic disorders (myelofibrosis, lymphoma, leukaemia, granulomatous diseases, osteopetrosis, storage disorders, and metastases) displace the haematopoietic stem cell lines into the peripheral circulation, resulting in pancytopenia and passive EMH. Peripheral haemolysis (as in hereditary spherocytosis, autoimmune haemolytic anaemias, and haemoglobinopathies) also cause passive EMH.9 Beta thalassemia is among the commonest causes of EMH worldwide. EMH is prevalent in 20% cases of beta thalassemia intermedia and 1% cases of beta thalassemia major.10 Despite thalassemia major being the more severe variant, this discrepancy occurs because most patients with thalassemia major are diagnosed early and undergo transfusions, which suppress the development of EMH; however, patients with the less severe thalassemia intermedia often go unnoticed and do not receive transfusions until late in the disease course. The causes of EMH are listed in Table 1.

Theories of extramedullary haematopoiesis Any extramedullary site of haematopoiesis is abnormal after birth.11 Several theories have been proposed to explain the genesis of EMH. The most convincing theory is that of redirected differentiation as it explains the occurrence of EMH in all organs.12 According to this theory, all tissues possess stem cells that can dedifferentiate into haematopoietic precursors in response to circulating factors. The myelostimulatory theory attributes the development of EMH to the recruitment of the embryonic sites of haematopoiesis. According to the filtration theory, the displaced haematopoietic stem cells in the circulation are filtered-off

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Figure 1 Sequence of events in the haematopoiesis of human embryo. Haematopoiesis begins in the yolk sac mesoderm on day 17, where an initial wave of primitive haematopoiesis is followed by a second wave of definitive haematopoiesis. The first hepatic colonisation occurs on day 23 and by day 27, a third wave of definitive haematopoiesis occurs in the arterial clusters of the aortaegonademesonephros region. This is followed by the second hepatic colonisation on day 30. Bone marrow colonisation begins in the 11th week; however, the liver continues to be the major site of haematopoiesis until birth.

in organs such as the spleen where they establish, proliferate, and subsequently, differentiate.13,14 In another theory, the occurrence of para-osseous masses is explained by the extrusion of hyperplastic marrow through the thinned cortex.15

Locations of EMH EMH is usually a microscopic finding. The most common sites in adults include the spleen and liver, which together account for 95% of the cases. EMH sometimes presents as a mass on imaging (mass-forming or tumefactive EMH) and may be easily mistaken as a tumour.16 EMH can occur virtually in every organ of the body. The notable sites include lymph nodes, kidneys, paraspinal location, adrenals, pleura, mesentery, dura, thymus, breast, pelvis, thymus, and skin.12,17 In an autopsy study, lymph nodes were reported to be the most common site of non-hepatosplenic EMH, followed by the kidneys18; however, on imaging, the microscopic deposits in the lymph nodes and kidneys may be less apparent and the paraspinal and intraspinal locations (particularly in the thorax) have been observed to be the most common sites (Fig 2a).12 Nevertheless, multifocality is

Table 1 Causes of postnatal extramedullary haematopoiesis. Reduced marrow production or peripheral destruction of blood cells

Displacement of marrow stem cells into peripheral circulation

Thalassemia Sickle cell disease Hereditary spherocytosis Autoimmune haemolytic anaemia Iron-deficiency anaemia Megaloblastic anaemia

Primary myelofibrosis Osteopetrosis Leukaemia Lymphoma Granulomatous diseases Metastasis Storage disorders

the rule and isolated non-hepatosplenic EMH is extremely rare.

General imaging manifestations The morphological appearance of EMH depends on the location and is described in the organ system-specific sections below. Broadly, tumefactive EMH can appear as welldefined masses or poorly defined, infiltrative lesions. Multifocality is the rule and the majority of non-hepatosplenic cases of EMH also have associated hepatosplenomegaly due to diffuse infiltration by haematopoietic cells. Due to the soft consistency, tumefactive EMH masses do not cause erosion or saucerisation of the adjacent bones. The attenuation characteristics on computed tomography (CT) and the signal intensity pattern on magnetic resonance imaging (MRI) depends on the age and activity of the lesions, and are comparable across the different sites of involvement. On unenhanced CT images, the newer lesions showing active haematopoiesis are generally hypoattenuating; whereas the older, burned-out lesions show attenuation comparable to the skeletal muscle (Fig 2b and c). Interspersed macroscopic fat may be observed in longstanding masses; however, calcification is very rare.15 After contrast medium administration, the newer masses show mild to moderate homogeneous enhancement, whereas the older masses show absent or minimal enhancement. The larger masses may show intralesional heterogeneity. It is not uncommon to see areas of both active as well as burned-out haematopoiesis within the same mass. On MRI, lesions with active haematopoiesis show intermediate signal intensity on T1-weighted images and are hyperintense on T2-weighted images in comparison to the skeletal muscle (Fig 2d). The T2-signal is generally isointense or mildly hyperintense relative to the other organs involved in active haematopoiesis (adjacent bone marrow, liver, and spleen). The signal intensity reduces with time;

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Figure 2 Thoracic paravertebral EMH in a 26-year-old man with beta thalassemia intermedia. (a) Frontal chest radiograph showing two paravertebral masses (arrows) on both sides of the lower dorsal spine. The ribs and clavicle show widening due to medullary expansion. (b) Axial unenhanced CT at the level of the left paravertebral mass shows the mass (arrow) to have a similar attenuation as the adjacent skeletal muscle (asterisk). (c) On the bone window CT images, there is medullary expansion and widely spaced trabeculae within the vertebral body secondary to marrow proliferation. (d) On the axial non-fat-saturated T2-weighted MRI image, the mass (arrow) has hypointense intense signal comparable to the bone marrow due to chronic haemosiderin deposition. (e) The mass shows no uptake on FDG-PET/CT, suggestive of inactive haematopoiesis within.

the older lesions being hypointense on both T1- and T2weighted images.19 This occurs due to magnetic susceptibility-related signal loss from haemosiderin accumulation and are accentuated on the T2*-weighted images.20,21 In all cases, the evolution of signal changes generally parallels that of the bone marrow.22 For the same reason, these lesions also show low signal on diffusionweighted imaging (DWI) despite high cellularity. The findings on T2*-weighted imaging and DWI may be valuable in differentiating EMH from malignant tumours or metastatic deposits, which would be hyperintense on both the sequences.23 As bone marrow is known to contain microscopic fat and shows significant loss of signal on opposedphase (OP) gradient-echo T1-weighted images, extramedullary foci also could potentially replicate the same finding24; however, this finding should be cautiously interpreted as iron deposition can paradoxically result in loss of signal on the in-phase (IP) images, which are obtained at a higher time-to-echo (TE). On post-contrast

images, the active lesions show mild to moderate enhancement, whereas the older lesions show minimal delayed enhancement (in fibrotic lesions) or no enhancement (in lesions with severe iron deposition or fatty metamorphosis).19 The general imaging features of EMH are summarised in Table 2. As marrow contains haematopoietic cells, radionuclide tracers, which localise in these cells, have been used to identify EMH, map their extent, and distinguish them from neoplastic lesions. This is particularly important in patients with malignant neoplasms causing myelophthisis, in whom tumour deposits and EMH can coexist. In addition, they are also useful in assessing the contribution of spleen to haematopoiesis in patients with chronic haemolytic anaemia, prior to splenectomy.25 52Fe (a positron emitter) and 111Inchloride (a gamma emitter) bind to transferrin, localise in the erythroid precursors and are the most specific radiotracers for haematopoietic cells. These have been used for positron-emission tomography (PET) and scintigraphy/

Table 2 Multimodality imaging manifestations of extramedullary haematopoiesis (EMH). Modality/sequence

Active EMH

Burnt-out EMH

Ultrasound CTa

Hypoechoic Hypo-attenuating Mild to moderate May show loss of signal on OP images Mildly hyperintense May be present Mild to moderate Show uptake

Variable; may be echogenic Iso-attenuating Absent or minimal May show loss of signal on IP images May be hypointense Often absent Absent or minimal May not show uptake

Attenuation on unenhanced images Enhancement on post-contrast images MRIa Signal on T1-weighted IP and OP images Signal on T2-weighted images Diffusion restriction on DWI Enhancement on post-contrast images Scintigraphy/PET with marrow-specific tracer agents

IP, in phase; OP, out of phase; MRI, magnetic resonance imaging; CT, computed tomography; PET, positron-emission tomography. a The attenuation on CT (in Hounsfield units) and signal intensity on MRI are compared to that of the nearest skeletal muscle.

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single-photon-emission CT (SPECT), respectively. The myeloid bone marrow can be imaged with white blood cells labelled with 99mTc-hexamethylpropyleneamineoxime (HMPAO), 111In-oxinate or 99mTc-anti-granulocyte murine monoclonal antibodies (AGAb). 99mTc-labelled sulphur colloid and nanocolloid are phagocytosed by the cells of the reticuloendothelial system and localise in the liver, spleen, and bone marrow. The marrow-specific tracers used in imaging of EMH are summarised in Table 3. 99mTc-labelled sulphur colloid is the most common agent used in bone marrow imaging. In all the above studies, the active red bone marrow in a normal person shows diffuse low-level uptake in the central (axial) bone marrow, proximal humerus and femur, liver, and spleen. Studies using labelled colloids show more liver uptake than the other tracers, and this may limit optimal assessment of the lower dorsal spine. In diseased states, the distribution, intensity, and homogeneity of marrow uptake is assessed, and a lookout is made for foci of EMH. In patients with bone marrow stimulation, the hyperplastic marrow showing increased tracer uptake is seen reaching up to or beyond the knees and elbows.26 The liver and spleen are enlarged and show increased uptake. Foci of nonhepatosplenic EMH may also be seen. On the contrary, in primary myelofibrosis, there is loss of activity in the central bone marrow. PET-CT using tracers assessing metabolism (18F-fluoro-2-deoxyglucose or FDG) and proliferation (18Ffluorothymidine or FLT) also have been used in imaging EMH. Unlike scintigraphy, PET-CT has higher image resolution and allows quantification of uptake. Normal bone marrow, liver, and spleen show diffuse low-level uptake. In EMH showing active erythropoiesis, there is mild to moderate uptake of the radiotracer; whereas the older, burntout lesions may show minimal or no uptake (Fig 2e).27 A high FDG avidity based on the maximum standardised uptake value (SUVmax) suggests malignant neoplasm; however, there is inadequate literature regarding the optimal cut-off value. In summary, no single mass may show all the typical findings, and a judgement based on the clinical background, combination of imaging findings and slow interval growth may be more appropriate and practical in making the correct diagnosis than expecting to find the ‘Aunt Minnie’.

Role of sampling A definitive diagnosis can be obtained with histological examination of the fine-needle aspiration (FNAC), biopsy, or surgical specimen. Macroscopically, tumefactive EMH Table 3 Marrow-specific tracer agents used in the imaging of extramedullary haematopoiesis. Tracers binding to erythroid precursors

Tracers binding to myeloid precursors

Tracers binding to cells of reticuloendothelial system

52

99m

99m

99m

99m

Fe In-chloride

111

Tc-HMPAO Tc-AGAb 111 In-oxinate

Tc-sulphur colloid Tc-nanocolloid

5

appears as a reddish mass with soft consistency, which resembles a haematoma on cross-section. On histology, it shows both red and yellow marrow elements in varying proportions with hyperplastic haematopoietic elements of all lineages interspersed between fat globules; however, sampling of vascular EMH masses is not without risk, especially in the thorax and spleen where massive haemorrhage can occur. FNA tends to be safer than biopsy with lesser risk of fatal haemorrhage. This stresses the importance of correctly diagnosing EMH on imaging, so that potentially catastrophic sampling may be avoided. On the corollary, imaging also helps in identifying atypical findings, which necessitate sampling.28

Location-specific imaging findings Thorax Thoracic paraspinal location below the D6 vertebral level is the commonest site for tumefactive EMH on imaging.12 The thymus, mediastinum, lungs, and pleura may also be affected. Paraspinal EMH is usually seen in patients with beta thalassemia, particularly the transfusion dependant variants.29 A male preponderance has been observed. Splenectomy is a known risk factor as the paucity of splenic EMH increases the burden on rest of the bone marrow.30 The origin of EMH at this location has been postulated to be the extrusion of hyperplastic marrow through the thinned-out cortex of the vertebrae and proximal ribs.31 Most patients are asymptomatic and the lesions are discovered incidentally on imaging.32 Primary lung involvement is rare and most commonly occurs in patients with primary myelofibrosis and haemolytic anaemia. These patients manifest with dyspnoea (from diffuse infiltration or pulmonary hypertension), respiratory failure, or haemoptysis (from alveolar haemorrhage). Spontaneous haemothorax (from pleural involvement) may also occur.33 Most cases of paraspinal EMH are not apparent on radiographs unless they are large. Cross-sectional imaging shows multiple well-defined paravertebral and subpleural paracostal masses having sharp interface (outer margin) with the pleura and lung15 The masses are often bilateral and multifocal, occurring in a segmental distribution (Fig 3aed).31 The larger masses often have lobulate contours. In some cases, similar masses can also be seen along multiple ribs, especially posteriorly (Fig 3e). The presence of associated medullary expansion, lacy internal architecture (widely spaced trabeculae), cortical thinning, and periosteal elevation of the adjacent ribs and vertebrae secondary to hyperplastic marrow may provide vital diagnostic clue in patients previously undiagnosed of their haemolytic anaemia34; however, the masses do not erode or saucerise the adjacent bones due to their soft and pliable consistency. The presence of fat is characteristic (Fig 3f). MRI is useful in assessing the presence of intraspinal EMH in patients with spinal cord compression. Differentials include other posterior mediastinal lesions, including neurogenic tumours and lymph nodes as in

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Figure 3 Three typical appearances of thoracic EMH. (aed) Thoracic paravertebral EMH in a 48-year-old woman with beta thalassemia intermedia. (a) Axial contrast-enhanced CT at the level of the lower dorsal spine shows a homogeneously enhancing mass (asterisk) in the right paravertebral location. (b) Bone window image shows medullary expansion, thinning and outward lifting of the cortex (arrow) from extrusion of the hyperplastic marrow. (c) Coronal and (d) sagittal CT images showing bilateral segmental distribution (arrowheads) of the paravertebral EMH masses. (e) Chest radiograph of a 14-year-old female patient with beta thalassemia intermedia showing irregular widening of the posterior ends of multiple ribs bilaterally, along with the presence of paracostal soft tissues (arrowheads) consistent with EMH. (f) Bilateral thoracic paravertebral EMH in a 34-year-old man with beta thalassemia major. On the axial CT images, the masses show large areas of macroscopic fat (arrows) within.

tuberculosis, lymphoma, germ cell tumours, and Castleman’s disease. Neurogenic tumours often show high T2 signal and enhancement, cause scalloping of the adjacent vertebrae and ribs with or without expansion of the neural foramen. Lymph nodes in infections and neoplasms are accompanied by involvement at other sites or lungs and are rarely seen in segmental distribution as in EMH. Castleman’s disease may present as a single enlarged lymph node; however, usually the enhancement is intense and calcification may or may not be present.15 Imaging findings of pulmonary EMH are non-specific and include nodules, masses, septal thickening, ground-glass

opacities, and infiltrates.11,35 Nodules may be single or multiple, unilateral or bilateral and may show calcification. One case report describes a pulmonary artery thrombus, which turned out to be a focus of EMH.36 With diffuse pulmonary involvement, the differentials are extensive and include infection, fluid overload, pulmonary haemorrhage, secondary alveolar proteinosis, hyperleucocytosis, and chemotherapy-induced toxicity. In such cases, uptake on 99m Tc-labelled sulphur colloid scintigraphy helps in establishing the diagnosis and avoids a risky biopsy.37 EMH may also form pleural deposits, which could result in spontaneous haemothorax.

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Liver Being an important part of the reticuloendothelial system (RES), the liver is a common site for EMH, the most common presentation being diffuse hepatomegaly; however, liver involvement may also occur as single or multiple focal lesions (Fig 4) or even rarely, as periportal and peribiliary infiltrative soft tissue (Fig 5).38 Generally, the lesions are well-defined and show absent or mild homogeneous contrast enhancement on CT. On MRI, the signal depends on the age and activity of the lesions. The newer, active lesions show T2-hyperintensity and mild to moderate postcontrast enhancement, whereas the older lesions are T2hypointense and show minimal or absent enhancement depending on the dominant pathological transformation (fibrosis and iron deposition respectively).39 Intralesional fat deposition may be seen in older lesions.40 Central stellate scar has also been reported in one case.41 The presence of a predisposing underlying disorder, relatively low signal on T2-weighted images and poor enhancement on post-contrast images helps to differentiate EMH from the more common liver lesions: haemangioma, focal nodular hyperplasia (FNH), adenoma, hepatocellular carcinoma (HCC), cholangiocarcinoma, and metastasis. As EMH contains RES cells, which take up superparamagnetic iron oxide (SPIO) and ultra-small superparamagnetic iron oxide (USPIO), it shows significant loss of signal on T2*weighted images after administration of these agents.42

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This finding can be used to differentiate EMH from the usual liver lesions which do not contain Kupffer or RES cells (the exceptions being focal nodular hyperplasia and welldifferentiated HCC). In patients with haemolytic anaemia showing diffuse iron deposition in the liver, any lesion that is not readily apparent on the T2*-weighted images should raise the suspicion of EMH.21 EMH with fat deposition should be differentiated from angiomyolipoma (AML) and HCC with fatty metamorphosis. In cases of dilemma, sampling may be performed.

Spleen Spleen is a common site for EMH, with diffuse splenomegaly being the most common presentation. EMH presenting as focal lesions is very rare and can be confused with the other commoner lesions of the spleen (Fig 5c).43 Splenic EMH is usually asymptomatic and when tumefactive, can be single or multiple with masses up to 12 cm having been reported. Most of the reported lesions were echogenic on ultrasound.43 The CT and MRI characteristics are similar to those in the liver and depend on the age and activity of the lesion. EMH can be suspected in the appropriate clinical setting; however, the most important differentials include lymphoma, metastasis, and tumefactive infarcts. Other rare differentials include mesenchymal tumours such as haemangioma, angiosarcoma, and hamartoma.44 Rarely EMH

Figure 4 Hepatic EMH in 48-year-old woman with beta thalassemia (same patient as in Fig 4). (a) Axial contrast-enhanced CT image showing a reasonably well-defined, hypo-enhancing focal lesion in segment VII (arrow) of liver. (b) Coronal section shows another well-defined lesion in segment V (arrow) and a poorly marginated lesion in segment IVb (curved arrow). (c) On the transverse ultrasound image, the lesion in segment V (asterisk) is hyperechoic. Please cite this article as: Malla S et al., Marrow outside marrow: imaging of extramedullary haematopoiesis, Clinical Radiology, https://doi.org/ 10.1016/j.crad.2019.12.016

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Figure 5 Hepatosplenic EMH in a 54-year-old man with primary myelofibrosis. (a) Axial and (b) coronal contrast-enhanced CT images at the level of the porta hepatis show hypo-enhancing periportal soft tissue (arrows). Note the presence of hepatosplenomegaly and portal hypertension as evident by the enlarged portal vein (P) and presence of perigastric collaterals (arrowheads). (c) Axial section at the level of the splenic hilum shows a poorly defined hypo-enhancing lesion within the spleen (arrow).

can also masquerade as granulomatous diseases such as sarcoidosis and tuberculosis.45 In such cases, 99mTc-labelled sulphur colloid scintigraphy is useful as tumours and infections show up as a defect (absent uptake) in the spleen, whereas EMH does not stand out.43 In doubtful cases, image-guided percutaneous splenic FNAC or core-needle biopsy may be obtained rather than splenectomy, which is associated with high risk of postoperative infections. FNAC is safer, but has lower diagnostic yield. As the risk of haemorrhage with EMH is higher, it is preferable to perform an FNAC first followed by biopsy only if the results are inconclusive. Current evidence indicates that splenic biopsy is safe to perform with low complication rates as long as cautious patient selection is made and the correct technique is followed (using 18-G or smaller needles, sampling peripheral lesions to avoid hilum, traversing some amount of normal parenchyma to provide tamponade, avoiding pleural transgression using real-time ultrasound guidance or gantry tilt CT technique, and using Gelfoam sponge for tract embolisation).46,47

Kidneys EMH can involve the renal parenchyma, pelvicalyceal system, or perirenal soft tissues, and is usually bilateral. Parenchymal involvement may manifest as diffuse enlargement of the kidney or as single or multiple focal lesions.48,49 Diffuse parenchymal involvement can result

in renal failure and proteinuria. On imaging, diffuse involvement presents as bilaterally enlarged kidneys, which are echogenic on ultrasound and homogeneously hypo-enhancing on CT. Biopsy can be misleading as it may resemble interstitial nephritis and Hodgkin’s lymphoma. Focal lesions are usually hypo-enhancing, and in isolation, are indistinguishable from renal cell carcinoma and lymphoma. Pelvicalyceal system involvement is usually an extension of the parenchymal involvement and may cause obstructive uropathy. On imaging, it manifests as thickening of the urothelium or as parapelvic masses (Fig 6).50 Perirenal involvement is the most common form of renal involvement and is seen as a hypo-enhancing soft-tissue rind or as multiple masses surrounding the kidneys without causing contour deformity. Older lesions may show macroscopic fat and haemosiderin deposition, the latter responsible for the low signal on MRI. A correct diagnosis can often be made in the appropriate clinical background; however, sampling is required for confirmation. The differentials for parapelvic involvement include lymphoma and urothelial carcinoma. The former is usually secondary to an already evident renal or extrarenal lymphoma and is accompanied by adjacent lymph node enlargement. Urothelial carcinomas usually present as intrapelvic masses and are rarely bilateral.51 The differentials for perirenal “rind”-like soft tissue include lymphoma, ErdheimeChester disease, Castleman’s

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Figure 6 EMH presenting as bilateral parapelvic soft tissue and retroperitoneal lymphadenopathy in a 36-year-old woman with autoimmune haemolytic anaemia. (a) Contrast-enhanced CT showing hypo-enhancing soft tissue (arrow) infiltrating the right renal sinus and encasing the pelvicalyceal system. Para-aortic lymph nodes are also present (arrowheads). (b) On the axial T2-weighted image, the soft tissue is hypointense, likely from haemosiderin deposition. Similar soft tissue is also seen in the left renal sinus (arrow). (c) Axial T1-weighted gradient-echo in-phase and (d) opposed-phase images showing the soft tissue to be mildly hyperintense in comparison to the skeletal muscle (asterisk). The higher time-to-echo (TE) in-phase images showed a signal loss of 9% in comparison to the lower TE opposed-phase images, confirming haemosiderin deposition. (e) On DWI images, the soft tissue is hypointense. (f) On the contrast-enhanced images, both the parapelvic soft tissue as well as the lymph nodes (arrowheads) show homogeneous enhancement. The soft tissue is also seen extending along the left ureter (arrow).

disease, and IgG4 disease.52 The pattern of perirenal involvement is rarely helpful in making the diagnosis; however, other associated organ involvement needs to be looked for. ErdheimeChester disease typically presents as “hairy” kidneys, bilateral symmetric long-bone sclerosis, and dural deposits. Renal involvement in IgG4 disease usually occurs alongside pancreatic and biliary involvement, and often extends along the periureteric soft tissue unlike the above two entities. If macroscopic fat is present, perirenal liposarcoma is an important differential not to be missed.

Adrenals Adrenals are extremely rare sites for EMH. Patients are usually asymptomatic, with the masses being detected incidentally on imaging.53 Unless a clinical suspicion is kept and biopsy perfomed, most of these lesions undergo adrenalectomy for presumed adrenal malignancy and are diagnosed subsequently on histopathological examination. Hence, timely suspicion based on the clinical and imaging characteristics, followed by image-guided biopsy, may obviate adrenalectomy.

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On imaging, the involvement may be unilateral or bilateral and the masses are well-defined and variably echogenic on ultrasound.54 The findings on CT, MRI, and PET resemble those of EMH elsewhere. The key diagnostic findings include the presence of signal intensity similar to the bone marrow on MRI, presence of iron, and microscopic as well as macroscopic fat (Fig 7). Uptake on 99Tc-sulphur colloid scintigraphy is also a helpful diagnostic feature. Myelolipoma is the closest differential as both are well encapsulated, show microscopic fat on imaging, and myeloid cells on histopathology. Most of myelolipomas occur in patients >40 years, whereas EMH may be seen at any age. The presence of underlying haematological disease and other sites of involvement also suggest the diagnosis of EMH. On histology, EMH usually shows a predominance of erythroid hyperplasia, whereas myelolipomas show predominantly fat and lymphoid precursors.55 Adenomas, adrenocortical carcinoma (particularly those with myelolipomatous metaplasia), and adrenal metastasis are other differentials for unilateral EMH; whereas metastasis, lymphoma, and granulomatous adrenalitis are the differentials for bilateral EMH. Generally, differentiation can be made based on the clinical and imaging profile of the masses.

Mesentery, peritoneum, and bowel Peritoneal and mesenteric involvement in EMH is rare and manifests as diffusely infiltrating, hypo-enhancing soft

tissue (Fig 8). Less commonly, it occurs as serosal deposits mimicking malignancies.56 Ascites is occasionally seen, the possible explanations being EMH infiltration causing presinusoidal or sinusoidal portal hypertension, exudative ascites resulting from rupture of hepatosplenic EMH into the peritoneum and direct peritoneal implants of EMH. Differentials include peritoneal carcinomatosis, lymphomatosis, leukaemic deposits, and tuberculosis. Biopsy is needed for the definitive diagnosis. Bowel involvement manifests usually as multifocal mucosal and submucosal deposits throughout the bowel causing ulceration and inflammation with resultant stenosis, obstruction, and adhesions.57,58 Any part of the gastrointestinal tract from oesophagus to the rectum may be involved. Less commonly, it manifests as single or multiple macroscopic masses mimicking malignancies.

Presacral location Presacral region is the second most common site of EMH after the thoracic paravertebral location.59 Similar to paraspinal EMH, presacral EMH is usually seen in haemolytic anaemias and results from expansion of hypercellular marrow beyond the confines of the sacrum into the presacral space. On imaging, EMH presents as well-defined round or lobulate masses contiguous with the sacrum and showing macroscopic fat interspersed with enhancing soft tissue. The underlying sacrum may

Figure 7 Adrenal EMH in a 26-year-old man with beta thalassemia intermedia (same patient as in Fig 2). (a) Axial unenhanced CT showing a right adrenal mass (asterisk), which is hypodense in comparison to the skeletal muscle. The liver is hyperdense secondary to haemosiderosis from repeated transfusions. (b) On axial and (c) coronal T2-weighted images, the mass shows T2-hyperintense areas consistent with active haematopoiesis, intermixed with markedly hypointense areas (arrow), which represent older, inactive areas showing haemosiderin deposition. The liver also shows markedly hypointense signal due to haemosiderin deposition. Please cite this article as: Malla S et al., Marrow outside marrow: imaging of extramedullary haematopoiesis, Clinical Radiology, https://doi.org/ 10.1016/j.crad.2019.12.016

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Figure 8 Mesenteric involvement of EMH in a 54-year-old man with primary myelofibrosis (same patient as in Fig 6). (a) Axial and (b) coronal contrast-enhanced CT images showing hypo-enhancing soft tissue (asterisk) causing diffuse infiltration of the mesentery. The mesenteric vessels (arrows) are delineated by a rim of fat. (c) On axial T2-weighted images, the soft tissue (asterisk) is mildly hyperintense in comparison to the skeletal muscle. (d) Coronal contrast-enhanced T1-weighted gradient-echo image showing uniform enhancement of the soft tissue (asterisk).

show medullary expansion, cortical interruption, and periosteal elevation without saucerisation (Fig 9). The soft tissue, when large, may cause mass effect and displacement of the rectum. The signal characteristics are similar to EMH occurring in other parts of the body. 99 Tc-labelled sulphur colloid scintigraphy also helps in establishing the diagnosis. The differentials include presacral AML, myelolipoma, liposarcoma, and leukaemic deposits.60 Presacral AML and myelolipoma are difficult to differentiate from EMH on imaging unless the appropriate clinical scenario is taken into consideration. Liposarcoma often shows nodular enhancing soft tissue along with variable amounts of fat, is poorly defined and infiltrative.60

Central nervous system Intracranial involvement in EMH is unusual. Most such patients are asymptomatic or present with headache and focal neurological deficits. In the spine, back pain, and focal neurological deficits could result from compression of the cord by the extradural masses. On imaging, extradural masses are seen as homogeneously enhancing plaque-like or lobular soft tissue based on the dura overlying the cerebral convexities, falx cerebri,

tentorium cerebelli, and in the spinal epidural spaces (Fig 10). Less commonly, EMH may occur as intraparenchymal or choroid plexus masses. Chronic EMH deposits often show T2-hypointense signal and blooming on susceptibility-weighted imaging (SWI) due to haemosiderin deposition.61 The larger lesions may cause mass effect; however, perilesional oedema is usually absent. The overlying bone may show diploic space expansion and crew-cut (hair-on-end) appearance in haemolytic anaemias and sclerosis in myelofibrosis and osteopetrosis. Intralesional fat, when seen, is supportive of the diagnosis of EMH. Differentials in the younger population include leukaemic or lymphoma deposits and metastasis from neuroblastoma; whereas in the older population, the differentials include chronic subdural haematoma, en-plaque meningioma, metastasis, lymphoma, and histiocytic disorders such as ErdheimeChester disease.23 The appropriate clinical background, presence of background bony changes, multifocal nature of the deposits and typical imaging features (blooming, intralesional fat, uptake on technetium scan) help in establishing the diagnosis. Intraspinal EMH is not easily differentiated from metastatic deposits in the absence of a known primary; however, the presence of a peripheral fat-intensity rim around the mass may be a helpful finding in differentiating EMH from metastasis.32

Please cite this article as: Malla S et al., Marrow outside marrow: imaging of extramedullary haematopoiesis, Clinical Radiology, https://doi.org/ 10.1016/j.crad.2019.12.016

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Figure 9 Presacral EMH in a 30-year-old man with hereditary spherocytosis. (a) Axial contrast-enhanced CT image showing a homogeneously enhancing lobular mass (asterisk) in the presacral space contiguous with the sacrum. (b) Bone window image showing loss of continuity of the anterior cortex of the sacrum (arrows) in contact with the mass, resulting from extrusion of the hyperplastic marrow. (c) Midline sagittal reconstruction showing the craniocaudal extent of the mass (arrows).

Figure 10 Intraspinal EMH in a 36-year-old woman with primary myelofibrosis. (a) Axial contrast-enhanced CT image showing homogeneously enhancing soft tissue (asterisk) filling-in the sacral spinal canal and effacing the epidural fat. (b) Coronal contrast-enhanced T1-weighted MRI image of the sacral spine showing enhancing soft-tissue tracking along the sacral neural foramina (arrows). (c) Sagittal T1-weighted image of the dorsal spine shows diffuse hypointense signal of the bone marrow in comparison to the intervertebral disc, secondary to myelofibrosis. Please cite this article as: Malla S et al., Marrow outside marrow: imaging of extramedullary haematopoiesis, Clinical Radiology, https://doi.org/ 10.1016/j.crad.2019.12.016

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Conclusion EMH is usually seen as an incidental finding when patients with haematological disorders are imaged for other purposes. The tumefactive form of EMH can masquerade a number of pathologies on imaging. It is important for the radiologist to be aware of the imaging features of EMH in order to make the correct diagnosis. Useful imaging findings suggestive of the diagnosis include the multifocal nature of the masses, segmental distribution, and associated bony changes in case of paravertebral or paracostal masses, low signal intensity on T1- and T2-weighted images, presence of haemosiderin or macroscopic fat, loss of signal on opposed-phase images, absence of diffusion restriction, lack of significant post-contrast enhancement, and presence of uptake on 99Tc-labelled sulphur colloid scintigraphy; however, these findings are more readily apparent in chronic lesions and may not be present in the newer lesions showing active haematopoiesis. As no single imaging finding is diagnostic, taking the underlying haematological condition into consideration as well as a combination of imaging findings and slow interval growth is more practical in establishing the correct diagnosis rather than expecting the “Aunt Minnie”.

Conflict of interest The authors declare no conflict of interest.

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