Extramedullary haematopoiesis (EMH) is defined as the presence/growth of haematopoietic tissue outside the bone marrow.1-4 The pathogenesis of EMH has been attributed to the stimulation and differentiation of “latent haematopoietic niches” outside the bone marrow, usually located in the liver, spleen, lymph nodes, and aortic-gonad-mesonephros spaces, that remained quiescent after embryonic/foetal development.4-9 This condition could affect at risk patients, such as those diagnosed with thalassemia Major (TM) or thalassemia Intermedia (TI), in whom chronic anaemia, hypoxemia, ineffective erythropoiesis, and high erythropoietin may interact together with EMH development.5,6,8-10

Historically EMH was considered a rare event but nowadays it is increasingly being recognized, as more accurate diagnostic tools have become available and been incorporated in the clinical practice, including magnetic resonance imaging (MRI).4,11-14 Studies reported the prevalence of EMH ranging from 2.2% to 25.0%, a variability that is likely due to heterogeneous patient cohorts assessed in different settings. 1-4,7,9,15,16

A systematic review, that united data from two important retrospective studies and seventy case reports, analysing a total of 253 patients with EMH and thalassemia, recently described the clinical features of EMH.4 This review observed that the mean age and mean haemoglobin level at presentation were 35.3 years old and 8.2 g/dL, respectively.4 Furthermore, two remarkable studies (OPTIMAL CARE2 and E-SAAN1) revealed that transfusion dependence, age, and thalassemia severity might be associated with the incidence of EMH.1,2 However, uncertainty and heterogeneity remain regarding epidemiological aspects, risk factors, clinical presentation and the optimal treatment approach.1,2,4

Other factors associated with an increased prevalence of EMH have been identified: the IVS–I–6-mutated allele, splenectomy, non-transfusion dependent phenotype, skeletal deformities, lower myocardial iron content, and higher levels of the soluble form of transferrin receptor (sTfR) and of growth differentiation factor 15 (GDF-15).3,5,10,11,15,16

The clinical presentation of EMH usually manifests as thoracic or abdominal masses, from asymptomatic cases to severe organ impairment due to tumour compression of adjacent structures including organs such as the spinal cord, lung, heart, or large central vessels. 4,12,13,14,17 Signs and symptoms of liver and/or spleen impairment may be present due to haematopoietic tissue expansion.18,19 Recurrent haemorrhagic or exudative pleural effusions have also been described.20

Imaging tests such as MRI and computed tomography (CT) have demonstrated good accuracy to diagnose EMH. 4 However, in a few patients, other invasive tests such as biopsy may be necessary to confirm EMH and exclude differential diagnoses such as mesenchymal tumours, neuronal tumours, lymphomas, hematomas, other causes of serositis, liver diseases and splenomegaly.4,9,14,18

The optimal treatment approach is not clearly defined. Studies have reported combined therapies based on radiotherapy, hydroxyurea, and higher haemoglobin transfusion thresholds.2,4,9 Some cases may need surgery or urgent spinal cord decompression.4 Recently, Janus kinase (JAK) inhibitors have also been used in the treatment of EMH with encouraging results.21

The objective of the current study was to describe the EMH clinical, epidemiological and MRI findings in patients with TI or TM and to explore potential risk factors for its occurrence.

In the study period, the MRIs and charts of 184 patients with thalassemia were reviewed in the centre. Of these, 168 patients had TM (92.0%) and 16 TI (8.0%); 82 were male (44.6%) with the median age being 22 years old (range 7-69; mean of 24 years). There was no reliable information in the medical records about the type of thalassemia (alpha or beta).

All but one patient had iron overload in at least one organ, predominantly hepatic (99%). Most patients were on a regular transfusion regimen (TM: 96%; TI: 50%) and being treated with chelation therapy (TM: 98%; TI: 86%); about 4% (n = 7) of the total cohort did not have complete clinical data regarding their transfusion regimen and chelation therapy and therefore they were excluded from the analysis of these variables. The proportion of patients on each chelation medication was desferrioxamine (64/36.2%), deferasirox (48/27.1%), deferiprone (17/9.6%), and a combined therapy of desferrioxamine and deferiprone (48/27.1%).

A total of 19 (10.3%) EMH cases were identified and distributed as 16 (9.5%) cases of TM patients and three (18.7%) cases of TI. The clinical characteristics of patients with or without EMH are provided in Table 2.

Among the EMH patients, 57.9% (n = 11) had masses that were < 5 cm in diameter, 21% (n = 4) between 5–10cm, and 21% (n = 4) >10 cm. Supplementary Table 1 details the features of the EMH patients. Four EMH images (Figures 1a-d) were selected to illustrate the radiologic characteristics of these patients. Figure 2 shows the anatomic distribution of EMH masses.

Figure 1.

T2 fast spin echo magnetic resonance imaging (MRI) scans: A) Coronal scan of case 9, showing large soft tissue mass in the thoracic and lumbar paravertebral space (arrows); hepatosplenomegaly and marked hypo intensity of the liver and spleen, which indicates iron deposition. B) Axial scan of case 124 showing small soft tissue mass in the right thoracic paravertebral space (arrow). C) Axial scan of case 13 showing small soft tissue nodule in the hepatorenal space (arrow), presenting marked hypo intensity, indicating iron deposition. D) Axial and coronal of case 132 showing large soft tissue mass in the thoracic paravertebral space. Note the marked hypo intensity of the liver and spleen (coronal), which indicates iron deposition.

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Figure 2.

Schematic illustration of the general anatomic distribution and number of cases of extramedullary haematopoiesis masses in patients with thalassemia major (black circles) and thalassemia intermedia (white circles).

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Univariate analysis showed a significant association between EMH and age (p-value < 0.001), with no cases of EMH in patients < 19 years old. A significant association was also observed between EMH and chronic liver disease (p-value = 0.006), as summarized in Table 3.

Multivariate analysis showed that EMH was significantly correlated with age (HR: 1.10/year; CI: 1.03-1.18; p-value < 0.001) as a risk factor, and with pancreatic T2* increment (HR: 0.94/ms; CI: 0.89-0.99; p-value < 0.049) as a protective factor. Twenty five percent (2/8) and 50% (2/4) of patients aged > 40 years with TM and TI, respectively had EMH. Only four patients with EMH did not have any pancreatic iron overload.

Assessment of survival in the EMH-free patients according to TM or TI is shown in Figure 3. Information on survival up to October 2017 was available for 94 (49%) of the studied population. The overall survival of 19 patients with EMH and the 75 patients without EMH was estimated using Kaplan-Meier curves (Figure 4). Overall survival was estimated for patients with available follow-up data up to October 2017 (19 EMH-positive patients and 75 in the EMH-negative group). There was a statistically significant difference in survival between patients with and without EMH (p-value = 0.013), possibly linked to existing baseline age differences at the study entry. Additionally, survival was compared between the TM (n = 82) and TI (n = 11) subgroups. Although the survival curves visually appear to be distinct (Figure 5), no statistically significant difference between them was found.

Figure 3.

Survival analysis of the subgroup of patients without extramedullary haematopoiesis masses.

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Figure 4.

Survival analysis of the subgroups of patients with or without extramedullary haematopoiesis masses (EMH).

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Figure 5.

Survival analysis of the subgroups of patients with thalassemia major and thalassemia intermedia.

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The prevalence of EMH observed in this cohort of patients with TM and TI was 10.3%, represented mostly by posterior thoracic masses of 5–10 cm. Age was strongly associated with higher risk to EMH, while chronic liver disease was only associated with EMH in the univariate analysis.

Literature on the clinical and epidemiological aspects of EMH has described massive marrow proliferation with extramedullary tumour masses in patients with homozygous beta-thalassemia inadequately transfused and even more frequently in patients with both TI (up to 20%) and hemoglobinopathies (E/beta).2,4,26 Another study observed a lower EMH prevalence (13.2%) in a large cohort of regularly transfused major thalassemic patients.15 In our cohort, the observed prevalence of EMH was 9.5% and 18.7% for TM and TI patients, respectively.

Besides transfusion dependence, age differences may also explain the disparities observed in EMH prevalence between studies; while a systematic review has shown a mean age of 35 years at EMH diagnosis, this study found median ages of 30 years and 39 years in the TM and TI subgroups, respectively.4,9 Moreover, one study of TI patients with low transfusion requirements reported an even higher EMH prevalence (21.2%), which increased up to 40% depending on the patients’ age.2 Other risk factors for EMH have been described in TI patients, such as low foetal haemoglobin and severe ineffective erythropoiesis.27 Splenectomy has been described as a protective factor for EMH development, but our study could not find such an association.2

There are few case reports of EMH in children and adolescents; one reports on low transfusion regimens in young patients.1,4,9 EMH was not observed in under 19-year-old patients in our cohort. EMH in older patients may be a consequence of a longer period of exposure to erythropoietic stimulation linked to the EPOR/JAK-STAT signalling pathway and differentiation of quiescent haematopoietic niches.1,2,4,6,9

Our study was not designed to explore correlations between transfusion regimen and EMH development due to the small percentage (50%; n = 8) of non-transfusion-dependent patients in the TI subgroup, however the literature addressing this issue suggests that non-transfusion-dependent TI are at higher risk of EMH. 1-8,11,13,15,26,27

Regular transfusion regimens may suppress erythropoietic stimulation thereby reducing the development of EMH as well as skeletal deformities in patients. 1-4,8,9,28 Moreover, there are observations of negative correlations between haemoglobin/erythropoietin ratios and markers of increased osteoclastic activity, such as the receptor activator of nuclear factor-kappa B ligand (RANKL), that suggest a similar etiopathogenic mechanism on bone remodelling may occur.28 However, correlations between EMH and skeletal changes in thalassemic patients is yet to be better explored in the literature.

In the current study, the main sites of EMH were thoracic and abdominal (88%), almost all of them in the thoracic paravertebral spaces as has previously been reported in thalassemic patients.1-4,26 Even so, clinicians should be aware that EMH may occur in less frequently reported sites, as was recently shown by a systematic review that revealed EMH cases in adrenal glands, the skull and even intracranial tissue.4

The survival data and the multivariate analysis must be interpreted cautiously, because EMH+ patients were already older than the EMH- patients in the enrolment phase of the study and there is uncertainty on the precise moment at which each patient developed EMH. Additionally, the EMH+ group may be more sensitive/responsive to erythroid factors, which could explain the better life expectancy observed compared to the EMH- group, however our data is limited and cannot conclude if EMH could really be positively influencing extended patient survival.

Our findings suggest that two factors might be linked to EMH: pancreatic iron T2* (ms) and chronic liver disease, while the latter was significant only in the univariate analysis. Higher pancreatic T2* MRI findings (lower pancreatic iron) was negatively associated with the presence of EMH in the multivariate analysis (HR: 0.94/ms; CI: 0.89-0.99; p-value = 0.049) which, although considered a statistically significant correlation, is a borderline result, that should be cautiously interpreted. This finding contrasts with two studies that observed lower/no cardiac iron overload in EMH-positive patients when compared to the EMH-negative group in a regularly transfused cohort, a subgroup which they named thalassemia intermedia-like pattern.6,15,16

The correlations between iron metabolism and EMH biology remain an open question. While excess exogenous iron appears to increase erythropoietic responsiveness and expansion of extramedullary erythroid mass in animal models of thalassemia29, iron overload may negatively affect effective erythropoiesis, but might be improved by iron chelation therapy by reducing reactive oxygen species (ROS).30

Our understanding is that patients with less risk of EMH and lower pancreatic iron concentration might have other protective factors that were not assessed in this study, such as higher mean haemoglobin levels, lower erythropoietin levels, and favourable pancreatic iron kinetics, similar to that observed in the myocardium in cases with the TI-like pattern.15,16

Regarding chronic liver disease as a risk factor for EMH, we consider that this could be a surrogate factor associated with increased age, higher LIC and hepatic fibrosis, but it could also be a consequence of microscopic foci of intrahepatic EMH inducing liver disease over the long term.18,19

The effective management of patients with thalassemia requires an optimal balance between iron chelation, haemoglobin target and organomegaly/EMH monitoring, organ dysfunction and bone health.4,9 Symptomatic EMH could be managed by surgery, irradiation, hydroxyurea and intensifying the transfusion regimen in TM patients.4,9

The prevalence of EMH was 10.3% in the current cohort, presenting mainly as tumoral masses (of 3 to 10 cm) located at the posterior mediastinum. Age was the main factor significantly associated with EMH risk. While lower pancreatic iron (higher T2* velocity - ms) might be a protective factor and chronic liver disease could be a risk factor for EMH, further studies are required. In this cohort, despite of analytic limitations, thalassemic patients who survived longer had a higher frequency of EMH. Further studies are needed to understand how EMH affects patient survival.