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Taher A, Vichinsky E, Musallam Ket al., authors; Weatherall D, editor. Guidelines for the Management of Non Transfusion Dependent Thalassaemia (NTDT) [Internet]. Nicosia (Cyprus): Thalassaemia International Federation; 2013.
This publication is provided for historical reference only and the information may be out of date.
A 25 year-old never-transfused man known to have hemoglobin E/β-thalassemia (moderate phenotype) presented to the emergency room with inability to walk for 3 days. His symptoms started 3 weeks prior to presentation with mild weakness that has been increasing progressively. He has become bedridden for the previous two days. He concomitantly felt a lower thoracic burning pain and breathing discomfort associated with the start of the weakness. He also reported pain (4/10), non-radiating, constant over time, and not relieved by paracetamol. His lower limbs sensation has also been affected, with a worsening tingling sensation. He also complained of difficulty with urination (not able to initiate a flow) in the past 3 days. He had 3 episodes of stool incontinence in the past 2 days, and denied any fever, chills, nausea, or vomiting. He also denied any history of discopathy, trauma to the back, or any previous episodes of back pain or prior limitation of movement. He had a negative family history of neurologic disease. His neurologic exam was consistent with spastic paraplegia. His muscle power was 3/5 in right leg and 2/5 in left leg. He also showed decreased sensation below the T10 level and deep tendon reflexes were increased. The patient was given dexamethasone for spinal cord syndrome and an emergency magnetic resonance imaging of the spine was done, which showed a posterior extradural mass compressing the spinal cord from levels T4 to T8. The patient was managed with a combination of radiotherapy and blood transfusion, and follow-up magnetic resonance imaging after 30 days showed resolution of the mass with no residual weakness.
Expansion of the erythron in the bone marrow in NTDT during ineffective erythropoiesis is not only associated with osteoporosis and bone deformities but is also associated with homing and proliferation of erythroid precursors in the spleen and liver as a physiological compensatory phenomenon termed extramedullary hematopoiesis, which leads to hepatosplenomegaly [1-2].
Ineffective erythropoiesis in NTDT patients also forces expansion of the hematopoietic tissue (extramedullary hematopoiesis) in areas other than the liver and spleen, mostly in the form of masses termed extramedullary hematopoietic pseudotumors. The prevalence of extramedullary hematopoietic pseudotumors is considerably higher in NTDT (~20%) than regularly-transfused β-thalassemia major patients (<1%) [3-5], and is mainly reported in β-thalassemia intermedia and hemoglobin E/β-thalassemia patients with few cases reported in haemoglobin H disease [6]. The prevalence is higher in older patients [7], as well as those with more severe ineffective erythropoiesis [8], and low fetal hemoglobin levels [9]. Almost all body sites may be involved including the lymph nodes, thymus, heart, breasts, prostate, broad ligaments, kidneys, adrenal glands, pleura, retroperitoneal tissue, skin, peripheral and cranial nerves, brain, and the spinal canal [10-15]. These sites are believed to normally engage in active hematopoiesis in the fetus during gestation. This pathway normally stops at birth, but the extramedullary hematopoietic vascular connective tissues retain the ability to produce red cells under conditions of longstanding ineffective erythropoiesis [10].
Among the various body regions reported, paraspinal involvement received special attention due to the debilitating clinical consequences secondary to neural element compression [10]. The origin of the spinal epidural hematopoietic tissue is still controversial. It has been hypothesized that this tissue could be extruded through the trabecular bone of the vertebral body with a circumferential involvement of the vertebra, or it may have extended through the thinned trabeculae at the proximal rib ends [16-17]. Others have proposed some embryological hematopoietic cell remnants within the epidural space, which would be stimulated along the course of chronic anemia. Development of hematopoietic tissue from branches of the intercostal veins has also been suggested [18], while others still attribute the masses to embolic phenomena [19-20]. Early in its evolution, the paraspinal extramedullary site of hematopoiesis reveals immature and mature cells mainly of the erythroid and myeloid series and dilated sinusoids containing precursors of red cells. The lesions eventually become inactive and reveal some fatty tissue and fibrosis or massive iron deposits [16]. There is some predilection for the site of spinal cord involvement by the hematopoietic tissue. The thoracic region and to a lesser extent the lumbar region are the most commonly involved sites. The reason for this predilection is uncertain, but because the subarachnoid space and the spinal canal are narrow in the thoracic region, which also has limited mobility [21-22], small intraspinal hematopoietic tissue may cause compression of the spine at this level. This is in contrast with other regions of the cord in which such tissues must reach larger sizes to exert enough pressure on the spinal cord and cause symptoms [23].
A paraspinal location for the hematopoietic tissue occurs in 11 to 15% of cases with extramedullary hematopoietic pseudotumors [24-25], and a large number of cases have been reported in the literature as reviewed recently [10]. Paraspinal extramedullary hematopoietic pseudotumors may cause a variety of neurological symptoms due to spinal compression. However, it is believed that more than 80% of cases may remain asymptomatic and the lesions are usually discovered incidentally by radiologic techniques [22, 26-27]. The development of neurologic symptoms depends on the chronicity of the disease with neurologic symptoms most frequently being reported during the third and fourth decades of life [28], although few reports described presentation as early as the first decade of life [19, 29-30]. The male to female ratio reaches 5:1 [28]. Various clinical presentations have been reported including: back pain, lower extremity pain, parasthesia, abnormal proprioception, exaggerated or brisk deep tendon reflexes, Babinski response, Lasegue sign, paraparesis, paraplegia, ankle clonus, spastic gate, urgency of urination, and bowl incontinence. The size and location of lesions and the extent of spinal cord involvement determine the severity, acuteness and multiplicity of signs and symptoms [10, 31].
Early diagnosis of paraspinal extramedullary hematopoietic pseudotumors will affect the course of management and may reduce the incidence of irreversible neurologic damage that would otherwise occur with prolonged undiagnosed cord compression [10, 31]. The medical history remains important to rule out other entities in the differential diagnosis of epidural masses including metastatic malignant disease, lymphoma, multiple myeloma, vascular anomalies, or an epidural abscess [10, 31]. In the past, the diagnosis of paraspinal extramedullary hematopoietic pseudotumors in patients with NTDT was suspected from the typical osseous abnormalities found on chest radiographs [32-34] or was confirmed after surgical removal of the mass [63]. Plain radiographs often reveal well demarcated paraspinal masses and bony changes associated with chronic anemia such as trabeculation, widened ribs, or thickened calvaria [35-36]. Bony destruction or pathological fractures are usually absent (Figure 11-1-A) [10]. In the early 1980s, several reports demonstrated that computed tomography was a more preferred diagnostic imaging method (Figure 11-1-B) [10]. 99 mTc bone scan has also been used to diagnose paraspinal extramedullary hematopoietic pseudotumors [37] but the diagnosis within the epidural space may be difficult due to the proximity to bone marrow [38]. Myelography is declining in popularity due to its invasiveness, the need for cisternal puncture in cases of complete block preventing passage of radiographic contrast [37, 39] and reports of neurological deterioration following the procedure [20, 40].
![Figure 11-1:. Representative images of paraspinal extramedullary hematopoietic pseudotumors. (A) Chest X-ray demonstrating expanded anterior rib ends consistent with medullary hyperplasia. A paraspinal mass is seen in the right lower zone (white arrow). (B) Computed tomography scan showing inactive paraspinal extramedullary hematopoietic lesion with increased density compared to soft tissue due to iron deposition (black arrowheads). (C) Magnetic resonance image of cervical and thoracic spine. T2-weighted sagittal image showing thoracic cord compression by extramedullary intraspinal epidural hematopoietic mass from T2 to T10 (white arrows). Reproduced with permission from reference [10].](/books/NBK190455/bin/ch11-f1.gif)
Representative images of paraspinal extramedullary hematopoietic pseudotumors. (A) Chest X-ray demonstrating expanded anterior rib ends consistent with medullary hyperplasia. A paraspinal mass is seen in the right lower zone (white arrow). (B) Computed (more...)
Currently, magnetic resonance imaging has eventually replaced all these methods and is considered the method of choice for the diagnosis and follow-up evaluation of spinal cord compression cases resulting from paraspinal extramedullary hematopoietic pseudotumors [10]. Magnetic resonance imaging can clearly show anatomical details with high quality including both site and extent of the masses within the spinal canal, while producing soft tissue delineation with high sensitivity. Active recent hematopoietic extramedullary lesions have rich vasculature while inactive older lesions have more fatty tissue and iron deposits [16, 38, 41]. If the patient is treated with blood transfusions, the lesion may decrease in size and appear on magnetic resonance imaging with massive iron deposition [41]. Fatty degeneration is most probably related to oxidative stress leading to lipid peroxydation of cell membranes and production of oxygen free radicals. This is probably the reason why foci with fatty content are observed in non-transfused, non-chelated NTDT patients in whom conditions of oxidative stress occur more often than in transfused and iron-chelated β-thalassemia major patients [10]. Although iron deposition and fatty replacement of the foci are inactivity procedures, they seem to never coexist, probably because of the different oxidative stress conditions [41]. Active lesions show intermediate signal intensity in both T1- and T2- weighted magnetic resonance images (Figure 11-1-C). Gadolinium enhancement is minimal or absent differentiating it from other epidural lesions such as abscesses or metastases [38, 42]. Older inactive lesions show high signal intensity in both T1 and T2 weighted magnetic resonance images due to fatty infiltration or low signal intensity in both T1 and T2 weighted magnetic resonance images due to iron deposition [43-44]. Differential diagnosis is often very easy, when the lesion is multifocal (paravertebral and epidural) or bilateral, due to characteristic iron deposition or fatty replacement and the characteristic topography. The only diagnostic problem exists with the solitary, unilateral active lesion. Mesenchymal tissue tumors or tumors from neural tissue elements are in the differential diagnosis but the clinical history of congenital hemolytic anemia usually helps correct diagnosis [41]. Although biopsy remains the gold standard for establishing a tissue diagnosis, it is an invasive procedure that carries the risk of catastrophic hemorrhage and is therefore not usually advocated. It may be of value reserved for older patients with a high probability of malignant disease and for cases in which the clinical and radiological picture is equivocal [10].
Observational studies, case series, and case reports confirm that both transfusion and hydroxyurea therapy may have a role in the prevention and management of extramedullary hematopoietic pseudotumors [3, 10-12]. A beneficial role of Janus Kinase 2 (JAK2) inhibitors on extramedullary hematopoiesis in the spleen is suggested by animal studies, and further clinical evaluation is underway [1, 45-48].
Aside from blood transfusions and hydroxyurea, management options of paraspinal extramedullary hematopoietic pseudotumors may also include radiotherapy or surgical decompression, or any combination of these modalities [10]. Therapy usually depends on the severity of symptoms, size of the mass, patient’s clinical condition, and previous treatment. Because the extramedullary hematopoiesis in NTDT patients is only a compensatory mechanism for ineffective erythropoiesis and chronic anemia, initiation of blood transfusions can decrease the need for extramedullary hematopoiesis; thus resulting in relative inactivity of these tissues, and leading to the shrinkage of the mass size, decompression of the spinal cord, and neurologic improvement [10]. The initial response results primarily from a decrease in blood flow to these tissues even before reduction in the size of the mass can be detected [22, 49]. Blood transfusion (commonly hypertransfusion) is commonly used as the principal treatment modality. Some authors have reported cases treated exclusively by this modality as a first choice or in cases where surgical decompression or radiotherapy were contraindicated e.g. pregnancy or severe anemia [22, 49-54]. The target hemoglobin level was usually >10 g/dl [10]. Blood transfusion was even considered of diagnostic value since only cases of cord compression secondary to extramedullary hematopoiesis, and not other entities on the differential diagnosis, could respond to transfusion therapy [22]. However, several reports also showed that improvement may be slow, insufficient and only temporary [19, 29, 35, 42, 55]. Moreover, while blood transfusion may prevent further progression of the mass, it may be unable to reverse preexisting cord compression. Its role in the management of patients with symptoms of acute onset may therefore be limited [22, 54]. Thus, many advocate using blood transfusion only as an adjunct to surgery (preparation and/or postoperative course) as correction of the hemoglobin level can be helpful in the immediate pre-operative period in order to insure an optimal oxygenation of the spinal cord during surgery [28, 38, 40, 50].
Low-dose radiation as a monotherapy has been reported to yield excellent results in up to 50% of patients with neurological improvement observed as soon as 3 to 7 days after initiation of treatment [23, 35, 39, 56-57]. Hematopoietic tissue is extremely radiosensitive and undergoes shrinkage after radiotherapy [58]. Dosages reported in the literature range from 900 to 3500 cGy [23, 28, 32, 39, 51]. A high risk of recurrence up to 19-37%, is the main drawback of radiotherapy [32, 39]. These recurrences, however, are often amenable to further doses. The risks of radiotoxicity on an already compressed and injured spinal cord remain a concern [35]. Tissue edema associated with radiation can sometimes result in neurological deterioration during the initial phase of treatment which is minimized by concomitant high-dose steroid therapy [40]. The immunosuppressive effect of radiotherapy is usually monitored with frequent peripheral blood counts as the resultant pancytopenia may further aggravate the condition [24, 32, 53]. In patients who need rapid therapeutic response due to severe neurological symptoms, radiotherapy is usually considered the primary treatment. In addition to primary treatment, radiotherapy is commonly employed as a post-operative adjunct following laminectomy to reduce the likelihood of recurrence [23, 25, 28, 38].
NTDT patients with paraspinal extramedullary hematopoietic pseudotumors have been successfully treated with hydroxyurea alone especially in thalassemic patients who are unable to receive blood transfusions due to alloimmunization [59-60].
Successful combination therapy of any two of the three modalities (low-dose radiation, blood transfusion, and hydroxyurea) has been reported as a therapeutic option, either for cases of recurrence after using a single treatment method alone or as an initial treatment regimen [22, 30, 32, 35, 39, 51, 59, 61-64].
Laminectomy is usually reserved for cases of acute presentation which do not respond to adequate transfusion or radiotherapy [24, 38-39]. Surgery confers the benefits of immediate relief of cord compression and histological diagnosis [38, 65-66]. Disadvantages include risk of bleeding associated with the high vascularity of the mass in question and the risks of operating on anemic individuals who are predisposed to shock, incomplete excision in cases of diffuse involvement, instability and kyphosis associated with multilevel laminectomy [20, 28, 34, 40, 42]. Another drawback is that the procedure is not always possible or desirable due to diffuse nature of the mass and the possibility of recurrence. Moreover, immediate total resection of extramedullary hematopoietic pseudotumors can lead to clinical decompensation and deterioration because these masses play a crucial role in maintaining an adequate hemoglobin level [39].
![Figure 11-2:. Algorithm for the management of paraspinal extramedullary hematopoietic pseudotumors in patients with NTDT. Reproduced with permission from reference [10].](/books/NBK190455/bin/ch11-f2.gif)
Algorithm for the management of paraspinal extramedullary hematopoietic pseudotumors in patients with NTDT. Reproduced with permission from reference [10].
All rights reserved. The publication contains the collective views of an international group of experts and does not necessarily represent the decisions or the stated policy of the Thalassaemia International Federation.
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