British Journal of Radiology (2005) 78, 272-281
© 2005 British Institute of Radiology
doi: 10.1259/bjr/55402388
Non-infectious manifestations of stem cell transplantation
D Beckett, MBBS
and
J Olliff, MBBS, FRCR
Queen Elizabeth Hospital, Edgbaston, Birmingham B15 2TH, UK
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Abstract
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Stem cell transplantation (SCT) is now commonplace within medical practice. With growth in transplant activities, outcomes are likely to continue to improve. Increasing numbers of the population now face life after transplantation. The aetiology of post transplant complications is multifactorial. Background knowledge of SCT and common, radiographically detectable, non-infective complications are important in everyday clinical practice. A review of these complications using a variety of imaging modalities is presented and the process of SCT briefly described. Tumour recurrence is outside the remit of this review.
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Introduction
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Stem cell transplantation (SCT) is now commonplace within medical practice [1, 2]. Estimates suggest 30 000–40 000 SCT are performed annually worldwide [3]. The role of SCT is restoration of immunohaemopoietic function in the recipient after elimination of the underlying disease. Autologous transplantation involves high dose chemotherapy with stem cell rescue, the stem cells having been collected from the patient during periods of low tumour load. Allogeneic transplantation is when another individual, a sibling, haplo-identical parent or unrelated individual, is used as the donor. In order to maximize graft viability a full or near human leukocyte antigen (HLA) match is required. Varying conditioning regimens aim to ablate the existing recipient marrow and tumour load and to suppress graft rejection. While true in myelo-ablative regimens, mini-allogeneic or non-myelo-ablative transplantation seeks to facilitate engraftment and augment the "graft versus tumour" effect. Early transplant related morbidity and mortality is reduced through the use of less toxic conditioning. Still in its infancy, this form of transplantation is largely experimental.
Following suitable pre-conditioning, donor cells harvested from marrow or peripheral blood are infused into the recipient. These have usually been accumulated by extracorporeal separation of peripheral stem cells following cellular mobilization of the donor using granulocyte colony stimulating factor. A varying degree of engraftment ensues, but for up to approximately 21 days the patient is haematologically and immunologically incompetent. This period of engraftment has been shown to be reduced by the use of peripheral blood stem cell infusion. Full immunological restitution may take up to 1 year following transplant. In addition regimens using cyclosporin are used in the prophylaxis of graft-versus host disease (GVHD).
Conventional SCT has established roles within the management of lymphohaemopoietic, immunological, metabolic and other conditions, as well as non-haematological malignancies (Table 1
).
With growth in transplant activities, outcomes are likely to continue to improve. Increasing numbers of the population now face life after transplantation. Cure, however, comes with a price. Transplant morbidity is high.
A multifactorial aetiology for post transplantation complications was given by Wingard et al, in which total body irradiation, chemotherapy, GVHD and immunodeficiency act alone or in combination [3]. While non-infective manifestations account for a significant proportion of transplant related morbidity and may affect all organ systems, infection within the setting of SCT, is common and remains the most significant cause of morbidity and mortality.
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Imaging
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Imaging has a central role in the initial diagnosis and staging of SCT complications. Both during SCT and thereafter, clinicoradiological collaboration allows prompt management of complications. Plain radiography is used initially in suspected abdominal and pulmonary pathology, as well as in the investigation of musculoskeletal disease in the post transplant period. CT and high resolution computed tomography (HRCT) are useful in the classification of pulmonary pathology [4]. Interpretation of imaging findings should be related to the time elapsed since SCT. Furthermore CT guides the physician with regard to subsequent diagnostic procedures. CT and MRI form the mainstay of investigation of cerebral pathology. The widespread availability of MRI has seen an increase in the use of this modality.
Ultrasound, CT and MRI all have a role in the investigation of abdominal pathology, including veno-occlusive disease. Conventional contrast studies have a limited role. The role of the radiologist is pivotal during every step of the patient management.
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Musculoskeletal complications
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Long term musculoskeletal complications are not uncommon (Table 2), and these include benign and malignant conditions [5–11]. Psoriatic arthropathy is reported in the literature but not commonly seen [11]. More commonly, reduction in bone mineral density occurs, peaking at 6 months following SCT and is associated with chemoradiotherapy, steroid usage and malnutrition [10].
Skeletal abnormalities previously associated with external beam irradiation are now being seen in long term survivors of SCT (enchondromas, slipped femoral epiphysis, metaphyseal abnormalities, osteochondromas) who have received total body irradiation (TBI) [7].
Signal changes within the marrow have been observed on MRI following high doses of irradiation during pre-conditioning (Figure 1). Red marrow within the axial skeleton is replaced by fat containing yellow marrow. The subsequent signal change is best appreciated on T1 weighted MRI sequences. The bone marrow shows a steady and marked increase in the pre-contrast signal intensity. The converse, i.e. increased volume of low signal red marrow, may be seen in patients receiving granulocyte colony stimulating factor. Stem cell harvesting using repeated trephine aspiration from the ileum causes focal abnormalities which may be seen on plain radiography and CT (Figure 2).
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Figure 1. Marrow signal change following stem cell transplantation. T1 weighted MRI sequence of the cervical spine demonstrates diffuse increase in the marrow signal reflecting the increase in yellow marrow seen following high dose irradiation therapy.
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Figure 2. Routine follow up CT in a 29-year-old male following autologous stem cell transplant taken at the level of sacroiliac joints. Bilateral lucencies with a narrow zone of transition are demonstrated within both posterior iliac wings from trephine marrow aspiration.
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Avascular necrosis has an incidence of 4.3% at 5 years [6]. Symptoms develop between 2 months and 132 months with the femoral head being the most commonly affected site (Figure 3). Significant morbidity is seen with up to half of these patients requiring joint replacement. Patient age, a diagnosis of aplastic anaemia or acute leukaemia, GVHD and prophylactic treatment with steroids have all been associated with an increased risk of avascular necrosis [6].
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Figure 3. Avascular necrosis. 35-year-old female with bilateral hip pain at 1 year following a matched unrelated transplant. The patient had recently completed a course of steroids for an episode of GVHD. (a) Coronal T1 weighted MRI image of the hips and (b) sagittal T1 weighted MRI of the left hip showing a serpiginous zone of low signal around the avascular area (arrow).
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Neuropathological complications
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Neurological complications are frequent, particularly during the first 3 months following SCT and affect patient survival [12]. The peak occurrence for neurological complications is quoted to be at week 3–4 following SCT. Central nervous system (CNS) related mortality accounts for approximately 15–20% of overall early transplant related mortality [13]. With the development of metabolic encephalopathy (seen in up to a third of patients with CNS complications) patient survival within 100 days falls from 87% to 27%.
There is a complex interplay between pre-conditioning with chemoradiotherapy, the immunohaematological incompetence within the transplant period, GVHD and GVHD prophylaxis in causation of neuropathological complications [12, 14]. Complications may be broadly classified into treatment induced, cerebrovascular and GVHD. Anecdotal reports of inflammatory demyelinating polyneuropathy and immune-mediated myelopathy have been described [15]. Multifocal cerebral demyelination with fulminant, widespread white matter lesions on MRI is documented [16].
Cerebrovascular
Cerebrovascular events may complicate SCT [12–17] (Figure 4). Contributing factors include TBI, haemopoietic incompetence and platelet refractoriness. Cerebral infarction is more common than haemorrhage. TBI is associated with an increased risk of cerebrovascular events. Subdural haematoma (SDH) is common within the haemorrhagic group. The main risk factor for development of SDH is platelet refractory disease [17]. SDH is more common within autologous transplantation [17]. Resolution with conservative management is expected. Anecdotal reports of subarachnoid haemorrhage as a sequlae to Cyclosporin neurotoxicity and GVHD cerebral angiitis have been described [18–20].
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Figure 4. Axial CT of the head through the level of the lateral ventricles. An area of high attenuation is seen within the left thalamus demonstrating a thalamic haemorrhage. A minor degree of cortical atrophy within the frontal lobes is shown.
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Treatment induced
Total body irradiation
Standard autologous and allogeneic SCT involves pre-conditioning with TBI. A standard regimen would consist of eight fractions over 4 days (approximately 14.4 Gy). Cerebral infarction, diffuse white matter disease, and cortical atrophy have been reported with this form of conditioning.
Cyclosporin neurotoxicity
Regimens incorporating Cyclosporin are used in the prophylaxis of GVHD following allogeneic SCT. Patients may continue with Cyclosporin prophylaxis for a variable time period dependant on initial transplant (myelo-ablative vs non-myelo-ablative), and ongoing GVHD. It is not uncommon for patients to remain on Cyclosporin for up to 2 years and beyond. Cyclosporin neurotoxicity has been characterized by hypertension, seizures and reversible posterior leukoencephalopathy [21–23]. Low attenuation on CT and increased signal on T2 MR which characteristically does not enhance are typical radiographic findings.
Specific conditioning prior to SCT may alter the pattern of toxicity [24]. TBI has been associated with white matter lesions while those conditioned with chemotherapy develop mixed cortical and white matter lesions.
Secondary malignancy
Chromosomal instability, immunosuppression, conditioning with TBI and viral pathogens have been linked to the development of malignant disease within the post-transplant period [25]. The risk of developing a solid tumour at 15 years post SCT is in the order of 7–8% [25]. Head and neck squamous cell carcinoma, melanoma, and solid tumours of brain and thyroid are seen (Figure 5). Reported neoplasms of bone following total body irradiation include osteosarcoma, fibrosarcoma, malignant fibrous histiocytoma and chondrosarcoma.
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Figure 5. Biopsy proven squamous cell carcinoma of the roof of the mouth in a 39-year-old female, 8 years following stem cell transplantation. Contrast enhanced axial CT through the roof of the oral cavity. A heterogeneous mass involving the roof of the mouth adherent to the alveolar aspects of the maxilla is demonstrated (arrows). There was no evidence of bony destruction.
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Cardiothoracic pathology
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Pulmonary system
Pulmonary complications in the setting of SCT are a common cause of morbidity and mortality [26].
Three discrete phases which reflect the immunological state of the patient have been identified [26]. The neutropenic phase, lasting up to 30 days is characterized by alveolar haemorrhage, drug toxicity and capillary leak syndrome. The second phase, 30–100 days, consists of radiation/drug induced damage. The third, or late phase, is strongly associated with chronic GVHD (cGVHD). Accordingly, bronchiolitis obliterans, bronchiolitis obliterans with organizing pneumonia (BOOP), and lymphocytic interstitial pneumonitis (LIP) are seen within this phase.
0–30 days
Non-cardiogenic pulmonary oedema occurs frequently within SCT [27]. There is a strong correlation with the time of engraftment. Circulating lymphocytes are thought to be involved. Up to 25% of patients may develop this form of capillary leak syndrome (CLS) [27]. Pulmonary features tend to be accompanied by hepatic and renal dysfunction. CLS is seen in both allogeneic and autologous transplantation. With engraftment occurring earlier in allogeneic transplantation, CLS will be seen earlier within this group. Classical septal lines, alveolar oedema and pleural effusions are seen. Capillary leak syndrome may also develop in response to granulocyte stimulating factor treatment or chemotherapy.
Diffuse alveolar haemorrhage (DAH) may occur early or late within the transplant period, although DAH tends to be associated with granulocyte recovery (first 30 days) [28, 29]. DAH is linked to the conditioning regimen, infections and inflammatory pneumonitis. DAH has been reported in up to 20% of patients. Patients may present with dyspnoea (96%), fever (67%) and cough (56%) [29]. Haemoptysis is rare. Up to 90% require ventilation and high dose methlyprednisolone (1.5 g day–1) for about 4 days. Mortality is significantly higher within allogeneic transplantation and those presenting with late haemorrhage [29]. Radiographic findings include bilateral reticular or patchy alveolar opacities, usually in the mid to lower lung zones (Figure 6a). Rapid progression to a severe diffuse alveolar pattern is characteristic. On CT small areas of ground glass attenuation confined to the secondary lobules can be seen. The pattern is non-specific and has a variety of causes (infectious, neoplastic, idiopathic and inhalational disorders) (Figure 6b).
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Figure 6. Diffuse alveolar haemorrhage. (a) Chest radiograph taken 22 days following allogeneic SCT shows bilateral alveolar opacification. (b) CT from a different patient with dyspnoea taken at 29 days following transplantation demonstrates patchy ground glass attenuation within the mid zones.
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Drug toxicity changes are non-specific and include ground glass opacification, nodules, consolidation and later fibrosis [30]. These tend to occur within phases 1 or 2.
Late onset pulmonary complications
Chronic pulmonary complications affect approximately 10% of patients [28]. Abnormal pulmonary function is associated with higher non-relapse mortality [21, 32].
Obliterative bronchiolitis and obliterative bronchiolitis with organizing pneumonia
Obliterative bronchiolitis is seen in up to 15% of patients with cGVHD [33–35]. Typical presentation is at 6–12 months. Little or no treatment exists apart from treating the underlying GVHD. Mortality is up to 40%.
Histologically there is inflammation and lymphocytic infiltration with progressive destruction of the small airways.
Hyperinflation of the lungs, flattening of the diaphragm, and recurrent pneumothoraces are seen on the chest radiograph. HRCT may show decreased pulmonary vasculature, peribronchial thickening, and areas of air trapping, seen best on expiratory HRCT (Figure 7). Ventilation scans show reduced tracer activity in areas of obliteration of bronchiolar walls, along with atelectatic areas.
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Figure 7. Bronchiolitis obliterans. High resolution CT shows decreased pulmonary vasculature and subsegmental bronchial dilatation (asterisk). Obvious areas of air trapping giving the "mosaic perfusion" appearance are not readily apparent. (Image courtesy of Dr J Reynolds. Consultant Radiologist at Heartlands and Solihul Hospital, Birmingham.)
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Organizing pneumonia may be associated with or without obliterative bronchiolitis. Typically, a meandering pattern of multifocal consolidation may be seen on the chest radiograph or CT (Figure 8). CT is of use in targeting for open lung biopsy. Biopsy confirms an organizing pneumonia in the absence of micro-organisms.
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Figure 8. Organizing pneumonia. 32-year-old male with increasing breathlessness at 5 months following stem cell transplantation. (a) Chest radiograph demonstrates upper zone, peripheral areas of consolidation and interstitial shadowing. (b) CT demonstrates areas of ill defined ground glass attenuation in association with more focal areas of consolidation in a predominantly subpleural distribution. (Images courtesy of Dr J Reynolds. Consultant Radiologist at Heartlands and Solihul Hospital, Birmingham.)
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Lymphocytic interstitial pneumonitis
LIP is seen more frequently within the setting of allogeneic transplantation. There is a strong association with cGVHD and patients frequently show other manifestations of cGVHD [36]. Histology shows lymphocyte infiltrate of the interstitium with alveolar sparing. The chest radiograph and cross sectional imaging show diffuse micronodular opacification. Consolidation is not typical early on in the disease process. HRCT findings include diffuse bilateral ground glass opacification and poorly defined centrilobular nodules, subpleural nodules, thickening of the bronchovascular bundles, cystic airspaces and patchy ground glass (Figure 9). Interstitial damage may progress to fibrosis with impaired gas exchange and respiratory dynamics. A definitive diagnosis may be made by open lung biopsy. Treatment primarily consists of steroids and immunosuppression to arrest cGVHD.
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Figure 9. Lymphocytic interstitial pneumonitis. 33-year-old male with increasing breathlessness 3 months following stem cell transplantation. (a) Chest radiograph demonstrates bilateral mid and lower zone pulmonary nodules measuring 1–5 mm in the absence of clinical infection. (b) High resolution CT through the lower lobes demonstrates widespread nodules throughout the lungs and patchy ground glass opacification. (Images courtesy of Dr J Reynolds. Consultant Radiologist at Heartlands and Solihul Hospital, Birmingham.)
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Cardiovascular pathology
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Cardiotoxic events result from intensive conditioning during SCT [37–41]. Cardiotoxicity may be associated with septic shock, pneumonitis or multiorgan failure. Although infrequent, cardiomyopathy has been observed [39–41]. Overall, major cardiotoxic events are infrequent (<1%) [37]. Various subclinical events have been reported and include impaired systolic and diastolic function [38]. Complications related to catheter placement are seen within interventional radiology [42] (Figure 10). Occlusion caused by thrombus, and/or fibrin sheath formation are common (Figure 11). Catheter migration and malfunction have been reported.
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Figure 10. A misplaced single lumen central venous catheter. (a) The tip is seen to lie within the left axillary vein (arrow). (b) Using a common femoral vein approach the tip is snared and manipulated into the correct position. (Images courtesy of Dr P Crowe. Consultant Radiologist at Heartlands and Solihul Hospital, Birmingham.)
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Figure 11. A snare catheter via a femoral vein approach may be used to strip the tip of a central venous catheter when a fibrin sheath is seen to overlie the tip. (Image courtesy of Dr P Crowe. Consultant Radiologist at Heartlands and Solihul Hospital, Birmingham.)
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Gastrointestinal/hepatobilary manifestations
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Acute abdominal complications in SCT may be broadly categorised as those arising from intensive conditioning through chemoradiotherapy, acute or chronic GVHD, or miscellaneous conditions.
Chemoradiotherapy
Chemotherapy and TBI may cause ileocolitis, pancreatitis, cholangitis, appendicitis, gastric perforation and hepatic veno-occlusive disease (VOD) [43]. VOD has a reported incidence of 0–70% [44]. 30% of patients are affected within the first 2 weeks. The aetiology of VOD is complex and not fully understood. It is thought that chemoradiotherapy leads to endothelial injury of small hepatic veins and sinusoids [45]. Concentrated antineoplastic agents within the centrilobular zone leads to necrotic oedematous hepatocytes obstructing sinusoidal flow. Tumour necrosis factor alpha is released leading to cytotoxicity and coagulation. Histopathology shows centrilobular congestion, oedema, venular occlusion, atrophy of pericentral hepatocytes, recanalization of venules and centrilobular cholestasis. Diagnosis is non-specific. Clinical presentation is that of jaundice, weight gain and ascites. Radiographically detectable findings include hepatomegaly with or without major hepatic vein collapse, gallbladder thickening, ascites and bidirectional or reversed portal flow on Doppler [45]. Liver biopsy is used to differentiate VOD from other causes of hepatic dysfunction (infective, GVHD, drug induced toxicity) [46].
Neutropenic colitis (NC) is an acute necrotizing inflammatory condition predominantly affecting the caecum and right colon. NC is rare within the setting of SCT [47]. Ischaemia, secondary bacterial invasion and sepsis are seen. If untreated patients may develop transmural necrosis and perforation. CT findings include bowel wall thickening, pericolic inflammatory changes and pneumoperitoneum (Figure 12).
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Figure 12. Neutropenic colitis. 28-year-old male with abdominal pain. CT with oral contrast through the level of the caecum in a neutropenic patient. There is marked thickening of the caecum (arrows) and descending colon. The caecal pole is dilated and there is streaking of the mesenteric and retroperitoneal fat planes.
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GVHD
GVHD refers to the process by which donor T-cells may elicit disease within recipient tissue. 60% of patients may be affected. GVHD is characterized as acute or chronic depending whether presentation is before or after 100 days from SCT. Any organ system may be involved.
Chronic involvement of the oesophagus and stomach is occasionally seen. If untreated cGVHD may lead to stricture and web formation of the oesophagus requiring endoluminal dilatation. Isolated cases of oesophageal and bowel carcinoma have been reported in the literature.
Diffusely affected abnormal, dilated, fluid filled loops of small bowel with or without bowel wall thickening are seen [48]. Granulation tissue replaces destroyed bowel mucosa. The characteristic target sign of mucosa oedema with abnormal contrast enhancement of the bowel wall is a feature on contrast enhanced CT [49].
Miscellaneous
An increased incidence of cholelithiasis is seen in patients following SCT [43]. Splenic and renal infarction has been described [43]. Pneumatosis intestinalis is a rare yet important phenomenon within SCT [50, 51]. The aetiology is multifactorial. Chemoradiotherapy, GVHD and corticosteroids have been implicated [50]. Presentation is with diarrhoea, abdominal pain and bleeding per rectum. The right colon is predominantly affected [50]. Pneumatosis intestinalis is predominantly linear on plain radiography.
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Post-transplant lymphoproliferative disorder
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The cumulative probability of developing post-transplant lymphoproliferative disorder (PTLD) has been estimated at 1.6% at 4 years [52]. The pathology involves uncontrolled, B-cell derived donor lymphocyte proliferation. PTLD is strongly associated with Epstein-Barr virus in the setting of stem cell transplantation. Risk factors include T-cell depletion, HLA mismatch, conditioning, and a diagnosis of primary immunodeficiency. Clinical presentation is with fever and associated lymphadenopathy of the bowel, spleen, liver and other organs.
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Conclusion
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Specificity of diagnosis is achieved with clinicoradiological collaboration. Knowledge of the transplant process and multifactorial nature of the ensuing complications is required for the successful management of this patient subgroup.
Received for publication January 5, 2004.
Revision received October 4, 2004.
Accepted for publication October 13, 2004.
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C. L. Hollingsworth, D. P. Frush, J. Kurtzburg, and V. K. Prasad
Pediatric Hematopoietic Stem Cell Transplantation and the Role of Imaging
Radiology,
August 1, 2008;
248(2):
348 - 365.
[Abstract]
[Full Text]
[PDF]
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Abstract
Introduction
