DOI: 10.1148/rg.272065088
RadioGraphics 2007;27:307-324
© RSNA, 2007
Imaging the Complications of Bone Marrow Transplantation in Children1
Daniel S. Levine, MBChB2,
Oscar M. Navarro, MD,
Gulraiz Chaudry, MBChB,
John J. Doyle, MD and
Susan I. Blaser, MD
1 From the Department of Diagnostic Imaging (D.S.L., O.M.N., G.C., S.I.B.) and the Department of Pediatrics, Division of Hematology/Oncology (J.J.D.), Hospital for Sick Children and University of Toronto, 555 University Ave, Toronto, Ontario, Canada M5G 1X8. Recipient of a Certificate of Merit award for an education exhibit at the 2005 RSNA Annual Meeting. Received May 3, 2006; revision requested June 5 and received July 19; accepted July 21. J.J.D. is a medical consultant for Insception Biosciences, Toronto, Ontario, Canada; all remaining authors have no financial relationships to disclose.
Address correspondence to O.M.N. (e-mail: oscar.navarro{at}sickkids.ca).
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Abstract
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Bone marrow transplantation is frequently performed to restore hematologic and immunologic competence after chemotherapy and radiation therapy for a range of childhood malignancies, as well as to treat various congenital conditions in which hematologic and immunologic functions are depressed or absent. Potentially devastating complications may occur during the pre-engraftment period after bone marrow transplantation, when marrow aplasia may supervene for several weeks until engraftment occurs, as well as during the postengraftment period (the 3 months after engraftment) and in subsequent months and years. Complications of bone marrow transplantation may be classified either according to the time interval between transplantation and the occurrence of the complication or according to the organ system affected. The range of complications that may affect the central nervous system and the rest of the body may be detected with ultrasonography, computed tomography, and magnetic resonance imaging. Neurologic, paranasal sinus, pulmonary, and abdominopelvic complications all may be seen after bone marrow transplantation. Graft-versus-host disease and lymphoproliferative disorders also may occur. The increasing use of bone marrow transplantation mandates that the radiologist be familiar with the full range of potential complications and their imaging appearances.
© RSNA, 2007
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LEARNING OBJECTIVES FOR TEST 2
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After reading this article and taking the test, the reader will be able to:- Explain the basic principles of and indications for pediatric bone marrow transplantation.
- Describe the range of potential clinical complications of pediatric bone marrow transplantation.
- Identify the imaging manifestations of those complications.
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Introduction
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Bone marrow transplantation is performed to restore hematologic and immunologic competence after chemotherapy and radiation therapy for a range of childhood malignancies, as well as to treat congenital conditions in which these functions are depressed or absent.
The relationship between the marrow donor and the recipient may be syngeneic if they are genetically identical individuals (eg, identical twins), allogenic if they are genetically different individuals who have been matched according to HLA type, or autologous if they are the same individual (the patient’s own stem cells are harvested and later reinfused). In the latter situation, stem cells are obtained from peripheral blood rather than bone marrow, a reflection of the first and full name of the technique, blood and marrow transplantation; however, bone marrow transplantation is a more commonly used term.
To prepare the recipient for grafting, malignant cells must be eradicated and immunologic resistance must be reduced. These goals are achieved with high-dose chemotherapy, which often is used in combination with total body irradiation. Such therapeutic regimens increase the risk of patient morbidity and mortality in both the short and the long term. The timing of complications that occur after transplantation may be described with reference to three periods: the pre-engraftment period, which typically lasts 15–30 days and is characterized by marrow aplasia, followed by engraftment and the restoration of hematopoiesis; the early postengraftment period (the first 100 days after engraftment); and subsequent months and years, which are usually referred to as the late postengraftment period.
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Pulmonary Complications
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Early complications—complications that occur at any point from the time of transplantation to the end of the early postengraftment period—include interstitial pneumonitis (infective and noninfective types), infection, edema, hemorrhage, thromboembolism, and calcification. Bronchiolitis obliterans with organizing pneumonia (BOOP) is a rare complication that may occur during the early or late postengraftment period.
Interstitial Pneumonitis
Interstitial pneumonitis is a major cause of morbidity and mortality after bone marrow transplantation. Cases of interstitial pneumonitis may be divided into infectious and noninfectious categories, with viruses being the main causal agent in the former group. Clinically, the symptoms are similar regardless of the cause, and dyspnea, fever, and a nonproductive cough are common manifestations.
Infectious Causes of Interstitial Pneumonitis.—
Cytomegalovirus (CMV) is the most important viral pathogen that causes pneumonia in transplant recipients. Because both the pathogen and the antiviral agents used in its treatment may cause further myelosuppression, CMV infection is associated with a potentially high mortality rate. Infection most often occurs when the latent virus is reactivated as a consequence of immunosuppression or when CMV-positive bone marrow or blood products are infused into a CMV-negative recipient (1). Respiratory syncytial virus, adenovirus, and human herpesvirus 6 all have been detected in patients with diffuse pneumonitis (2,3). Pneumocystis jiroveci (formerly known as Pneumocystis carinii), which recently was reclassified as a fungus, is another potential cause of interstitial pneumonia; however, because of the standard antimicrobial prophylaxis regimens used in patients undergoing bone marrow transplantation, it is seen less frequently.
Noninfectious Causes of Interstitial Pneumonitis.—
Idiopathic interstitial pneumonitis and idiopathic pneumonia syndrome are synonyms for the same process: widespread alveolar injury without evidence of an infective cause at lavage, biopsy, or autopsy. Typically occurring within the early posttransplantation period and less frequently occurring as a late complication, idiopathic pneumonia syndrome is thought to result from a variety of lung insults, including those secondary to chemo-and radiation therapy, immune-mediated injury and cytokine release, and occult infection (4–6). In addition, acute graft-versus-host (GVH) disease (discussed more fully in the section on "Abdominopelvic Complications") appears to be a significant risk factor for the development of idiopathic pneumonia syndrome (3,5,6).
Indeed, it is thought that many of the pulmonary complications of bone marrow transplantation are related to GVH disease, as either primary manifestations or secondary complications (2,4).
Unfortunately, the radiographic and computed tomographic (CT) appearances of both infectious and noninfectious interstitial pneumonitis are nonspecific. Notable features include increased interstitial markings, multilobar infiltrates, areas of ground-glass opacity, and nodules (2,6,7) (Fig 1). Biopsy is frequently undertaken to identify the cause (2,4).
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Figure 1. Idiopathic interstitial pneumonitis in a 14-year-old boy 8 months after bone marrow transplantation for acute lymphoblastic leukemia. CT image shows extensive bilateral ground-glass opacities and pleural effusions.
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Pulmonary Infections
Prolonged neutropenia is a major risk factor for fungal infections such as those due to Aspergillus, Candida, Chrysosporium, and Mucor species, the last of which is associated with a particularly poor prognosis. Not surprisingly, chest CT is more sensitive than radiography for the detection of these conditions; airspace opacification and parenchymal nodules with halos of ground-glass attenuation are common CT appearances. Histopathologically, the latter reflect a central area of infective consolidation with a surrounding zone of hemorrhagic infarction due to thrombosis caused by fungal vascular invasion (1). Less frequently, cavitation may be seen, and this finding often coincides with a recovery of the neutrophil count (1–4) (Fig 2). Bronchoalveolar lavage or open lung biopsy may be required for diagnosis (2).
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Figure 2. Fungal abscess in a 15-year-old boy 1 year after bone marrow transplantation for acute lympho-blastic leukemia. CT image shows confluent areas of consolidation in the lower lobe of the right lung, with a central region of cavitation (arrows) that represents an abscess. An Aspergillus species grew at laboratory culture of a lobectomy specimen.
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Bacterial pneumonia also may occur but is seen less commonly because of the widespread use of antibiotic prophylaxis (4). Infections due to Gram-negative organisms such as Klebsiella pneumoniae predominate in the early posttransplantation period, whereas those due to Gram-positive organisms such as Streptococcus pneumoniae tend to occur later (7). Impaired IgA secretion, abnormal humoral response to bacterial antigens, and splenic dysfunction are implicated as causes of increased susceptibility to such infections (2).
Pulmonary Edema
Pulmonary edema may occur as an early complication of bone marrow transplantation, usually within the first 2–3 weeks after the procedure. Edema may be due to a multitude of causes, including pulmonary vascular damage, renal impairment, and cardiotoxic effects of chemotherapy, radiation therapy, or both. It also may be a response to iatrogenic fluid overload. Radiographic appearances are the same regardless of the cause and include a prominent pulmonary vasculature, increased interstitial markings, and peribronchial thickening. Perihilar shadowing, pleural effusions, and airspace opacification also may be seen in severe cases (4).
Pulmonary Hemorrhage
Platelet production is usually the last function to be recovered after marrow engraftment. Consequently, pulmonary hemorrhage represents another significant early complication, occurring within the first few weeks after transplantation (8). The radiographic features of pulmonary hemorrhage are nonspecific and may include patchy or diffuse airspace consolidation and ground-glass opacification (Fig 3).
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Figure 3. Pulmonary hemorrhage in an 11-month-old boy 3 weeks after bone marrow transplantation for Hurler syndrome. CT image shows bilateral basal ground-glass opacities and pleural effusions, features that would be found also in the presence of infection and pulmonary edema.
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Bronchiolitis Obliterans with Organizing Pneumonia
BOOP, also known as cryptogenic organizing pneumonia, has been described as a rare complication that generally occurs 2–3 months after bone marrow transplantation but may occur later (4,9–12). BOOP is thought to be predominantly a reaction to GVH disease, although other causes, such as infection and drug toxicity, also have been postulated in this clinical context (13). Pathologically, BOOP is characterized by granulation tissue within the bronchiolar lumen that proliferates and involves adjacent alveoli. Clinical manifestations include a dry cough, dyspnea, and a low-grade fever. The radiographic appearance typically comprises patchy airspace opacity. CT shows foci of airspace consolidation and ground-glass opacity, usually with a peripheral distribution (9) (Fig 4). Mild bronchial and bronchiolar dilatation may be present, and well-defined nodules also may be seen occasionally (1).
Pulmonary Calcification
Diffuse pulmonary calcification observed in children after bone marrow transplantation has been described as the result of either abnormal calcium metabolism (metastatic) or calcium deposition in damaged pulmonary tissue (dystrophic); the latter was observed in patients with leukemia (14). The extent of calcifications does not correlate with the magnitude of the patient’s symptoms, which typically include dyspnea and a chronic unproductive cough. The calcifications occur in areas of previous parenchymal consolidation and appear radiographically as persistent pulmonary opacities that may be misinterpreted as pulmonary disease that is unresponsive to treatment. Dual-energy digital radiography and high-resolution CT are more sensitive for the detection of calcification than is radiography (14).
Late pulmonary complications—complications that occur more than 100 days after engraftment—include chronic GVH disease, infections, bronchiolitis obliterans, fibrosis, and lymphoid interstitial pneumonitis.
Chronic GVH disease is a major multisystem complication for patients who survive 6 months or longer after bone marrow transplantation. Affected patients are susceptible to the same bacterial, fungal, and viral pneumonias that may occur in the early posttransplantation period; these patients also are predisposed to chronic obstructive lung disease, termed bronchiolitis obliterans—a condition that, in the general population, often results from connective tissue disease, drug toxicity, inhalational injury, or viral pneumonia (4,15). The main clinical symptoms of bronchiolitis obliterans are coughing, progressive dyspnea, and wheezing (2). Chest radiographs may be normal or may demonstrate hyperinflation, but high-resolution CT images typically show mosaic attenuation and expiratory air trapping; the use of expiratory CT imaging is therefore important (Fig 5). Bronchial dilatation may be evident in advanced cases.
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Figure 5. Bronchiolitis obliterans in a 2-year-old girl 9 months after bone marrow transplantation for severe combined immunodeficiency. CT image shows areas of mosaic attenuation and air trapping in both lungs.
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Restrictive lung disease is also relatively common after bone marrow transplantation and is thought to have a multifactorial etiology including drug toxicity and radiation effects. Pulmonary fibrosis and lymphoid interstitial pneumonitis are two causes of late posttransplantation restrictive disease that have been described in the literature (1,6).
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Abdominopelvic Complications
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GVH Disease
GVH disease is not only a primary complication of bone marrow transplantation but also acts as a predisposing factor for other complications. GVH disease occurs when donor T lymphocytes damage the epithelium of the skin, liver, gastrointestinal tract, and other recipient organs. Moderate to severe GVH disease develops simultaneously with engraftment in 30%–50% of allogenic bone marrow transplant recipients. Its clinical manifestations may include a maculopapular rash, hyper-bilirubinemia and hepatic dysfunction, diarrhea, malabsorption, and even gastrointestinal hemorrhage (16).
CT findings suggestive of GVH disease include abnormal bowel wall enhancement that affects both the small bowel and the colon, with or without bowel wall thickening (Fig 6). This finding has been documented also at magnetic resonance (MR) imaging (17) and appears to correlate histologically with mucosal destruction and replacement by a thin layer of granulation tissue. Abnormal enhancement of the gallbladder and the urinary bladder wall, with or without thickening, also may occur and may represent a similar histopathologic process (18). However, current imaging techniques are not useful for differentiating GVH disease from infective enteritis, and a biopsy is often required (17) (Fig 7). Ultimately, the radiographic abnormalities may resolve completely, although cases of secondary stricture formation requiring surgical resection have been documented in the literature (16). Imaging manifestations of hepatic GVH disease are not specific and may overlap with those of veno-occlusive disease and acalculous cholecystitis.
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Figure 6. Small-bowel GVH disease in a 7-year-old boy 2 months after bone marrow transplantation for aplastic anemia. CT image shows multiple fluid-filled bowel loops with increased wall enhancement. The differential diagnosis included infective enteritis and mucositis secondary to chemotherapy.
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Figure 7. Infective enteritis in a 3-year-old boy 1 week after autologous bone marrow transplantation for neuroblastoma. CT image shows diffuse small- and large-bowel wall enhancement with focal wall thickening in the jejunum and descending colon (arrows). The differential diagnosis included chemotherapy-induced mucositis, but GVH disease was excluded because the transplant was autologous.
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Neutropenic Colitis
Mucosal damage secondary to pretransplantation chemotherapy and radiation therapy regimens, together with immunosuppression in the pre-engraftment period, places the bone marrow transplant recipient at significant risk of other gastrointestinal complications. Severe diarrhea is very common, with multiple fluid-filled bowel loops visible at abdominal radiography. Ileus and bowel distention also may be seen, but concurrent neutropenic colitis or typhlitis (from typhlon, the Greek word for cecum) remains the primary concern. Clinically manifested by the triad of abdominal pain or tenderness, fever, and neutropenia, this condition was first described by Wagner in 1970. It is now most frequently seen in patients with hematologic malignancies but also may be seen after bone marrow transplantation (19,20).
Pathologically, the process of mucosal edema and ulceration may involve the whole thickness of the bowel wall and may include secondary necrosis and perforation. Bacterial, fungal, or viral infection may be present and may lead to secondary septicemia (16). These abnormalities are usually localized to the cecum and ascending colon, but the appendix and terminal ileum also may be involved (19,21). Abdominal radiographs may show a paucity of right lower quadrant bowel gas with thickening of the cecal wall. Ultrasonographic (US) and CT images may demonstrate cecal wall thickening with hyperemia (Fig 8). Additional findings at CT may include inflammatory stranding in the pericecal fat, as well as free intra-abdominal gas and fluid collections in cases complicated by perforation.
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Figure 8a. Neutropenic colitis in a 6-year-old girl 3 months after bone marrow transplantation for lymphoma. (a) US image shows marked thickening of the cecum. (b) CT image shows marked thickening and increased enhancement of the fluid-filled cecum and terminal ileum.
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Figure 8b. Neutropenic colitis in a 6-year-old girl 3 months after bone marrow transplantation for lymphoma. (a) US image shows marked thickening of the cecum. (b) CT image shows marked thickening and increased enhancement of the fluid-filled cecum and terminal ileum.
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Pneumatosis Intestinalis
A finding of pneumatosis intestinalis in association with neutropenic colitis is very worrisome because it implies imminent bowel perforation. However, pneumatosis also may be seen in patients who are relatively well clinically after bone marrow transplantation. The complication appears to be related to the use of high doses of corticosteroids. It has been postulated that consequent hypertrophy of Peyer patches produces mucosal defects through which intraluminal gas may track (22,23). In these so-called benign cases, the radiographic findings usually resolve after a period of conservative management (4). Two distinct features of pneumatosis intestinalis, "bubbly" and "linear" intramural lucencies, have been described. The former represent submucosal gas, and the latter, subserosal gas (Fig 9). The tracking of gas into the mesentery, portal venous gas, and pneumoperitoneum are potential sequelae of benign pneumatosis. Unless these findings are accompanied by signs of a more serious condition, they do not warrant surgical intervention (23).
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Figure 9. Pneumatosis coli in a 6-year-old girl 6 months after bone marrow transplantation for severe combined immunodeficiency. CT image shows marked pneumatosis in the colon (black arrows) and adjacent mesentery (white arrows). There was no evidence of concurrent typhlitis.
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Hepatosplenic Complications
Three major hepatic complications are seen after bone marrow transplantation: hepatic veno-occlusive disease, acute GVH disease, and other types of hepatocellular injury presumed to be medication related (24). Hepatic veno-occlusive disease is a potentially disastrous complication that usually occurs within 2 weeks of bone marrow transplantation and produces clinical symptoms of painful hepatomegaly, jaundice, and fluid retention. Histopathologically, this condition reflects concentric narrowing of the terminal hepatic venules and necrosis of the adjacent hepatocytes. Etiologically, this condition appears to be related to the pretransplantation preparatory regimen, although preexisting hepatic dysfunction and infection also are implicated (25). Although veno-occlusive disease is potentially reversible, it may be fatal in one-third of cases (16). Hepatofugal flow on Doppler US images, an increased hepatic arterial resistive index, hepatosplenomegaly, periportal areas of low attenuation, small-caliber hepatic veins, gallbladder wall thickening, and ascites have been associated with this diagnosis (4) (Fig 10). However, a recent study found that neither gray-scale nor Doppler US findings are reliable for the prediction or diagnosis of veno-occlusive disease in pediatric bone marrow transplant recipients; the authors suggested that clinical assessment remains the best means of diagnosing this condition (26).
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Figure 10a. Hepatic veno-occlusive disease in a 21-month-old boy 3 weeks after bone marrow transplantation for thalassemia. (a) Gray-scale US image shows hepatomegaly. (b) Color Doppler US image shows reversal of the main portal venous flow. At subsequent biopsy, veno-occlusive disease was found.
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Figure 10b. Hepatic veno-occlusive disease in a 21-month-old boy 3 weeks after bone marrow transplantation for thalassemia. (a) Gray-scale US image shows hepatomegaly. (b) Color Doppler US image shows reversal of the main portal venous flow. At subsequent biopsy, veno-occlusive disease was found.
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In the posttransplantation setting, the liver is also vulnerable to the formation of bacterial or fungal infective abscesses (16). Generally, these appear as hypoechoic foci on US images. Fungal lesions, in particular, tend to be small, commonly only 1–3 mm in diameter, and are often better appreciated with the use of a high-frequency linear-array transducer (Fig 11a). It has been suggested that contrast-enhanced CT is superior to US for fungal lesion detection, and the results of recent studies suggest that the phase of contrast enhancement during which image acquisition occurs is critical with regard to lesion conspicuity. In one series, one-third of 536 hepatic fungal lesions in adults would have been missed with the sole use of portal venous phase imaging, compared with the use of both arterial phase and portal venous phase acquisitions. In this series, the most common lesional appearance on arterial phase images consisted of either a uniformly hyperattenuating focus (Fig 11b) or a hypoattenuating center with a hyperattenuating rim (27).
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Figure 11a. Visceral fungal infection. (a) High-resolution US image obtained with a linear-array transducer shows a hypoechoic splenic nodule in an 8-year-old girl 6 weeks after bone marrow transplantation for acute lymphoid leukemia. (b) Contrast material–enhanced CT image shows multiple lesions in the kidneys, liver, and spleen in a 7-year-old boy 5 days after bone marrow transplantation for acute lymphoid leukemia. All the lesions were believed to have been caused by the same fungus.
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Figure 11b. Visceral fungal infection. (a) High-resolution US image obtained with a linear-array transducer shows a hypoechoic splenic nodule in an 8-year-old girl 6 weeks after bone marrow transplantation for acute lymphoid leukemia. (b) Contrast material–enhanced CT image shows multiple lesions in the kidneys, liver, and spleen in a 7-year-old boy 5 days after bone marrow transplantation for acute lymphoid leukemia. All the lesions were believed to have been caused by the same fungus.
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Focal liver lesions also may be manifestations of posttransplantation lymphoproliferative disorder. Regenerative hepatic nodules have been described as typically occurring some time following treatment for malignancy (Fig 12). With regard to their imaging characteristics, they may mimic metastatic disease. The lesions usually have a lobulated contour and often a hypervascular center on US, CT, and MR images. Typically showing hypervascularity during the arterial phase of dynamic CT and MR imaging, the lesions usually appear isoattenuated or isointense during the delayed phase. Their development may be related to hepatotoxic effects of pretransplantation chemotherapy (28), and an association with veno-occlusive disease has been described (29).
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Figure 12a. Regenerative hepatic nodules in a 10-year-old boy 8 years after bone marrow transplantation for neuroblastoma. (a) CT image shows multiple enhancing hepatic nodules that had grown slowly over several years. (b) T1-weighted MR image shows the nodules as round areas of signal hypointensity compared with the signal intensity of the normal hepatic parenchyma. (c) Contrast-enhanced arterial phase MR image shows avid enhancement of the nodules in comparison with the normal hepatic parenchyma.
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Figure 12b. Regenerative hepatic nodules in a 10-year-old boy 8 years after bone marrow transplantation for neuroblastoma. (a) CT image shows multiple enhancing hepatic nodules that had grown slowly over several years. (b) T1-weighted MR image shows the nodules as round areas of signal hypointensity compared with the signal intensity of the normal hepatic parenchyma. (c) Contrast-enhanced arterial phase MR image shows avid enhancement of the nodules in comparison with the normal hepatic parenchyma.
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Figure 12c. Regenerative hepatic nodules in a 10-year-old boy 8 years after bone marrow transplantation for neuroblastoma. (a) CT image shows multiple enhancing hepatic nodules that had grown slowly over several years. (b) T1-weighted MR image shows the nodules as round areas of signal hypointensity compared with the signal intensity of the normal hepatic parenchyma. (c) Contrast-enhanced arterial phase MR image shows avid enhancement of the nodules in comparison with the normal hepatic parenchyma.
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The etiology of regenerative hepatic nodules and focal nodular hyperplasia may be similar, although they are two different entities. The latter disease is rare in children, but there is evidence that it may arise as a consequence of tissue reperfusion following an episode of local hepatic arterial or portal venous thrombosis secondary to chemotherapy or radiation therapy (30,31). Indeed, chemotherapeutic agents used specifically to prepare patients for bone marrow transplantation appear to have a particular association both with veno-occlusive disease and with the subsequent development of focal nodular hyperplasia, lending further weight to the hypothesis that vascular insult is an underlying cause of the latter (32). At US, focal nodular hyperplasia appears as an iso-or hypoechoic mass, and, at unenhanced CT, as an iso- or hypoattenuating mass, compared with the normal liver parenchyma. After the administration of contrast material, both CT and MR images show homogeneous arterial phase enhancement of focal nodular hyperplasia, which has attenuation or signal intensity similar to that of the normal liver during the portal venous phase and the delayed phase. The most characteristic finding, that of a central scar that exhibits delayed enhancement, may be seen in up to 50% of cases (32).
Increased hepatic, splenic, and bone marrow iron deposition exhibited as relative hypointensity on T1- and T2-weighted MR images, with an associated increase in the serum level of ferritin, was observed in a series of patients undergoing bone marrow transplantation (33) (Fig 13). The MR findings were thought to be related to multiple blood transfusions that were required over a relatively short period of time before and during engraftment. Interestingly, in this series, iron overload was not always manifested in the characteristic appearance of posttransfusional hemochromatosis; MR images from as many as 40% of patients showed normal splenic signal intensity.
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Figure 13. Hepatic iron deposition in a 5-year-old boy 4 months after bone marrow transplantation for acute lymphoblastic leukemia. T2-weighted fat-saturated MR image shows marked signal hypointensity in the liver in comparison with the muscles and spleen. Ascites also is visible.
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Splenomegaly is a very common finding after bone marrow transplantation and may reflect the underlying condition that required treatment with bone marrow transplantation, as well as infection, infarction, or posttransplantation lymphoproliferative disorder (16).
Renal and Urinary Tract Complications
Fungal and bacterial renal abscesses are relatively common complications after bone marrow transplantation. In addition, hemolytic uremic syndrome (34), papillary necrosis, renal vein thrombosis, nephrolithiasis, and spontaneous subcapsular hematoma have been reported as rarer complications (16). Hemorrhagic cystitis may be seen, secondary to the use of cyclophosphamide: CT and US images show focal or diffuse bladder wall thickening, and intraluminal hematoma also may be present (4) (Fig 14).
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Figure 14. Hemorrhagic cystitis in a 7-year-old girl 1 month after bone marrow transplantation for acute lymphoblastic leukemia. CT image shows marked wall thickening and increased mucosal enhancement of the bladder after treatment with cyclophosphamide.
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Posttransplantation Lymphoproliferative Disorder
When an Epstein-Barr viral infection occurs in an immunodeficient host, uncontrolled proliferation of B lymphocytes may result in a spectrum of abnormalities, including mononucleosis sepsis, polyclonal B cell hyperplasia, and monoclonal B cell malignancies. These abnormalities may occur in primary or secondary immunodeficiency, regardless of the cause. In the setting of organ transplantation, however, this process is termed posttransplantation lymphoproliferative disorder and usually occurs within a year of transplantation (4). In its most severe form, it is manifested clinically as lymphoma. The imaging appearances comprise lymphadenopathy, focal parenchymal masses and nodules, and diffuse organ infiltration without a focal mass (Fig 15). The disease has been described as involving virtually all organ systems. Unfortunately, unlike the prognosis for solid organ transplant recipients, that for bone marrow transplant recipients is exceedingly poor because the therapeutic option of decreasing the degree of immunosuppression is not feasible in such patients (35).
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Figure 15. Adenoidal posttransplantation lympho-proliferative disorder in a 12-year-old boy 8 years after bone marrow transplantation for acute lymphoblastic leukemia. CT image shows enlargement of the right-sided adenoidal tissue (arrows), which at biopsy was proved to be due to posttransplantation lymphoprolif-erative disorder. Opacification of the left maxillary sinus also is evident.
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Musculoskeletal and Other Complications
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Bone infarction and avascular necrosis, which may be related to total body irradiation in preparation for transplantation as well as to either GVH disease or the steroids used to treat GVH disease, present further potential complications for bone marrow transplant recipients. In one series, avascular necrosis of the femoral head occurred in 20% of patients (36). The MR imaging appearances are identical to those for patients without a history of bone marrow transplantation and include heterogeneous signal intensity changes, with or without collapse of the articular surface (37,38) (Figs 16–18).
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Figure 16. Bone infarcts in a 13-year-old girl 1 year after bone marrow transplantation for lymphoma. Coronal T1-weighted MR image shows multiple geographic areas of abnormal signal intensity in the metaphyses and diaphyses of both femora and tibiae.
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Figure 17. Avascular necrosis of the knee in a 15-year-old boy 4 months after bone marrow transplantation for acute myeloid leukemia. Coronal short inversion time inversion recovery MR image shows geographic areas of avascular necrosis in the epiphyses at both knee joints.
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Figure 18. Talar avascular necrosis in a 7-year-old boy 10 months after bone marrow transplantation for Fanconi anemia. Coronal short inversion time inversion recovery MR image shows signal hyperintensity in the medial aspect of the talar dome, a finding that represents edema.
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Chronic atrophy of the subcutaneous tissues, as well as renal parenchymal loss, may be evident in patients who have undergone local radiation therapy as the initial treatment for a malignancy, before bone marrow transplantation (Fig 19).
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Figure 19. Renal atrophy in a 10-year-old boy 8 years after bone marrow transplantation for neuroblastoma. CT image shows atrophy of the left kidney and of the subcutaneous fat and musculature in the left side of the abdomen, conditions secondary to radiation therapy.
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Finally, the possibility of recurrence of the original malignancy due to persistent foci of malignant cells despite intensive preparatory chemo-and radiation therapy also must be considered. Recurrent malignancies usually are manifested within 2 years after transplantation. Imaging appearances may either mimic the original disease manifestations or may reflect distant recurrence (Fig 20).
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Figure 20a. Tumor recurrence in a 5-year-old girl after bone marrow transplantation for neuroblastoma. (a) CT image obtained 21 months after transplantation shows a recurrent left paravertebral soft-tissue mass (arrows). (b) CT image obtained 4 months earlier shows no evidence of the mass.
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Figure 20b. Tumor recurrence in a 5-year-old girl after bone marrow transplantation for neuroblastoma. (a) CT image obtained 21 months after transplantation shows a recurrent left paravertebral soft-tissue mass (arrows). (b) CT image obtained 4 months earlier shows no evidence of the mass.
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Central Nervous System Complications
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Central nervous system complications are common after bone marrow transplantation, and 70% of patients are affected. These complications include infection, infarction, hemorrhage, therapy-induced toxic effects, and recurrent malignancy (39). It is noteworthy that acute GVH disease has not been confirmed to affect the central nervous system directly, possibly because of the lack of lymphatics within the brain (39,40). However, patients with systemic GVH disease have an elevated risk of central nervous system complications due to the consequent delay in the reconstitution of their immunologic function as well as to the immunosuppressive treatment required for treatment of systemic GVH disease (41). Severe GVH disease affecting the bowel has been described as a cause of metabolic encephalopathy after bone marrow transplantation (39).
Infection
Infection is the most common complication of bone marrow transplantation, although the frequency of its occurrence may be decreasing (42,43). Like that seen in other organ systems after transplantation, the immune impairment seen at various stages after bone marrow transplantation dictates the types of infections that may occur. In the pre-engraftment period (the first 15–30 days after transplantation), neutropenia in combination with damaged mucosal defenses places the patient at a high risk of sepsis due to Gram-negative bacterial infection as well as various fungal and viral infections. During the early postengraftment period (the first 100 days after engraftment), cellular immunity is profoundly depressed because of GVH disease and immunosuppressive therapy; CMV, fungal, and Gram-positive bacterial infections predominate at this time. During the late postengraftment period (the months and years after transplantation), there is a slow recovery of both humoral and cellular immunity; infections due to encapsulated bacteria and herpes zoster virus are most commonly seen at this time.
Aspergillus is the most common cause of focal infective cerebral lesions after bone marrow transplantation. Such lesions typically appear on CT images as multiple low-attenuation foci with minimal mass effect and negligible contrast enhancement. Lack of perifocal edema, as is also the case with other types of infective cerebral lesions, may reflect the maintenance of an intact blood-brain barrier in the absence of an inflammatory response. T2-weighted MR images depict foci of intermediate signal intensity with a peripheral ring of hyperintensity (42). Pathologically, these lesions consist of infarcts caused by the occlusion of intracerebral vessels by fungal hyphae; the presence of ringlike enhancement is suggestive of a less invasive form of the disease and implies that a host immune response has occurred (44). Mucor infection is associated with an even more aggressive large-vessel occlusive pattern as a consequence of vascular invasion. Bacterial abscesses and meningitis are relatively rare because of routine antimicrobial prophylaxis. Toxoplasmosis also is rare; when it does occur, enhancing basal ganglia lesions often are seen.
Documented viral infections of the central nervous system appear to be rare, although herpes simplex mucositis, systemic CMV infection, and cutaneous varicella zoster infections are relatively common in bone marrow transplant recipients. Herpes encephalitis may cause selective changes in the signal intensity of the temporal lobe on MR images, as well as white matter demyelination (45). Epstein-Barr virus is known to cause focal infarcts with rimlike enhancement (Fig 21).
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Figure 21a. Cerebral Epstein-Barr viral infection in an 11-year-old boy 4 months after bone marrow transplantation for acute lymphoblastic leukemia. (a) Fluid-attenuated inversion recovery MR image shows a lesion in the deep gray matter on the left side. (b) Gadolinium-enhanced MR image shows rimlike enhancement of the lesion in a, as well as a second lesion with similar features in the right temporal lobe. The signal hyperintensity in the periventricular white matter is likely treatment related.
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Figure 21b. Cerebral Epstein-Barr viral infection in an 11-year-old boy 4 months after bone marrow transplantation for acute lymphoblastic leukemia. (a) Fluid-attenuated inversion recovery MR image shows a lesion in the deep gray matter on the left side. (b) Gadolinium-enhanced MR image shows rimlike enhancement of the lesion in a, as well as a second lesion with similar features in the right temporal lobe. The signal hyperintensity in the periventricular white matter is likely treatment related.
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Cerebrovascular Complications
Intraparenchymal and intraocular hemorrhage may occur (Figs 22, 23), but the most common reported cerebrovascular complications are subdural hematoma (Fig 24), which may reflect thrombocytopenia, and cerebral infarction (Fig 25), which is most commonly attributable to either nonbacterial or infective endocarditis (39,41,43). The cumulative deleterious effects of the pretransplantation regimen also may play a causal role in infarction (39). These complications seen in patients after bone marrow transplantation have the same imaging appearances as those seen in the general population.
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Figure 22. Cerebral hemorrhage in an 8-year-old boy 6 weeks after bone marrow transplantation for acute myeloid leukemia. CT image shows an acute hemorrhage in the left frontal lobe.
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Figure 23. Intraocular hemorrhage in a 7-year-old boy 2 months after bone marrow transplantation for aplastic anemia. Unenhanced CT image shows the hemorrhage as an area of increased attenuation in the posterior aspect of the left globe.
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Figure 24. Subdural hemorrhage in a 21-month-old boy 1 month after bone marrow transplantation for thalassemia. T1-weighted MR image shows an extensive bilateral subacute subdural hemorrhage.
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Figure 25. Cerebral infarcts in an 8-year-old boy 4 weeks after bone marrow transplantation for acute myeloid leukemia. CT image shows extensive bilateral parenchymal infarcts secondary to mucormycosis-induced endocarditis.
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Therapy-induced Complications
Therapy-induced complications comprise those related to the pretransplantation regimen as well as to GVH disease prophylaxis. Radiation therapy may produce white matter lesions or even multiple foci of necrosis in the brainstem (40). Radiation-induced telangiectases (cavernomas) and lacunae are well documented in the pediatric population (44) (Fig 26).
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Figure 26a. Radiation-induced cerebral telangiectasia (cavernoma) in a 12-year-old boy 8 years after bone marrow transplantation for acute lymphoblastic leukemia. (a) Contrast-enhanced CT image shows a bilobed lesion with rimlike enhancement in the left temporal lobe. (b) Fluid-attenuated inversion recovery MR image shows signal hypointensity in the hemo-siderin-stained rim of the lesion.
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Figure 26b. Radiation-induced cerebral telangiectasia (cavernoma) in a 12-year-old boy 8 years after bone marrow transplantation for acute lymphoblastic leukemia. (a) Contrast-enhanced CT image shows a bilobed lesion with rimlike enhancement in the left temporal lobe. (b) Fluid-attenuated inversion recovery MR image shows signal hypointensity in the hemo-siderin-stained rim of the lesion.
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Cyclosporine is used, often in combination with methotrexate, as prophylaxis for systemic GVH disease. However, such treatment carries a risk of potentially reversible neurotoxic effects that are collectively termed posterior reversible encephalopathy syndrome. This complication typically occurs within 1 month of the initiation of prophylactic treatment and is manifested by severe visual disturbance, cerebellar ataxia, confusion, and seizures (41,46,47). CT and MR imaging may reveal characteristic focal wedge-shaped abnormalities that show enhancement in gray matter or white matter in the frontal, the posterior temporal, the parietal, and particularly the occipital lobes (Fig 27). Lesions in the basal ganglia also have been reported (46). After reduction in the serum cyclosporine level, these abnormalities tend to show almost complete resolution (4,47).
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Figure 27. Posterior reversible encephalopathy syndrome in a 5-year-old boy 9 months after bone marrow transplantation for neuroblastoma. Fluid-attenuated inversion recovery MR image shows a characteristic posterior wedge-shaped cortical and subcortical area of abnormal signal hyperintensity.
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Venous sinus thrombosis with a typical appearance at MR venography and without any apparent relationship to the usual risk factors is reported to have occurred after bone marrow transplantation for hematologic malignancy in two teenagers. The authors speculated that the condition was induced by cyclosporine therapy in both cases (48).
Generalized cerebral atrophy frequently is observed in patients with malignant disease and may reflect malnutrition or the administration of steroids, intrathecal chemotherapy, or irradiation (41,49). Last, radiation-induced secondary cerebral malignancies such as glioblastoma multiforme are well documented (Fig 28).
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Figure 28a. Radiation-induced cerebral malignancy in an 18-year-old boy 10 years after bone marrow transplantation for acute lymphoblastic leukemia. (a) Contrast-enhanced T1-weighted MR image shows a lesion with rimlike enhancement in the left frontal lobe. (b) T2-weighted MR image shows the lesion with a marked mass effect, loss of gray matter–white matter differentiation, and edema. Glioblastoma multiforme was diagnosed at biopsy.
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Figure 28b. Radiation-induced cerebral malignancy in an 18-year-old boy 10 years after bone marrow transplantation for acute lymphoblastic leukemia. (a) Contrast-enhanced T1-weighted MR image shows a lesion with rimlike enhancement in the left frontal lobe. (b) T2-weighted MR image shows the lesion with a marked mass effect, loss of gray matter–white matter differentiation, and edema. Glioblastoma multiforme was diagnosed at biopsy.
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Recurrence of Malignancy
Patients who have undergone a bone marrow transplantation for the treatment of primary brain tumors, neuroblastoma, and leukemia appear to have an increased risk for recurrent malignancy (4,40). There is some evidence that patients with pretransplantation leukemic central nervous system involvement may have a particularly elevated risk (43). Abnormal foci of contrast enhancement are typically seen at CT and MR imaging (4).
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Paranasal Sinus Complications
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More than one-third of patients develop paranasal sinusitis within 2 years after bone marrow transplantation, and this type of infection is thought to be an underrecognized source of fever in the post–bone marrow transplantation population (4,50,51). A fungal origin, usually an Aspergillus species, was identified in slightly fewer than one-fourth of the patients in one study (4,51); other organisms that cause sinus infection include Streptococcus pneumoniae and Haemophilus influenzae. Allogenic bone marrow transplant recipients are more likely to be affected than are autologous graft recipients, possibly because of the more intensive pretransplantation regimen (including total body irradiation), the occurrence of GVH disease, and the immunosuppressive therapy to which the former group of recipients are subject (51).
CT screening of the sinuses in children has been advocated before bone marrow transplantation because sinus abnormalities are likely to predispose graft recipients to sinusitis (50). The observation of such abnormalities may lead to more aggressive treatment of sinusitis before transplantation, as well as to a higher index of suspicion of sinusitis if unexplained fever occurs in graft recipients after transplantation. Even in children without pretransplantation sinus disease, an initial CT examination may allow a useful comparison with posttransplantation images acquired later because of the suspicion that sinusitis is present.
Radiographic and CT findings of paranasal sinusitis comprise air-fluid levels, which often are observed in association with soft-tissue thickening (Fig 29). Direct coronal CT is more sensitive than other techniques for detecting the subtle changes that may be important in this patient population and is therefore the preferred method.
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Figure 29. Maxillary sinusitis in a 6-year-old boy 10 days after bone marrow transplantation for lymphoma. CT image of the maxillary sinuses shows mucosal thickening in the right sinus and an air-fluid level in the left sinus.
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The term invasive sinusitis implies mucosal, submucosal, bone, or vascular invasion; this condition is usually due to Aspergillus species (52). The initial symptoms of invasive sinusitis—nasal obstruction, rhinorrhea, epistaxis, and fever—are nonspecific, are common in the posttransplantation population, and overlap with the symptoms of bacterial sinusitis. Consequently, the diagnosis may be delayed. Since rapid progression is the norm and the condition is frequently fatal, such a delay may be catastrophic (50,52,53). Mucosal thickening, paranasal sinus opacification, and facial soft-tissue swelling are common in both invasive sinusitis and bacterial sinusitis. Although CT findings of periantral soft-tissue invasion, bone erosion, and orbital invasion are classic signs of invasive sinusitis, these findings are not pathognomonic and are rarely seen (Fig 30). A definitive diagnosis can be made only on the basis of histopathologic evidence of tissue invasion by fungal hyphae. Information in a recent review article suggests that marked unilateral thickening of the paranasal sinus mucosa is the most common early CT sign of invasive sinusitis (52). Considering the rapid progression and potential fatality of this condition, this observation, if validated, may prove crucial.
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Figure 30a. Invasive fungal sinusitis in a 6-year-old girl 3 months after bone marrow transplantation for aplastic anemia. (a) Axial CT image shows bilateral maxillary sinus opacification, complete on the left, and premalar soft-tissue swelling and infiltration. (b) Axial CT image shows periorbital soft-tissue swelling and a subperiosteal abscess (arrow) with destruction of the orbital plate of the ethmoid bone.
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Figure 30b. Invasive fungal sinusitis in a 6-year-old girl 3 months after bone marrow transplantation for aplastic anemia. (a) Axial CT image shows bilateral maxillary sinus opacification, complete on the left, and premalar soft-tissue swelling and infiltration. (b) Axial CT image shows periorbital soft-tissue swelling and a subperiosteal abscess (arrow) with destruction of the orbital plate of the ethmoid bone.
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Conclusion
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The increasing use of bone marrow transplantation to treat a range of malignant and nonmalignant conditions mandates that radiologists be familiar with the range of potential complications and the associated imaging appearances.
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Footnotes
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Abbreviations: BOOP = bronchiolitis obliterans with organizing pneumonia, CMV = cytomegalovirus, GVH = graft-versus-host
2 Current address: Department of Radiology, British Columbia Children’s Hospital and University of British Columbia, Vancouver, British Columbia, Canada. 
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Abstract
LEARNING OBJECTIVES FOR TEST...
