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Imaging features of myeloproliferative neoplasms
Clinical Radiology 72 (2017) 801e809
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Clinical Radiology journal homepage: www.clinicalradiologyonline.net
Review
Imaging features of myeloproliferative neoplasms I.G. Murphy a, *, E.L. Mitchell b, L. Raso-Barnett c, A.L. Godfrey b, E.M. Godfrey a a
Department of Radiology, Addenbrooke’s Hospital, Hills Rd, Cambridge CB2 0QQ, UK Department of Haematology, Addenbrooke’s Hospital, Hills Rd, Cambridge CB2 0QQ, UK c Department of Histopathology, Addenbrooke’s Hospital, Hills Rd, Cambridge CB2 0QQ, UK b
art icl e i nformat ion Article history: Received 5 January 2017 Received in revised form 6 May 2017 Accepted 18 May 2017
Myeloproliferative neoplasms (MPNs) are a heterogeneous group of haematological disorders including polycythaemia vera (PV), essential thrombocythaemia (ET), primary myelofibrosis (PMF), and chronic myeloid leukaemia (CML). These disorders show large overlap in genetic and clinical presentations, and can have many different imaging manifestations. Unusual thromboses, embolic events throughout the systemic or pulmonary vasculature, or osseous findings can often be clues to the underlying disease. There is limited literature about the imaging features of these disorders, and this may result in under-diagnosis. Multiple treatments are available for symptom control, and the development of multiple new pharmacological inhibitors has significantly improved morbidity and prognosis. Knowledge of these conditions may enable the radiologist to suggest an MPN as a possible underlying cause for certain imaging findings, particularly unexplained splanchnic venous thrombosis, i.e. in the absence of chronic liver disease or pancreatitis. The aim of the present review is to outline using examples the different categories of MPN and illustrate the variety of radiological findings associated with these diseases. Ó 2017 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
Background Myeloproliferative neoplasms (MPNs) are a related group of haematological malignancies including polycythaemia vera (PV), essential thrombocythaemia (ET), primary myelofibrosis (PMF), and chronic myeloid leukaemia (CML). MPNs are characterised by clonal proliferation of stem and progenitor cells resulting in increased mature cells of one or more blood cell lineages. The pattern of these changes in the full blood count together with other clinical
* Guarantor and correspondent: I.G. Murphy, Department of Radiology, Addenbrooke’s Hospital, Hills Rd, Cambridge CB2 0QQ, UK. Tel.: þ44 1223245151. E-mail address: [email protected] (I.G. Murphy).
features, bone marrow histology, and molecular testing allow confirmation of the specific diagnosis (Table 1).1 The discovery of the Philadelphia (Ph) chromosome in CML over 50 years ago was instrumental in providing evidence for the genetic basis of cancer. The presence of this t(9;22)(q34;q11) translocation between the BCR and ABL1 genes must be confirmed to make a diagnosis of CML.1 More recently, the identification of additional specific genetic aberrations has allowed more reliable diagnosis and classification of the Ph-negative MPNs. Almost all PV patients have a mutation in the JAK2 gene,2 most often a V617F mutation, or occasionally a mutation in exon 12 of the gene,3 while the majority of patients with ET and PMF have a mutation in the JAK2, CALR4,5 or (least commonly) MPL genes.6 These mutations have numerous effects on intracellular signalling, but in particular, they result in
http://dx.doi.org/10.1016/j.crad.2017.05.014 0009-9260/Ó 2017 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
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Table 1 Clinical and epidemiological features of myeloproliferative neoplasms. MPN
Epidemiology
Clinical features
Laboratory features
Genetic basis
Management
ET
Incidence: 1.5e2.0/100,000 Median age 50e55 years F:M 2:1
Thrombosis Bleeding Headaches
JAK2 (55%) CALR (25%) MPL (5%)
PV
Incidence: 2.0e3.0/100,000 Median age 55e60 years F:M 1:1.2
Thrombosis Neurological Sx Pruritus Plethora Splenomegaly Splenomegaly Extra-medullary haematopoiesis Constitutional symptoms Cytopenias Splenomegaly Bleeding Anaemia Constitutional symptoms
Plt > 45010/l Normal iron levels and CRP Megakaryocytic hyperplasia/atypia in marrow High haematocrit:
Aspirin Hydroxycarbamide Anagrelide Interferon-a Aspirin Venesection Hydroxycarbamide Interferon alpha Ruxolitinib Blood transfusion Ruxolitinib Splenectomy Allogeneic stem cell transplant
PMF
Incidence: 0.5e1.5/100,000 Median age 50e60 years F:M 1:1
CML
Incidence: 1.5e2.0/100,000 Median age 50e60 years F:M 1:1.4
>0.52 in men >0.48 in women Bone marrow pan myelosis Cytopenias Leuco-erythroblastic blood film Tear drop red cells Increased bone marrow fibrosis
Leucocytosis 20e200109/l Full spectrum of normally maturing granulocytes in peripheral blood
JAK2 (>95%)
JAK2 (55%) CALR (30%) MPL (5%)
BCR-ABL1 (100%)
Imatinib Second generation inhibitors (e.g., dasatinib, nilotinib) Allogeneic stem cell transplantation
PV, polycythaemia vera; ET, essential thrombocythaemia; PMF, primary myelofibrosis; CML, chronic myeloid leukaemia; Plt, Sx.
constitutive activation of JAK/STAT growth pathways that leads to unregulated cell proliferation and contributes to the clinical phenotypes observed.7e10 A proportion of patients with MPNs are diagnosed incidentally after examination of a full blood count and/or peripheral blood film performed for other clinical reasons.11 Patients with an MPN diagnosis may present with thrombosis, bleeding, splenomegaly, or extramedullary haematopoiesis. Moreover patients occasionally present with these features, especially splanchnic thrombosis, in the absence of a pre-existing MPN diagnosis or blood count abnormality, but molecular testing may then confirm the presence of a JAK2 mutation and hence an underlying MPN.12 It is therefore important for radiologists to be familiar with these conditions so that they can raise the possibility of occult MPN in this clinical context. In a metaanalysis that included almost 2000 patients with BuddeChiari syndrome or portal vein thrombosis, 17% and 15% of
patients, respectively, had a JAK2 V617F mutation in the absence of typical blood count findings of an MPN.13 Other typical symptoms of PV and ET include headaches, gout, pruritus, small vessel symptoms such as erythromelalgia (burning pains in the fingers or toes), and pregnancy complications such as recurrent miscarriage. PMF and CML may also be associated with constitutional symptoms and symptomatic cytopenias (especially anaemia).
Imaging findings Thrombosis ET and PV both predispose to thrombotic events, which can present in an unusual fashion (Figs 1e3). Guidelines have been published regarding the appropriate investigation of atypical thrombosis.14 In the brain, arterial thrombi can occur as well as dural sinus thrombosis.15 The splanchnic
Figure 1 Axial contrast-enhanced CT image of a 71-year-old man with PV. There are infarcts in the kidneys, liver, right lung, and spleen (white arrows). The case demonstrates systemic arterial thromboembolism (visceral infarcts and mural thrombus in the aorta, black arrow), portal venous thrombus (white arrow head), and systemic venous thrombus (iliofemoral thrombus, leading to PE and pulmonary infarct).
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Figure 2 Axial T1 volumetric interpolated breath-hold examination (VIBE) MRI of the abdomen with intravenous contrast medium in a 40-year-old man positive for JAK2 mutation. Chronic portal vein thrombosis, leading to cavernous transformation (white arrowhead) and splenomegaly (white arrow).
circulation can be affected by arterial thrombi as well as portal vein thrombosis or BuddeChiari syndrome.16e19 Cavernous transformation of the portal vein is often seen in chronic porto-mesenteric thrombosis.20 Systemic venous thrombosis can lead to pulmonary emboli. Counterintuitively, haemorrhage can also be seen,21 most often in those with very high platelet counts (>1000103/ml).22
Osseous findings Findings typically result from marrow infiltration, but cortical bony changes may also be observed (Fig 4). In the marrow, diffuse infiltration is seen. The normal high T1 signal of bone marrow is typically completely replaced by
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Figure 4 (a) Anteroposterior radiograph of the lumbar spine of a 70year-old man with myelofibrosis, showing diffuse osteosclerosis. (b) T1-weighted coronal MRI of the left knee in a 26-year-old woman with JAK2-positive PV. Diffuse low signal is seen in the femur and tibia in keeping with marrow infiltration. At this age, the marrow signal should be hyperintense on T1-weighted imaging given the presence of yellow marrow; instead, the signal is isointense to adjacent muscle.
abnormally low T1 signal. Typical bone marrow should have higher T1 signal intensity than skeletal muscle.23 This is more difficult to detect on T2-weighted imaging. On plain radiographs, osteosclerosis is often seen in PMF.24 With diffuse marrow infiltration, bone scintigraphy can result in a “superscan” appearance, with diffusely increased skeletal uptake relative to the kidneys (Fig 5). Studies have shown that MRI can show the regression of myelofibrosis and osteosclerosis following haematopoietic cell transplantation.25
Figure 3 (a) Axial fluid-attenuated inversion recovery (FLAIR) image of a 75-year-old man with PV showing bilateral high signal in the cerebellar hemispheres consistent with infarcts from vertebrobasilar thrombosis. (b) Axial non-contrast CT image of the brain of a 65-year-old woman with acute left cerebellar infarct, also with PV.
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the spleen and liver but occasionally in the paravertebral regions (Fig 6).26 Transformation of all of the MPNs to acute myeloid leukaemia (AML) may occur, with a poor prognosis.27 This does not usually have imaging features per se, but rarely these patients may develop a focal extramedullary neoplastic mass known as a granulocytic or myeloid sarcoma, previously known as a chloroma (due to their typical green macroscopic colour). These can occur almost anywhere, including bone, chest wall, pleura, periosteum, soft tissue, lymph nodes, testes, skin, and CNS (Fig 7),28e31 It has been reported that the development of myeloid sarcoma can precede the onset of AML in up to a quarter of patients.32 Evidence is mixed on the prognostic significance of these lesions.33,32
Other
Figure 5 (a) Sagittal T1 MRI of the lumbar spine of a 68-year-old man with CML. Diffuse low signal marrow is noted. (b) Bone scintigraphy in a 70-year-old woman with PV transformed to myelofibrosis, showing patchy increased uptake of tracer in the skeleton with reduced conspicuity of the renal outline, verging on a “superscan” appearance.
Solid lesions The most typically encountered solid lesion is extramedullary haematopoiesis. Ineffective red cell production or inadequate bone marrow function can precipitate extramarrow creation of new blood elements, most commonly in
Iron deposition can be a feature of the repeated transfusions required in anaemic patients with PMF. The iron overload is therefore secondary, and is seen in the reticuloendothelial cells of the marrow, spleen, and Kupffer cells of the liver, and in the heart (Fig 8). On magnetic resonance imaging (MRI), this manifests itself as low signal intensity on T2, especially T2*, as signal drop-out on in-phase imaging, and on CT, as hyper-attenuation of the liver on unenhanced imaging.34
Discussion MPNs are uncommon but can be associated with significant morbidity.35 Their presence is suggested by the imaging findings described above; however, many of these findings are non-specific, with differential diagnoses that should be interpreted in context (see Table 2, Figs 9e12).
Figure 6 Sagittal T1 (a) and axial T2 (b) MRI images of the lumbosacral spine in a 65-year-old woman with JAK2-positive PV and myelofibrotic transformation. There is diffuse marrow infiltration as demonstrated by the low T1 signal throughout. There is a large mass extending through the S1 anterior sacral foramina bilaterally (white arrows), consistent with extramedullary haematopoiesis.
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Figure 7 (a) Testicular ultrasound in a 22-year-old man with AML. An enlarging 2-cm hypoechoic lesion that responded to chemotherapy and was felt to represent myeloid sarcoma in the testes. The patient died prior to histopathological confirmation. (b) Haematoxylin and eosin (H&E) staining 4, (c) H&E 40, showing histopathological features. Myeloid sarcoma involving the skin of a 78-year-old male patient with a history of AML (transformed MDS). The dermis is diffusely infiltrated by a population of blasts with prominent nucleoli and varying amounts of eosinophilic cytoplasm. These cells are myeloblasts expressing myeloperoxidase and CD117 (not shown). Myeloid sarcoma can be a presentation of blastic transformation of CML or less commonly the other MPNs, but is now rare in the context of CML as a result of the effectiveness of the new tyrosine kinase inhibitors.
Figure 8 (a) A 60-year-old man with ET, with transformation to myelofibrosis, who required regular blood transfusion. T2 fast spin-echo (FSE) imaging showing marked low signal intensity in the liver, in keeping with iron deposition. Note that the spleen is also T2 hypointense. (b) T2* short-axis image of the left ventricle. T2* time was 13 ms (normal >20 ms), again implying iron deposition.
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Table 2 Common differential diagnoses for imaging findings in myeloproliferative neoplasms (MPNs). Imaging findings in MPN
Potential differential diagnoses
Splanchnic thrombosis
Pancreatitis; pancreatic tumour; hepatocellular carcinoma; cirrhosis Metastasis; myeloma; normal red marrow (children) Neurogenic tumour; metastasis; lateral thoracic meningocoele Many causes including renal osteodystrophy; sickle cell disease; metastasis (Mnemonic: Regular Sex, etc. https:// radiopaedia.org/articles/osteosclerosismnemonic) Haemochromatosis versus secondary iron deposition related to therapy (see text)
Marrow infiltration Extramedullary haematopoiesis Osteosclerosis
Iron deposition
Management of PV and ET is predominantly focused on prevention of vascular events through the use of antiplatelet agents, modification of cardiovascular risk factors, and measures to bring blood counts into an acceptable range (venesection or cytoreductive treatment, most often hydroxycarbamide). PV or ET associated venous thrombosis is treated initially with low molecular weight heparin followed by anticoagulation with a vitamin K antagonist, typically indefinitely in the case of splanchnic thrombosis.36 Direct oral anticoagulants are also being used with increasing frequency, although evidence for their use, specifically in an MPN context, is lacking. The management of CML has been revolutionised by the introduction of targeted pharmacological inhibitors to the
Figure 10 Portal vein thrombosis (black arrows) in a 60-year-old man; however, note the pancreatic duct dilatation (white arrowhead) and ill-defined low-attenuation mass in the neck of the pancreas (white arrow), in keeping with pancreatic adenocarcinoma, in the setting of chronic pancreatitis (see pancreatic calcification, black arrowhead). In this setting, although portal vein thrombosis is present, there is no need to screen for MPN.
BCR-ABL1 tyrosine kinase (see Table 3). Imatinib was the first such drug to be approved for clinical use in 2001, but several more have entered the market in the last few years, including dasatinib and nilotinib. These drugs have transformed the prognosis of CML and dramatically reduced the need for allogeneic stem cell transplantation in its management (see Fig 13). Following the success of imatinib and subsequent identification of JAK2 mutations in Ph-negative MPNs, targeted inhibitors of JAK signalling have been developed, of which the most widely used is ruxolitinib in PMF and more recently in PV.7,37e39 National Institute for Health and Care Excellence (NICE) guidelines published in 2012 recommend computed tomography (CT) of the abdomen and pelvis in all patients over 40 with an unprovoked pulmonary embolus or deep venous thrombosis; however, studies have shown that whereas there is a large proportion of JAK2 mutation and latent MPN in patients with splanchnic vein thrombosis, in systemic thrombosis the gene mutation has not been shown to be more prevalent.40,41 Therefore the question of possible latent MPN should likely only be raised in the setting of splanchnic vein thrombosis, or in recurrent atypical nonsplanchnic thrombosis.
Conclusion
Figure 9 Paraspinal mass as a differential diagnosis for extramedullary haematopoiesis. Axial T2-weighted MRI image of the abdomen in a 47-year-old man. T2 iso- to hyperintense masses in the L3 exit foramina and retroperitoneal mass adjacent to the L3eL4 intervertebral disc (white arrowheads). The cortex is intact, and there are multiple similar smaller lesions in the soft tissues (white arrows). The patient had type 1 neurofibromatosis.
All patients presenting with unexplained portal vein thrombosis or BuddeChiari syndrome should be tested for JAK2 V617F, even if their blood counts are normal. Approximately 15% of patients presenting in this way have a JAK2 mutation despite a normal or near normal blood count (and therefore an occult MPN). These patients should be identified and be under the care of a haematologist; however, portomesenteric thrombosis in the presence of
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Figure 11 (a) T1-weighted gradient-echo (GRE) in-phase and out-of-phase imaging in a 48-year-old man with primary haemochromatosis shows (b) marked signal loss on the in-phase imaging relative to out-of-phase image due to marked elevated iron concentration, the inverse of the effect seen in hepatic steatosis. Note normal signal in the spleen, a hallmark of primary haemochromatosis. Images (c) and (d) correspond to T1 GRE in-phase and out-of-phase images following 2 years of venesection and marked reduction in the iron load, and normalisation of liver signal.
Figure 12 Marrow mimics of MPN. Diffuse low T1 marrow signal intensity, not due to infiltration. (a) Sagittal MRI of the spine in a 6-year-old demonstrating simple red marrow. (b) Sagittal MRI of the spine in a 30-year-old man with back pain. The low T1 signal was attributable to persistent red marrow likely due to heavy smoking, no MPN or other infiltration was present. (c) Back pain was due to prolapsed disc (white arrow).
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I.G. Murphy et al. / Clinical Radiology 72 (2017) 801e809 Table 3 Common therapies used in myeloproliferative neoplasm and their complications. Drug
Indication
Common side effects
BCR-ABL tyrosine kinase inhibitors (imatinib, dasatinib, nilotinib)
CML
Hydroxycarbamide Interferon-alfa Anagrelide Busulphan, pipobroman Ruxolitinib
PV, ET, PMF PV, ET ET PV, ET PMF, PV
Cytopeniasa, GI upset, myalgias, fluid retention Pleural effusion (dasatinib) Increased cholesterol/blood glucose, risk of cardiovascular events (nilotinib) Cytopenias, GI upset, leg ulcers, mouth ulcers Flu-like symptoms, depression, fatigue, cytopenias Headache, anaemia, fluid retention, palpitations/tachycardias Cytopenias, GI upset, increased risk of acute leukaemia Cytopenias, infections, GI upset, weight gain
PV, polycythaemia vera; ET, essential thrombocythaemia; PMF, primary myelofibrosis; CML, chronic myeloid leukaemia; GI, gastrointestinal. a If significant, cytopenias may be associated with bleeding, severe or atypical infections and symptoms of anaemia.
Figure 13 (a) A 65-year-old man with post-PV myelofibrosis treated with ruxolitinib, with marked splenomegaly, measuring 25 cm. (b) Reduction in size of the spleen after 1 year of treatment. Also noted is the resolution of the cachexia related to disease.
pancreatitis or cirrhosis and portal hypertension does not require a search for underlying MPN. Patients with a pre-existing diagnosis of an MPN are at an increased risk of thrombosis or haemorrhage at a variety of sites throughout the body, even with optimal treatment. They may also develop splenomegaly, extramedullary haematopoiesis or bone changes. Recognition of the various associated radiological findings, and the possibility of an underlying MPN in the setting of unusual thrombotic events, can lead to timely diagnosis.
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Review
Imaging features of myeloproliferative neoplasms I.G. Murphy a, *, E.L. Mitchell b, L. Raso-Barnett c, A.L. Godfrey b, E.M. Godfrey a a
Department of Radiology, Addenbrooke’s Hospital, Hills Rd, Cambridge CB2 0QQ, UK Department of Haematology, Addenbrooke’s Hospital, Hills Rd, Cambridge CB2 0QQ, UK c Department of Histopathology, Addenbrooke’s Hospital, Hills Rd, Cambridge CB2 0QQ, UK b
art icl e i nformat ion Article history: Received 5 January 2017 Received in revised form 6 May 2017 Accepted 18 May 2017
Myeloproliferative neoplasms (MPNs) are a heterogeneous group of haematological disorders including polycythaemia vera (PV), essential thrombocythaemia (ET), primary myelofibrosis (PMF), and chronic myeloid leukaemia (CML). These disorders show large overlap in genetic and clinical presentations, and can have many different imaging manifestations. Unusual thromboses, embolic events throughout the systemic or pulmonary vasculature, or osseous findings can often be clues to the underlying disease. There is limited literature about the imaging features of these disorders, and this may result in under-diagnosis. Multiple treatments are available for symptom control, and the development of multiple new pharmacological inhibitors has significantly improved morbidity and prognosis. Knowledge of these conditions may enable the radiologist to suggest an MPN as a possible underlying cause for certain imaging findings, particularly unexplained splanchnic venous thrombosis, i.e. in the absence of chronic liver disease or pancreatitis. The aim of the present review is to outline using examples the different categories of MPN and illustrate the variety of radiological findings associated with these diseases. Ó 2017 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
Background Myeloproliferative neoplasms (MPNs) are a related group of haematological malignancies including polycythaemia vera (PV), essential thrombocythaemia (ET), primary myelofibrosis (PMF), and chronic myeloid leukaemia (CML). MPNs are characterised by clonal proliferation of stem and progenitor cells resulting in increased mature cells of one or more blood cell lineages. The pattern of these changes in the full blood count together with other clinical
* Guarantor and correspondent: I.G. Murphy, Department of Radiology, Addenbrooke’s Hospital, Hills Rd, Cambridge CB2 0QQ, UK. Tel.: þ44 1223245151. E-mail address: [email protected] (I.G. Murphy).
features, bone marrow histology, and molecular testing allow confirmation of the specific diagnosis (Table 1).1 The discovery of the Philadelphia (Ph) chromosome in CML over 50 years ago was instrumental in providing evidence for the genetic basis of cancer. The presence of this t(9;22)(q34;q11) translocation between the BCR and ABL1 genes must be confirmed to make a diagnosis of CML.1 More recently, the identification of additional specific genetic aberrations has allowed more reliable diagnosis and classification of the Ph-negative MPNs. Almost all PV patients have a mutation in the JAK2 gene,2 most often a V617F mutation, or occasionally a mutation in exon 12 of the gene,3 while the majority of patients with ET and PMF have a mutation in the JAK2, CALR4,5 or (least commonly) MPL genes.6 These mutations have numerous effects on intracellular signalling, but in particular, they result in
http://dx.doi.org/10.1016/j.crad.2017.05.014 0009-9260/Ó 2017 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
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Table 1 Clinical and epidemiological features of myeloproliferative neoplasms. MPN
Epidemiology
Clinical features
Laboratory features
Genetic basis
Management
ET
Incidence: 1.5e2.0/100,000 Median age 50e55 years F:M 2:1
Thrombosis Bleeding Headaches
JAK2 (55%) CALR (25%) MPL (5%)
PV
Incidence: 2.0e3.0/100,000 Median age 55e60 years F:M 1:1.2
Thrombosis Neurological Sx Pruritus Plethora Splenomegaly Splenomegaly Extra-medullary haematopoiesis Constitutional symptoms Cytopenias Splenomegaly Bleeding Anaemia Constitutional symptoms
Plt > 45010/l Normal iron levels and CRP Megakaryocytic hyperplasia/atypia in marrow High haematocrit:
Aspirin Hydroxycarbamide Anagrelide Interferon-a Aspirin Venesection Hydroxycarbamide Interferon alpha Ruxolitinib Blood transfusion Ruxolitinib Splenectomy Allogeneic stem cell transplant
PMF
Incidence: 0.5e1.5/100,000 Median age 50e60 years F:M 1:1
CML
Incidence: 1.5e2.0/100,000 Median age 50e60 years F:M 1:1.4
>0.52 in men >0.48 in women Bone marrow pan myelosis Cytopenias Leuco-erythroblastic blood film Tear drop red cells Increased bone marrow fibrosis
Leucocytosis 20e200109/l Full spectrum of normally maturing granulocytes in peripheral blood
JAK2 (>95%)
JAK2 (55%) CALR (30%) MPL (5%)
BCR-ABL1 (100%)
Imatinib Second generation inhibitors (e.g., dasatinib, nilotinib) Allogeneic stem cell transplantation
PV, polycythaemia vera; ET, essential thrombocythaemia; PMF, primary myelofibrosis; CML, chronic myeloid leukaemia; Plt, Sx.
constitutive activation of JAK/STAT growth pathways that leads to unregulated cell proliferation and contributes to the clinical phenotypes observed.7e10 A proportion of patients with MPNs are diagnosed incidentally after examination of a full blood count and/or peripheral blood film performed for other clinical reasons.11 Patients with an MPN diagnosis may present with thrombosis, bleeding, splenomegaly, or extramedullary haematopoiesis. Moreover patients occasionally present with these features, especially splanchnic thrombosis, in the absence of a pre-existing MPN diagnosis or blood count abnormality, but molecular testing may then confirm the presence of a JAK2 mutation and hence an underlying MPN.12 It is therefore important for radiologists to be familiar with these conditions so that they can raise the possibility of occult MPN in this clinical context. In a metaanalysis that included almost 2000 patients with BuddeChiari syndrome or portal vein thrombosis, 17% and 15% of
patients, respectively, had a JAK2 V617F mutation in the absence of typical blood count findings of an MPN.13 Other typical symptoms of PV and ET include headaches, gout, pruritus, small vessel symptoms such as erythromelalgia (burning pains in the fingers or toes), and pregnancy complications such as recurrent miscarriage. PMF and CML may also be associated with constitutional symptoms and symptomatic cytopenias (especially anaemia).
Imaging findings Thrombosis ET and PV both predispose to thrombotic events, which can present in an unusual fashion (Figs 1e3). Guidelines have been published regarding the appropriate investigation of atypical thrombosis.14 In the brain, arterial thrombi can occur as well as dural sinus thrombosis.15 The splanchnic
Figure 1 Axial contrast-enhanced CT image of a 71-year-old man with PV. There are infarcts in the kidneys, liver, right lung, and spleen (white arrows). The case demonstrates systemic arterial thromboembolism (visceral infarcts and mural thrombus in the aorta, black arrow), portal venous thrombus (white arrow head), and systemic venous thrombus (iliofemoral thrombus, leading to PE and pulmonary infarct).
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Figure 2 Axial T1 volumetric interpolated breath-hold examination (VIBE) MRI of the abdomen with intravenous contrast medium in a 40-year-old man positive for JAK2 mutation. Chronic portal vein thrombosis, leading to cavernous transformation (white arrowhead) and splenomegaly (white arrow).
circulation can be affected by arterial thrombi as well as portal vein thrombosis or BuddeChiari syndrome.16e19 Cavernous transformation of the portal vein is often seen in chronic porto-mesenteric thrombosis.20 Systemic venous thrombosis can lead to pulmonary emboli. Counterintuitively, haemorrhage can also be seen,21 most often in those with very high platelet counts (>1000103/ml).22
Osseous findings Findings typically result from marrow infiltration, but cortical bony changes may also be observed (Fig 4). In the marrow, diffuse infiltration is seen. The normal high T1 signal of bone marrow is typically completely replaced by
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Figure 4 (a) Anteroposterior radiograph of the lumbar spine of a 70year-old man with myelofibrosis, showing diffuse osteosclerosis. (b) T1-weighted coronal MRI of the left knee in a 26-year-old woman with JAK2-positive PV. Diffuse low signal is seen in the femur and tibia in keeping with marrow infiltration. At this age, the marrow signal should be hyperintense on T1-weighted imaging given the presence of yellow marrow; instead, the signal is isointense to adjacent muscle.
abnormally low T1 signal. Typical bone marrow should have higher T1 signal intensity than skeletal muscle.23 This is more difficult to detect on T2-weighted imaging. On plain radiographs, osteosclerosis is often seen in PMF.24 With diffuse marrow infiltration, bone scintigraphy can result in a “superscan” appearance, with diffusely increased skeletal uptake relative to the kidneys (Fig 5). Studies have shown that MRI can show the regression of myelofibrosis and osteosclerosis following haematopoietic cell transplantation.25
Figure 3 (a) Axial fluid-attenuated inversion recovery (FLAIR) image of a 75-year-old man with PV showing bilateral high signal in the cerebellar hemispheres consistent with infarcts from vertebrobasilar thrombosis. (b) Axial non-contrast CT image of the brain of a 65-year-old woman with acute left cerebellar infarct, also with PV.
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the spleen and liver but occasionally in the paravertebral regions (Fig 6).26 Transformation of all of the MPNs to acute myeloid leukaemia (AML) may occur, with a poor prognosis.27 This does not usually have imaging features per se, but rarely these patients may develop a focal extramedullary neoplastic mass known as a granulocytic or myeloid sarcoma, previously known as a chloroma (due to their typical green macroscopic colour). These can occur almost anywhere, including bone, chest wall, pleura, periosteum, soft tissue, lymph nodes, testes, skin, and CNS (Fig 7),28e31 It has been reported that the development of myeloid sarcoma can precede the onset of AML in up to a quarter of patients.32 Evidence is mixed on the prognostic significance of these lesions.33,32
Other
Figure 5 (a) Sagittal T1 MRI of the lumbar spine of a 68-year-old man with CML. Diffuse low signal marrow is noted. (b) Bone scintigraphy in a 70-year-old woman with PV transformed to myelofibrosis, showing patchy increased uptake of tracer in the skeleton with reduced conspicuity of the renal outline, verging on a “superscan” appearance.
Solid lesions The most typically encountered solid lesion is extramedullary haematopoiesis. Ineffective red cell production or inadequate bone marrow function can precipitate extramarrow creation of new blood elements, most commonly in
Iron deposition can be a feature of the repeated transfusions required in anaemic patients with PMF. The iron overload is therefore secondary, and is seen in the reticuloendothelial cells of the marrow, spleen, and Kupffer cells of the liver, and in the heart (Fig 8). On magnetic resonance imaging (MRI), this manifests itself as low signal intensity on T2, especially T2*, as signal drop-out on in-phase imaging, and on CT, as hyper-attenuation of the liver on unenhanced imaging.34
Discussion MPNs are uncommon but can be associated with significant morbidity.35 Their presence is suggested by the imaging findings described above; however, many of these findings are non-specific, with differential diagnoses that should be interpreted in context (see Table 2, Figs 9e12).
Figure 6 Sagittal T1 (a) and axial T2 (b) MRI images of the lumbosacral spine in a 65-year-old woman with JAK2-positive PV and myelofibrotic transformation. There is diffuse marrow infiltration as demonstrated by the low T1 signal throughout. There is a large mass extending through the S1 anterior sacral foramina bilaterally (white arrows), consistent with extramedullary haematopoiesis.
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Figure 7 (a) Testicular ultrasound in a 22-year-old man with AML. An enlarging 2-cm hypoechoic lesion that responded to chemotherapy and was felt to represent myeloid sarcoma in the testes. The patient died prior to histopathological confirmation. (b) Haematoxylin and eosin (H&E) staining 4, (c) H&E 40, showing histopathological features. Myeloid sarcoma involving the skin of a 78-year-old male patient with a history of AML (transformed MDS). The dermis is diffusely infiltrated by a population of blasts with prominent nucleoli and varying amounts of eosinophilic cytoplasm. These cells are myeloblasts expressing myeloperoxidase and CD117 (not shown). Myeloid sarcoma can be a presentation of blastic transformation of CML or less commonly the other MPNs, but is now rare in the context of CML as a result of the effectiveness of the new tyrosine kinase inhibitors.
Figure 8 (a) A 60-year-old man with ET, with transformation to myelofibrosis, who required regular blood transfusion. T2 fast spin-echo (FSE) imaging showing marked low signal intensity in the liver, in keeping with iron deposition. Note that the spleen is also T2 hypointense. (b) T2* short-axis image of the left ventricle. T2* time was 13 ms (normal >20 ms), again implying iron deposition.
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Table 2 Common differential diagnoses for imaging findings in myeloproliferative neoplasms (MPNs). Imaging findings in MPN
Potential differential diagnoses
Splanchnic thrombosis
Pancreatitis; pancreatic tumour; hepatocellular carcinoma; cirrhosis Metastasis; myeloma; normal red marrow (children) Neurogenic tumour; metastasis; lateral thoracic meningocoele Many causes including renal osteodystrophy; sickle cell disease; metastasis (Mnemonic: Regular Sex, etc. https:// radiopaedia.org/articles/osteosclerosismnemonic) Haemochromatosis versus secondary iron deposition related to therapy (see text)
Marrow infiltration Extramedullary haematopoiesis Osteosclerosis
Iron deposition
Management of PV and ET is predominantly focused on prevention of vascular events through the use of antiplatelet agents, modification of cardiovascular risk factors, and measures to bring blood counts into an acceptable range (venesection or cytoreductive treatment, most often hydroxycarbamide). PV or ET associated venous thrombosis is treated initially with low molecular weight heparin followed by anticoagulation with a vitamin K antagonist, typically indefinitely in the case of splanchnic thrombosis.36 Direct oral anticoagulants are also being used with increasing frequency, although evidence for their use, specifically in an MPN context, is lacking. The management of CML has been revolutionised by the introduction of targeted pharmacological inhibitors to the
Figure 10 Portal vein thrombosis (black arrows) in a 60-year-old man; however, note the pancreatic duct dilatation (white arrowhead) and ill-defined low-attenuation mass in the neck of the pancreas (white arrow), in keeping with pancreatic adenocarcinoma, in the setting of chronic pancreatitis (see pancreatic calcification, black arrowhead). In this setting, although portal vein thrombosis is present, there is no need to screen for MPN.
BCR-ABL1 tyrosine kinase (see Table 3). Imatinib was the first such drug to be approved for clinical use in 2001, but several more have entered the market in the last few years, including dasatinib and nilotinib. These drugs have transformed the prognosis of CML and dramatically reduced the need for allogeneic stem cell transplantation in its management (see Fig 13). Following the success of imatinib and subsequent identification of JAK2 mutations in Ph-negative MPNs, targeted inhibitors of JAK signalling have been developed, of which the most widely used is ruxolitinib in PMF and more recently in PV.7,37e39 National Institute for Health and Care Excellence (NICE) guidelines published in 2012 recommend computed tomography (CT) of the abdomen and pelvis in all patients over 40 with an unprovoked pulmonary embolus or deep venous thrombosis; however, studies have shown that whereas there is a large proportion of JAK2 mutation and latent MPN in patients with splanchnic vein thrombosis, in systemic thrombosis the gene mutation has not been shown to be more prevalent.40,41 Therefore the question of possible latent MPN should likely only be raised in the setting of splanchnic vein thrombosis, or in recurrent atypical nonsplanchnic thrombosis.
Conclusion
Figure 9 Paraspinal mass as a differential diagnosis for extramedullary haematopoiesis. Axial T2-weighted MRI image of the abdomen in a 47-year-old man. T2 iso- to hyperintense masses in the L3 exit foramina and retroperitoneal mass adjacent to the L3eL4 intervertebral disc (white arrowheads). The cortex is intact, and there are multiple similar smaller lesions in the soft tissues (white arrows). The patient had type 1 neurofibromatosis.
All patients presenting with unexplained portal vein thrombosis or BuddeChiari syndrome should be tested for JAK2 V617F, even if their blood counts are normal. Approximately 15% of patients presenting in this way have a JAK2 mutation despite a normal or near normal blood count (and therefore an occult MPN). These patients should be identified and be under the care of a haematologist; however, portomesenteric thrombosis in the presence of
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Figure 11 (a) T1-weighted gradient-echo (GRE) in-phase and out-of-phase imaging in a 48-year-old man with primary haemochromatosis shows (b) marked signal loss on the in-phase imaging relative to out-of-phase image due to marked elevated iron concentration, the inverse of the effect seen in hepatic steatosis. Note normal signal in the spleen, a hallmark of primary haemochromatosis. Images (c) and (d) correspond to T1 GRE in-phase and out-of-phase images following 2 years of venesection and marked reduction in the iron load, and normalisation of liver signal.
Figure 12 Marrow mimics of MPN. Diffuse low T1 marrow signal intensity, not due to infiltration. (a) Sagittal MRI of the spine in a 6-year-old demonstrating simple red marrow. (b) Sagittal MRI of the spine in a 30-year-old man with back pain. The low T1 signal was attributable to persistent red marrow likely due to heavy smoking, no MPN or other infiltration was present. (c) Back pain was due to prolapsed disc (white arrow).
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I.G. Murphy et al. / Clinical Radiology 72 (2017) 801e809 Table 3 Common therapies used in myeloproliferative neoplasm and their complications. Drug
Indication
Common side effects
BCR-ABL tyrosine kinase inhibitors (imatinib, dasatinib, nilotinib)
CML
Hydroxycarbamide Interferon-alfa Anagrelide Busulphan, pipobroman Ruxolitinib
PV, ET, PMF PV, ET ET PV, ET PMF, PV
Cytopeniasa, GI upset, myalgias, fluid retention Pleural effusion (dasatinib) Increased cholesterol/blood glucose, risk of cardiovascular events (nilotinib) Cytopenias, GI upset, leg ulcers, mouth ulcers Flu-like symptoms, depression, fatigue, cytopenias Headache, anaemia, fluid retention, palpitations/tachycardias Cytopenias, GI upset, increased risk of acute leukaemia Cytopenias, infections, GI upset, weight gain
PV, polycythaemia vera; ET, essential thrombocythaemia; PMF, primary myelofibrosis; CML, chronic myeloid leukaemia; GI, gastrointestinal. a If significant, cytopenias may be associated with bleeding, severe or atypical infections and symptoms of anaemia.
Figure 13 (a) A 65-year-old man with post-PV myelofibrosis treated with ruxolitinib, with marked splenomegaly, measuring 25 cm. (b) Reduction in size of the spleen after 1 year of treatment. Also noted is the resolution of the cachexia related to disease.
pancreatitis or cirrhosis and portal hypertension does not require a search for underlying MPN. Patients with a pre-existing diagnosis of an MPN are at an increased risk of thrombosis or haemorrhage at a variety of sites throughout the body, even with optimal treatment. They may also develop splenomegaly, extramedullary haematopoiesis or bone changes. Recognition of the various associated radiological findings, and the possibility of an underlying MPN in the setting of unusual thrombotic events, can lead to timely diagnosis.
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