Bone Marrow Disorders: Non-Neoplastic Conditions

This chapter deals with a variety of non-neoplastic blood-related disorders that have a major influence on imaging of the skeletal system.

Disorders of Red Cells

In late fetal life and infancy, the entire bone marrow is utilised for red blood cell (RBC) production, supplemented by extramedullary haematopoiesis (EHM) in the liver and spleen. As the child becomes older and RBC life span increases, erythropoiesis is withdrawn from the liver and spleen, then gradually from the diaphyses of the long bones so that by the age of 25 years, active bone marrow is confined to the axial skeleton, the flat bones and the proximal ends of the femora and humeri. This process of withdrawal will not occur with a need for extra erythropoiesis and reverses in the presence of increased RBC destruction.

Physiological Marrow Reconversion

Physiological marrow reconversion is commonly seen on musculoskeletal magnetic resonance imaging (MRI) studies in response to increased haematopoietic needs of the body, as may occur in heavy smokers, athletes (particularly those involved in high altitude training), obesity and chronic respiratory disorders including obstructive sleep apnoea. Marrow hyperplasia is most commonly noted in the distal femur and proximal tibia on magnetic resonance (MR) examinations of the knee, and in the proximal humerus on MR examinations of the shoulder. The hyperplastic marrow has a well-defined ‘geographical’ margin with normal yellow marrow, shows signal intensity (SI) which is intermediate between yellow marrow and skeletal muscle on unenhanced T ₁ weighted spin echo ( Fig. 66.1A ) and T ₂ weighted fast spin echo sequences, mildly hyperintense on short-tau inversion recovery (STIR) and fat-suppressed sequences ( Fig. 66.1B ), and is hypointense on gradient echo imaging. It should not be mistaken for marrow infiltration. Symmetrical marrow reconversion may also be seen in oncology patients who have been treated with granulocyte colony-stimulating factor (GCSF) ( Fig. 66.2 ).

Fig. 66.2, Granulocyte Colony-Stimulating Factor Effect.

Not uncommonly, focal nodular hyperplasia (FNH) of the marrow may also be seen mimicking medullary bone tumours or metastases, but the marrow SI is again typical of hyperplastic red marrow. Common sites include the vertebrae and long bone metaphyses ( Fig. 66.3A and B ). Rarely, FNH may show increased activity on fluorodeoxyglucose-positron-emission tomography (FDG-PET) studies, and biopsy may be required to exclude metastatic involvement.

The Anaemias

Only chronic anaemias affect the imaging appearances of bone. Anaemias that do not produce reactive erythropoiesis, such as aplastic anaemia, do not affect the skeletal radiograph but may manifest on MRI as a generalised increase in fatty marrow SI.

The Myelodysplastic Syndromes

The myelodysplastic syndromes (MDSs) comprise a variety of clonal stem cell disorders which have an overall incidence of approximately 3.3/100,000, which can rise to between 15 and 50/100,000 in patients older than 70 years of age. They result in variable symptoms and signs of chronic anaemia, bleeding and frequent infections due to defective RBC, platelet and white blood cell production. MDS has been reclassified into various subtypes by the World Health Organisation (WHO) in 2016, replacing the previously used French–American–British (FAB) classification. The disease is progressive, with allogenic stem cell transplantation being the only curative treatment, and carries a 25%–40% risk of transformation to acute leukaemia.

MRI may demonstrate nodular, patchy or diffuse reduction of T ₁ weighted marrow SI ( Fig. 66.4A ), with corresponding hyperintensity on fat-suppressed proton density weighted (PDW)/T ₂ weighted or STIR sequences ( Fig. 66.4B ). The patchy or diffuse pattern of marrow abnormality is associated with poorer prognosis and earlier development of leukaemia. Presacral EMH is also a recognised complication.

The Haemoglobinopathies

The haemoglobin (Hb) molecule consists of a protein (globin) and four haem groups, each with four pyrrole rings surrounding an iron atom. The protein moiety consists of 574 amino acids arranged in four spiral polypeptide chains. The different chains are designated by letters of the Greek alphabet (α, β), and the three normal Hbs A, A2 and F each contain two α chains, differing only in their second pairs.

Summary Box: Disorders of Red Cells

Physiological marrow reconversion is very commonly seen on magnetic resonance imaging (MRI), occurring in any conditions resulting in chronic marrow stress, or chronic anaemia associated with myelodysplastic syndromes
MRI is characterised by focal or diffuse reduction of T ₁ weighted marrow signal intensity (SI) which is intermediate between that of medullary fat and skeletal muscle
Focal nodular hyperplasia of the marrow may mimic a bone tumour or metastasis but should be recognised based on the typical T ₁ weighted marrow SI

Haemoglobinopathies are genetic conditions which result in either defective or deficient globin chains and include:

1.
Thalassaemia: an inherited defect of HbA synthesis with inadequate manufacture of α- or β-chains.
2.
Hb variants: inherited defects of HbA synthesis producing abnormal α- or β-chains. All the variants differ from HbA by the substitution of only one amino acid in the chain: e.g. HbS (sickle cell anaemia) where valine is substituted for glutamine at residue six in the β-chain.
3.
Combination of thalassaemia and abnormal Hb: for example, HbS–thalassaemia.

Thalassaemia

Thalassaemia is an autosomal recessive disorder that affects the production of either α- or β-chains, resulting in the development of α-thalassaemia or β-thalassaemia, respectively. The purely heterozygous form of each condition results in an asymptomatic carrier state. The homozygous form of α-thalassaemia (α-thalassaemia major; α-TM) is one of the commonest causes of hydrops fetalis and usually results in intrauterine or perinatal death. The homozygous form of β-thalassaemia (β-thalassaemia major; β-TM) results in severe childhood anaemia and affects the skeleton in a variety of ways. Compound heterozygosity can also occur in α- and β-thalassaemia resulting in haemoglobin H disease and β-thalassaemia intermedia (β-TI), respectively, which are both typically non-transfusion-dependent conditions that can affect the skeleton due to marked marrow hyperplasia.

Clinical Features

β-TM is prevalent in those originating from the Mediterranean countries (Greece, southern Italy and the Mediterranean islands) and causes severe childhood anaemia resulting in massive hepatosplenomegaly, skeletal deformity due to chronic marrow hyperplasia, and EHM. Treatment is by regular blood transfusion commencing in infancy aiming to maintain an Hb level of >95 g/L, iron chelation with agents such as deferoxamine, deferiprone or deferasirox to prevent/reduce iron overload, and bisphosphonates to treat the associated osteoporosis. With the introduction of successful transfusion regimes, the skeletal changes due to the disorder itself are now less commonly encountered, but osseous complications related to repeated transfusion and the effects of chelation therapy may occur. Bone disease may also be contributed to by endocrinopathy due to iron overload, including hypogonadism, growth hormone deficiency, hypoparathyroidism, vitamin D deficiency, hypothyroidism, diabetes and renal dysfunction. The only curative treatment is allogenic bone marrow transplantation.

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