(Radiology. 2000;217:16-25.)
© RSNA, 2000
Posttransplantation Lymphoproliferative Disorder in Children: Clinical, Histopathologic, and Imaging Features1
Perry J. Pickhardt, MD,
Marilyn J. Siegel, MD,
Robert J. Hayashi, MD and
Michael Kelly, MD
1 From the Mallinckrodt Institute of Radiology, Washington University School of Medicine, 510 S Kingshighway Blvd, St Louis, MO 63110 (P.J.P., M.J.S.); the Department of Radiology/Nuclear Medicine, F. Edward Hébert School of Medicine, Uniformed Services University of the Health Sciences, Bethesda, Md (P.J.P.); and the Department of Pediatrics, Division of Hematology Oncology, Washington University School of Medicine, St Louis, Mo (R.J.H., M.K.). Received July 16, 1999; revision requested August 24; revision received September 14; accepted September 24. Address correspondence to M.J.S.
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ABSTRACT
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Posttransplantation lymphoproliferative disorder (PTLD) is a condition in patients who receive transplants in which chronic immunosuppression leads to an unregulated expansion of lymphoid cells; the condition ranges from hyperplasia to malignant lymphoid proliferation. Risk factors affecting the incidence of PTLD include allograft type, Epstein-Barr virus infection, and immunosuppression. In this article, we review the clinical, histopathologic, and imaging features of PTLD in children. Because PTLD can affect nearly any organ system, a wide variety of clinical manifestations is possible. The heterogeneous nature of the disease is also reflected on imaging studies. The goals of imaging in patients with PTLD are to detect disease, guide biopsy, and direct appropriate follow-up imaging rather than to establish a specific diagnosis. Because the clinical and imaging manifestations of PTLD are nonspecific and are not reliably predictive of histopathologic subtype, tissue biopsy is necessary for final diagnosis.
Index terms: Epstein-Barr virus, **.20692 • Heart, transplantation, 51.45 • Kidney, transplantation, 81.45 • Liver, transplantation, 761.45 • Lung, transplantation, 60.45 • Lymphoma, CT, 99.12911, 99.12912, 99.834 • Lymphoma, in infants and children, 99.834 • Lymphoma, MR, 99.12941, 99.834 • State of the Art • Transplantation, 99.45 • Ultrasound (US), in infants and children, 99.1298, 99.834
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INTRODUCTION
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Solid organ transplantation has become an established treatment for many previously fatal conditions of the liver, kidney, heart, and lung in children (1–6). Success rates for organ transplantation have increased with the advent of new immunosuppressive regimens, advances in surgical technique, and improved postoperative care (7). However, antagonistic posttransplantation complications, such as opportunistic infection, secondary malignancies, posttransplantation lymphoproliferative disorder (PTLD), and allograft rejection, may occur, reflecting the altered immunologic balance in transplant recipients.
PTLD represents a spectrum of unregulated lymphoid expansion that ranges from polyclonal hyperplasia to monoclonal malignant lymphoma (8–14). In most cases, the disorder results from Epstein-Barr virus (EBV)–induced B cell lymphoproliferation that is unopposed by the pharmacologically suppressed T cell system (15–17). The clinical, histopathologic, and imaging features of PTLD differ from those of lymphoma in immunocompetent patients, although they bear some resemblance to the lymphomas that arise in other immunocompromised patients, most notably those with acquired immunodeficiency syndrome, or AIDS, or congenital T cell immunodeficiencies (18–20).
Recognized characteristics of PTLD include a proclivity toward extranodal involvement and a variable response to treatment that ranges from disease regression to a rapidly fatal course (8,12,21,22). The increase in solid organ transplantation among children in recent years has led to a larger population at risk for PTLD.
The purpose of this article is to review the clinical features of PTLD in pediatric allograft recipients, the histopathologic features of this disorder and their effect on treatment and prognosis, and the wide variety of imaging findings. Knowledge of the various appearances of PTLD is important because PTLD is an increasing problem in children, and prompt and appropriate treatment affects outcome.
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CLINICAL FEATURES
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Incidence and Risk Factors
PTLD can occur in any transplantation setting. Most estimates of the frequency of PTLD are around 2% (8,9). During the past decade, the incidence at our institution for both children and adults was 2%–3% of more than 2,300 solid organ transplantations. Data for a pediatric population are more limited, but the frequency of PTLD is consistently higher than it is in adults (14,23–25). In our experience with more than 450 pediatric allograft recipients younger than 15 years, the incidence of PTLD is approximately 8% (36 children).
There are at least three major risk factors for the development of PTLD: allograft type, EBV infection or reactivation, and immunosuppressive regimens (8,9). Several centers have demonstrated that the incidence of PTLD varies with the type of graft (23–30). In general, renal transplant recipients have consistently lower risks, while liver, lung, and heart recipients have substantially higher incidences. The reported incidence of PTLD is 4%–15% in pediatric liver recipients; 7.7%–19.5% in pediatric lung, heart, and heart-lung recipients; and 1%–8% in pediatric kidney recipients (23–30). In our experience with pediatric allograft recipients, the incidence of PTLD is 14% for liver, 8% for lung, 7% for heart, and 6% for renal transplants. Reyes et al (31) reported a 19% incidence of PTLD in a small series of children who underwent intestinal transplantation.
The suspicion that EBV plays an important role in the development of PTLD stems from observations that primary EBV infection in patients who receive solid organ transplants results in profound lymphoid hyperplasia, which appears to be atypical for just simple infection by the virus (14). Findings of several studies have shown that the frequency of PTLD is higher for EBV-seronegative recipients than for EBV-seropositive recipients (14,32–35). Walker et al (34) observed only three cases of PTLD in 367 patients who were EBV seropositive before transplantation versus 11 cases in 22 patients who were EBV seronegative before transplantation. Concomitant cytomegalovirus infection appears to further increase the risk for PTLD in patients who are EBV seronegative at the time of transplantation (34,36).
An increased level of immunosuppression is another predisposing factor for PTLD, possibly because it allows for greater expansion of EBV (8,37). In solid organ transplant recipients, the use of more intensive immunosuppression, particularly in the setting of treating rejection, has often been identified as a risk factor for developing PTLD (24,27,30). In a study of pediatric patients undergoing liver transplantation, Newell et al (27) reported that the use of tacrolimus (FK 506) plus OKT3 to treat rejection resulted in a 28% incidence of PTLD versus a 6% incidence in those who did not receive such therapy. An increased total lifetime exposure to immunosuppression also increases the risk for PTLD. Patients who receive a renal transplant require less immunosuppression than do other allograft recipients, which may account for their lower incidence of PTLD (13).
Clinical Manifestation
PTLD usually occurs within the 1st year after transplantation (8,9,12). The time from organ transplantation to diagnosis of PTLD has ranged from 6 weeks to 7 years in our pediatric population, with approximately 60% of cases occurring within the 1st year after transplantation. The mean time to diagnosis is 22 months.
PTLD can affect nearly any organ system, and the disease may be focal or diffuse. In our experience with children, the overall distribution of PTLD in descending frequency is abdominal (64%), thoracic (50%), head and neck (25%), and brain (6%) PTLD. Bone marrow and cutaneous diseases are sporadic. Involvement of the allograft by PTLD is not uncommon, with the frequency varying with the graft. In a combined group of pediatric and adult transplant recipients, Cohen (32) reported allograft involvement in 80% of lung transplants, 33% of liver transplants, 32% of kidney transplants, and 0% of heart transplants. Cardiac involvement by PTLD is rare regardless of transplant type. In our experience with 36 children, allograft involvement occurred in 47% of cases, including 79% of lung transplants, 57% of liver transplants, 33% of kidney transplants, and 0% of heart transplants. Distinguishing allograft involvement by PTLD from rejection or infection is critical with regard to treatment but can be difficult on clinical grounds alone.
The clinical manifestations of PTLD are protean. Affected patients can present with nonspecific constitutional symptoms of fever and malaise, an infectious mononucleosis-like syndrome, palpable lymphadenopathy, or symptoms referable to solid or hollow organ involvement with consequent dysfunction (9,16). PTLD can also be an incidental finding on routine surveillance imaging studies or at autopsy (8,25).
In our experience, most children with abdominal PTLD present with abdominal pain (52%) and occasionally with hepatomegaly, splenomegaly, or other palpable abdominal masses (24%). Involvement of the gastrointestinal tract is seen in approximately 30% of children and may result in gastrointestinal bleeding, anemia, intussusception, diarrhea, protein-losing enteropathy, or weight loss (28,38–40). Patients with small-bowel involvement by PTLD are at increased risk of perforation and intussusception (40). On occasion, at presentation children have a fulminant course characterized by sepsis and multiorgan failure from disseminated abdominal and thoracic involvement by PTLD (9).
Compared with abdominal PTLD, pulmonary involvement is usually asymptomatic, and patients often present with only fever, or the diagnosis is suspected first from radiographic findings (25). Suspicion should be raised when pulmonary infiltrates fail to respond to antibiotic therapy. At presentation, some children, particularly lung transplant recipients, have respiratory compromise or new abnormalities during pulmonary function testing.
Head and neck involvement often manifests as a mononucleosis-like syndrome characterized by constitutional symptoms, pharyngitis, tonsillar enlargement, and cervical lymphadenopathy (41,42). The clinical similarity with infectious mononucleosis is not coincidental, since both result from primary EBV infection. Central nervous system involvement by PTLD may manifest as seizures, lethargy, or focal neurologic deficits (43). Isolated skin involvement is rare but has been reported (44).
The extent of disease can be minimal or modest at first, with progression that can either follow a rapid course or wax and wane over several weeks. Left untreated, this disease invariably progresses, which results in widespread dissemination. Mortality due to progressive disease is universal and can account for up to 15% of all transplantation-related deaths (26). Thus, a high index of suspicion for the diagnosis of PTLD is essential for therapy to be instituted as quickly as possible.
Diagnosis
Physical examination and imaging studies are important components in the clinical diagnosis of PTLD. Enlarged lymph nodes at examination, especially in the cervical region, palpable abdominal masses, and organomegaly should raise a suspicion for PTLD. A presumptive diagnosis of PTLD can be made on the basis of EBV seroconversion, compatible symptoms, and characteristic imaging findings (29). Definitive diagnosis of PTLD requires tissue biopsy. The most appropriate site for biopsy is determined from integration of all clinical and imaging data. Excisional or core biopsy is generally preferred, but some centers have had success with cytologic diagnosis after fine-needle aspiration biopsy (45–47).
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HISTOPATHOLOGIC FEATURES
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A tendency among organ transplant recipients to develop lymphoma or lymphoma-like tumors has been noted since the early years of transplantation (48,49). However, it later became apparent that the histopathologic features of these lesions were distinct from those of typical lymphoid malignancies and ranged from hyperplastic to neoplastic. Approximately 85% of PTLD cases are of B cell origin and contain EBV (15–17). The remaining cases include T cell lymphomas, Hodgkin disease, and myeloma (8,15,16,50). These tumors may be EBV negative. For example, only 40% of cases of PTLD of T cell origin contain EBV (51).
Several classification schemes have been developed to categorize the histopathologic findings of PTLD (8,10,52,53). Recently, the American Society of Hematopathology incorporated many of the features of several classification schemes to develop a consensus system to categorize the disease. This classification delineates three general categories for lymphoproliferation in the posttransplantation setting (Table) (50).
Early hyperplastic lesions include plasma cell hyperplasia and infectious mononucleosis. The underlying nodal architecture is maintained, although proliferation may extend beyond nodal confines in the latter.
Polymorphic PTLD refers to a heterogeneous population of lymphoid cells that destroy the underlying nodal architecture and locally invade the involved organs. In some instances, polymorphic PTLD has an appearance that is indistinguishable from that seen in infectious mononucleosis; in other instances, it has an appearance somewhere between that of benign lymphoid hyperplasia and that of primary lymphoma. Polymorphic lesions are further subdivided on a nonmorphologic basis into polyclonal and monoclonal types.
Monomorphic PTLD, originally referred to as immunoblastic sarcoma, is indistinguishable from primary lymphoma and can be further subdivided according to histopathologic features by using standard lymphoma nomenclature. The most commonly reported tumors are large cell lymphoma and diffuse undifferentiated non-Hodgkin lymphoma. T cell lymphoma, Hodgkin disease, and multiple myeloma also can be encountered, although these conditions are not as common (50). In our pediatric population, the most common histopathologic subtype was large cell lymphoma (31%); less common histopathologic subtypes included small non–cleaved cell lymphoma and Hodgkin disease.
The importance of the histopathologic subtypes lies in their response to reduced immunosuppression (17,23,53–55). Patients with polymorphic features are more likely to respond to immunosuppressive reduction than are patients with monomorphic features. Thus, the histopathologic features of the disease can aid in identifying a high-risk population who may require more aggressive therapy for disease control. The ratio of polymorphic to monomorphic lesions varies from institution to institution (9,56). In our pediatric patients, polymorphic and monomorphic disease are equally represented, with 18 cases each.
The unique features of PTLD, including its diverse and unusual histopathologic appearance and potential to progress in a malignant fashion, have enticed some investigators to examine the molecular defects that underlie the various forms of the disease. This was based on the presumption that clonal lesions were more likely to be malignant in their clinical behavior than nonclonal lesions. Simple approaches involved the use of immunohistochemistry and genotyping. In an analysis of 34 patients with PTLD, Nalesnik et al (10) found that all monomorphic lesions were clonal in nature, while only 45% of polymorphic disease was clonal. However, a significant correlation between the presence of a clonal cell population and malignant behavior could not be demonstrated.
More recently, studies have been performed to determine the specific mutations in genes that have been observed in primary lymphoid malignancies. A variety of mutations in oncogenes and punitive tumor suppressor genes have been identified in selected patients with PTLD (53,55–58).
Knowles et al (53) analyzed 28 PTLD specimens for correlation of morphology, clonality, and the presence of mutations in BCL1, BCL2, c-myc, H-ras, K-ras, and N-ras. This analysis demonstrated that patients with polymorphic disease, regardless of clonality, uniformly lacked genetic alterations of the oncogenes or tumor suppressor genes. Aggressive clinical behavior of the PTLD was present in only 21% of patients with polymorphic disease.
By comparison, the most aggressive disease was found in patients whose lesions were monomorphic, had a clonal population, and showed mutations in various oncogenes or tumor suppressor genes. Patients in this category had a 67% mortality rate. Thus, it appears that some forms of PTLD have acquired molecular alterations in genetic material that result in the transformation of the growing cell population. This may provide a means of identifying a subpopulation of patients who will fail to achieve disease control with conservative measures.
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TREATMENT AND OUTCOME
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The strategies for treating PTLD fall into four categories: reduction in immunosuppression, control of EBV replication, immunotherapy, and conventional antineoplastic therapy. Immunosuppressive drug reduction remains the primary clinical intervention for PTLD (23,59). Disease regression in response to a reduction in immunosuppression is a unique feature of PTLD and distinguishes this condition from other malignant diseases, such as primary lymphoma. This treatment approach, however, involves an acceptance of an increased risk of allograft rejection, for which patients should be monitored (60). Regression rates for PTLD after immunosuppression reduction have ranged from 23% to 65% when all subtypes are considered (10,11,21–23). When immunosuppression was reduced in our patient population, 16 of 18 children (89%) with polymorphic disease and only five of 18 children (28%) with monomorphic disease showed regression (P < .001).
The suspicion that EBV contributes to disease development and progression has provided the basis for the use of antiviral agents to treat PTLD. Acyclovir and ganciclovir have both been used to block the replication of EBV (33,61,62). Of note, antiviral therapy suppresses replication of EBV in its linear form but not in its latent form. Most patients with PTLD, however, have latent rather than linear EBV; therefore, in this group, treatment is likely to be ineffective. Other treatment strategies designed to control viral replication include the use of cytokines, particularly interferon alfa and cytomegalovirus hyperimmune globulin, and the infusion of donor leukocytes (21,62–64). As of the time this article was written, results are inconsistent, and further experience will be necessary to determine the role of this strategy in the management of PTLD.
Because chronic immunosuppression appears to be central to the development of PTLD, some efforts have been made to use immunotherapy to treat PTLD. Such therapies have included cytotoxic lymphocytes and anti–B cell monoclonal antibodies (65,66). The effects of these reagents on long-term survival are not yet known.
More aggressive treatment measures, for example, surgical resection and chemotherapy, have been used in the management of progressive PTLD and PTLD that fails to respond to conservative therapies (17,22,54,60,65–67). Surgical resection has been shown to be useful in isolated instances in the control of limited disease (10). Findings of more recent studies have demonstrated that regimens designed for lymphoma can be given to treat PTLD with acceptable levels of toxicity (60,67). Swinnen et al (60) reported on their experience with eight cardiac transplant recipients who were treated with chemotherapy after developing progressive disease despite immunosuppression reduction. Six of the eight patients achieved complete remission, and all maintained their remission with a median of 38 months of follow-up.
Patient prognosis is best when PTLD is associated with polymorphic histopathologic subtype, polyclonality, confinement to lymph nodes or a single organ system, and response to decreased immunosuppression. A worse prognosis is associated with disseminated disease, central nervous system involvement, monomorphic or monoclonal lesions, and concurrent opportunistic infections (9–11).
Patients with monomorphic monoclonal PTLD have a higher mortality rate. In several series, mortality rates greater than 90% have been reported in adults with monomorphic disease (56,68,69). Of the 18 children with monomorphic disease at our institution, four died, nine had progressive disease, and five showed regression. Two of the 18 children with polymorphic disease died.
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IMAGING FEATURES
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Goals of Imaging
The role of imaging in the evaluation of transplant recipients is the detection of disease, including PTLD, infection, and bronchiolitis obliterans; assessment of the extent of an abnormality; follow-up assessment of response of disease to treatment; and guidance of biopsy. Recognition of clinically unsuspected disease of any nature is important, as early diagnosis may improve the response to therapy, especially in patients with PTLD (10,11,70). Distinguishing PTLD from other processes, such as infection, can be difficult, and the histopathologic form of PTLD (ie, polymorphic vs monomorphic) cannot be reliably ascertained from its imaging appearance (25,38,39,43). Therefore, tissue sampling is generally for definitive diagnosis.
Our strategies for following up transplant recipients are similar for both lung and intraabdominal solid organ allografts. Our standard protocol for surveillance of asymptomatic pediatric allograft recipients requires acquisition of chest radiographs and computed tomographic (CT) scans at 3, 6, and 12 months after transplantation and yearly thereafter. Additional imaging is performed any time patients are symptomatic. In symptomatic patients with measurable (ie, obvious) disease, tissue sampling of one of the lesions is performed. In asymptomatic patients and/or symptomatic patients with tiny lesions that are too small to characterize with CT, closer-interval scanning, usually at 4-week intervals, is performed. If disease persists or increases in volume, tissue sampling is performed to obtain a definitive diagnosis (eg, distinguish between PTLD and infection). Once thoracic or abdominal PTLD has been documented, the abdomen in patients with thoracic PTLD and the chest in patients with abdominal PTLD are examined with CT to stage the extent of disease.
Abdominal Imaging
CT is the preferred imaging examination for the detection of abdominal and pelvic disease. On occasion, abdominal PTLD that involves an allograft is a finding not suspected at sonography performed for other clinical indications or during sonographic guidance of biopsy of the transplant.
The abdomen is the most common anatomic region involved by PTLD. In up to 50% of patients, the abdomen is the only site of involvement (38,39). As many as 30% of patients with extraabdominal PTLD have unsuspected abdominal involvement at CT (39). Extranodal abdominal disease is three to four times more frequent than nodal disease (39). In patients evaluated with CT, abdominal PTLD is more common among heart (100%) and liver (88%) recipients than lung (61%) and kidney (53%) recipients (P < .01) (39).
In a combined series of children and adults with abdominal PTLD, the frequency of liver involvement was 53% (39). Three patterns of hepatic PTLD can be seen at sonography or CT (38,39,71). In the first pattern of hepatic PTLD, that seen most often, hepatic disease appears as discrete hypoechoic or low-attenuation nodular 1–4-cm lesions (Fig 1a) (72). The second pattern consists of infiltrative hepatic lesions that are poorly defined and may result in hepatomegaly and even liver failure (Fig 1b) (38,39). The third pattern of hepatic PTLD is characterized by porta hepatis involvement, often with periportal infiltration or direct extension into the biliary tree (39,71). This third pattern appears to be unique to liver transplant recipients and may result in biliary obstruction (Fig 2). Primary biliary localization of PTLD has been suggested in these patients (73).
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Figure 1a. Hepatic PTLD. (a) Transverse sonogram of a hepatic allograft in a 3-year-old boy presenting with fever and abdominal pain 4 months after liver transplantation shows a focal hypoechoic lesion (arrows). (b) Contrast material-enhanced transverse CT scan obtained in a 12-year-old girl with liver failure at presentation 4 months after lung transplantation shows marked hepatomegaly and diffusely heterogeneous parenchyma. The child died of fulminant PTLD less than 1 week later.
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Figure 1b. Hepatic PTLD. (a) Transverse sonogram of a hepatic allograft in a 3-year-old boy presenting with fever and abdominal pain 4 months after liver transplantation shows a focal hypoechoic lesion (arrows). (b) Contrast material-enhanced transverse CT scan obtained in a 12-year-old girl with liver failure at presentation 4 months after lung transplantation shows marked hepatomegaly and diffusely heterogeneous parenchyma. The child died of fulminant PTLD less than 1 week later.
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Figure 2a. Hepatobiliary PTLD in a 5-year-old girl with a history of polysplenia who as an infant underwent left hepatic lobe transplantation for biliary atresia. The patient had abdominal pain and an elevated serum bilirubin level at presentation. (a) Longitudinal sonogram obtained through the right upper quadrant of the abdomen shows a homogeneous soft-tissue mass (M) that is slightly hypoechoic to the liver (L) allograft. The mass protrudes into a dilated fluid-filled bowel loop (b) that forms part of the choledochojejunostomy. RK = right kidney. (b) Percutaneous left lateral oblique cholangiogram obtained through the jejunal access shows a large lobulated filling defect (arrowheads) outlined with contrast material near the choledochojejunal anastomosis that corresponds to the mass in a. The mass fills the proximal portion of the jejunal loop, compresses the distal portion of the loop (arrow), and causes mild biliary ductal dilatation. (c) Contrast-enhanced transverse CT scan obtained after percutaneous biliary drainage shows the mass (M) within the bile-filled jejunal loop. The mass extended into the liver on more caudal images (not shown). Note the drainage catheter (arrowhead), prominent extrahepatic bile duct (arrow), and multiple spleens (S).
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Figure 2b. Hepatobiliary PTLD in a 5-year-old girl with a history of polysplenia who as an infant underwent left hepatic lobe transplantation for biliary atresia. The patient had abdominal pain and an elevated serum bilirubin level at presentation. (a) Longitudinal sonogram obtained through the right upper quadrant of the abdomen shows a homogeneous soft-tissue mass (M) that is slightly hypoechoic to the liver (L) allograft. The mass protrudes into a dilated fluid-filled bowel loop (b) that forms part of the choledochojejunostomy. RK = right kidney. (b) Percutaneous left lateral oblique cholangiogram obtained through the jejunal access shows a large lobulated filling defect (arrowheads) outlined with contrast material near the choledochojejunal anastomosis that corresponds to the mass in a. The mass fills the proximal portion of the jejunal loop, compresses the distal portion of the loop (arrow), and causes mild biliary ductal dilatation. (c) Contrast-enhanced transverse CT scan obtained after percutaneous biliary drainage shows the mass (M) within the bile-filled jejunal loop. The mass extended into the liver on more caudal images (not shown). Note the drainage catheter (arrowhead), prominent extrahepatic bile duct (arrow), and multiple spleens (S).
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Figure 2c. Hepatobiliary PTLD in a 5-year-old girl with a history of polysplenia who as an infant underwent left hepatic lobe transplantation for biliary atresia. The patient had abdominal pain and an elevated serum bilirubin level at presentation. (a) Longitudinal sonogram obtained through the right upper quadrant of the abdomen shows a homogeneous soft-tissue mass (M) that is slightly hypoechoic to the liver (L) allograft. The mass protrudes into a dilated fluid-filled bowel loop (b) that forms part of the choledochojejunostomy. RK = right kidney. (b) Percutaneous left lateral oblique cholangiogram obtained through the jejunal access shows a large lobulated filling defect (arrowheads) outlined with contrast material near the choledochojejunal anastomosis that corresponds to the mass in a. The mass fills the proximal portion of the jejunal loop, compresses the distal portion of the loop (arrow), and causes mild biliary ductal dilatation. (c) Contrast-enhanced transverse CT scan obtained after percutaneous biliary drainage shows the mass (M) within the bile-filled jejunal loop. The mass extended into the liver on more caudal images (not shown). Note the drainage catheter (arrowhead), prominent extrahepatic bile duct (arrow), and multiple spleens (S).
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Involvement of the gastrointestinal tract is common; it is seen in approximately 30% of all patients with PTLD (28,39). The small bowel is most frequently involved; colonic and gastric disease are less common. At CT, the typical appearance is circumferential wall thickening of a segment of bowel (Fig 3a). Aneurysmal dilatation with luminal excavation, ulceration, or perforation may be an associated finding (Fig 3b). Intussusception is another imaging manifestation of bowel involvement (Fig 4). Skip lesions and polypoid intraluminal masses are less common findings. Bowel obstruction is unusual, despite the often large lymphoid masses.
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Figure 3a. Gastrointestinal PTLD. (a) Contrast-enhanced transverse CT scan obtained in a 14-year-old boy 10 months after renal transplantation shows circumferential wall thickening (arrows) that involves the transverse colon. Colonic thickening was presumed to represent PTLD on the basis of proved concurrent renal and cervical nodal PTLD and the response to subsequent therapy. Note the cyst (arrowhead) in the native kidney. (b) Contrast-enhanced transverse CT scan obtained in a 2-year-old girl with gastrointestinal bleeding 10 months after lung transplantation shows aneurysmal dilatation of a small-bowel loop (arrowheads), with irregular wall thickening. BL = urinary bladder.
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Figure 3b. Gastrointestinal PTLD. (a) Contrast-enhanced transverse CT scan obtained in a 14-year-old boy 10 months after renal transplantation shows circumferential wall thickening (arrows) that involves the transverse colon. Colonic thickening was presumed to represent PTLD on the basis of proved concurrent renal and cervical nodal PTLD and the response to subsequent therapy. Note the cyst (arrowhead) in the native kidney. (b) Contrast-enhanced transverse CT scan obtained in a 2-year-old girl with gastrointestinal bleeding 10 months after lung transplantation shows aneurysmal dilatation of a small-bowel loop (arrowheads), with irregular wall thickening. BL = urinary bladder.
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Figure 4a. Gastrointestinal PTLD with intussusception in a 12-year-old girl who presented with abdominal pain and bloody stools 18 months after renal transplantation. (a) Oblique sonogram obtained through the right lower quadrant of the abdomen shows a complex mass with a hyperechoic center and a thick-walled hypoechoic rim (arrows): a "pseudokidney" appearance. Note the adjacent transplanted kidney (TK). (b) Frontal spot radiograph obtained with rectal contrast material shows a filling defect (arrowhead) with a coiled spring appearance in the ascending colon, which represents ileocolic intussusception. Surgical exploration revealed an ileal lead mass containing PTLD.
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Figure 4b. Gastrointestinal PTLD with intussusception in a 12-year-old girl who presented with abdominal pain and bloody stools 18 months after renal transplantation. (a) Oblique sonogram obtained through the right lower quadrant of the abdomen shows a complex mass with a hyperechoic center and a thick-walled hypoechoic rim (arrows): a "pseudokidney" appearance. Note the adjacent transplanted kidney (TK). (b) Frontal spot radiograph obtained with rectal contrast material shows a filling defect (arrowhead) with a coiled spring appearance in the ascending colon, which represents ileocolic intussusception. Surgical exploration revealed an ileal lead mass containing PTLD.
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Splenic involvement by PTLD, occurring in 28% of allograft recipients with abdominal disease, manifests as discrete hypoechoic or low-attenuation lesions, splenomegaly, or both (Fig 5) (39). Splenic enlargement is more common in our experience (90% of cases), with the maximal splenic length usually greater than 16 cm.
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Figure 5. Splenic PTLD. Contrast-enhanced transverse CT scan obtained in a 5-year-old girl with hepatosplenomegaly after cardiac transplantation shows diffuse enlargement of the liver (L) and spleen (S), without focal lesions. Diffuse PTLD was confirmed at biopsy.
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Renal involvement by PTLD occurs in less than 20% of patients with abdominal disease (39). Unlike renal lymphoma in the general population, PTLD of the kidney tends to be unilateral and unifocal (39). A round, solitary, low-attenuating lesion at CT or a hypoechoic lesion at sonography, without renal enlargement, is most common (Fig 6). Diffuse infiltration by PTLD with nephromegaly is a less frequent manifestation but is more likely to extend beyond the renal capsule (39).
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Figure 6a. Renal PTLD in a 16-year-old girl who had undergone cardiac transplantation 7 years earlier. (a) Nonenhanced transverse CT scan shows a round, low-attenuating lesion (arrow) in the upper pole of the left kidney. A lesion (arrowheads) in the left hepatic lobe is barely perceptible. (b) Longitudinal sonogram obtained through the left kidney confirms a hypoechoic lesion (arrow). PTLD was diagnosed with sonographically guided biopsy of the hepatic lesion.
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Figure 6b. Renal PTLD in a 16-year-old girl who had undergone cardiac transplantation 7 years earlier. (a) Nonenhanced transverse CT scan shows a round, low-attenuating lesion (arrow) in the upper pole of the left kidney. A lesion (arrowheads) in the left hepatic lobe is barely perceptible. (b) Longitudinal sonogram obtained through the left kidney confirms a hypoechoic lesion (arrow). PTLD was diagnosed with sonographically guided biopsy of the hepatic lesion.
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Renal allograft involvement by PTLD must be distinguished from other posttransplantation complications (Fig 7). Findings of one study of five patients suggest that renal allograft PTLD is better evaluated with magnetic resonance (MR) imaging (74). At MR imaging, renal allograft PTLD appears as a poorly enhancing hilar mass that is hypointense on both T1- and T2-weighted images. Adrenal disease is less frequent than renal PTLD and usually manifests as nonspecific diffuse enlargement of the gland.
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Figure 7. Renal allograft PTLD. Contrast-enhanced transverse CT scan obtained in a 14-year-old boy (same patient as in Fig 3a) with cervical lymphadenopathy 10 months after renal transplantation shows a heterogeneous low-attenuation mass (arrows) in the renal allograft. Note also the mild wall thickening (arrowhead) of the descending colon. The wall thickening resolved following the reduction of immunosuppression and presumably was due to PTLD.
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Abdominal lymph node involvement is seen in about 20% of patients with abdominal disease, appearing as nonspecific nodal enlargement (Fig 8) (38,39). Involved nodes are typically 2–3 cm in diameter but may coalesce to form larger masses (Fig 8b). Central low-attenuating areas from necrosis are uncommon. Any combination of peritoneal, retroperitoneal, and extraperitoneal nodes may be enlarged (38,39).
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Figure 8a. PTLD of abdominal lymph nodes. (a) Nonenhanced transverse CT scan obtained in a 17-year-old boy with fever and abdominal pain 4 years after cardiac transplantation shows multiple, enlarged, retroperitoneal lymph nodes (arrows). (b) Contrast-enhanced transverse CT scan obtained in a 17-year-old girl presenting with left-lower-extremity edema 4 years after cardiac transplantation shows a large left iliac nodal mass (M) and collateral vessels (arrowheads) in the abdominal wall. The leg swelling was due to venous compression by the PTLD mass.
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Figure 8b. PTLD of abdominal lymph nodes. (a) Nonenhanced transverse CT scan obtained in a 17-year-old boy with fever and abdominal pain 4 years after cardiac transplantation shows multiple, enlarged, retroperitoneal lymph nodes (arrows). (b) Contrast-enhanced transverse CT scan obtained in a 17-year-old girl presenting with left-lower-extremity edema 4 years after cardiac transplantation shows a large left iliac nodal mass (M) and collateral vessels (arrowheads) in the abdominal wall. The leg swelling was due to venous compression by the PTLD mass.
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Omental and mesenteric involvement by PTLD, seen in about 10% of patients with abdominal disease (39), appears as extranodal masses. These may be well circumscribed or infiltrative, representing either primary tumor involvement or direct extension from an abdominal organ (38). Other uncommon sites of abdominal involvement include the gallbladder, abdominal wall musculature, and subcutaneous fat (38,39).
Thoracic Imaging
The frequency of thoracic involvement by PTLD is highly dependent on allograft type. In lung transplant recipients, thoracic PTLD is present in 69%–100% of cases (25,75,76). By comparison, thoracic involvement has been observed in less than 10% of recipients of other solid organ transplants (10,11). Another difference between lung recipients and recipients of other organs is the relative frequency of mediastinal lymphadenopathy. In lung transplant recipients, pulmonary parenchymal disease is about four times as common as mediastinal lymphadenopathy, whereas with other allograft types, these two complications occur with equal frequency (25,76,77). Therefore, the higher frequency of thoracic PTLD in lung recipients is due to the predilection for allograft involvement.
Discrete nodules and airspace consolidation occur in 50% and 42%, respectively, of children with lung allografts (25). In other allograft recipients, nodular disease is five times more common than alveolar disease (77). At chest radiography, parenchymal nodules may be solitary or multiple and are typically 1–4 cm (Fig 9). Additional smaller nodules may be detected with CT, but this information alone does not appear to alter management (Fig 9b) (25). Individual nodules are usually well defined at CT, but, on occasion, a rim of infiltrate surrounds the nodules (Fig 10). This CT halo sign can mimic fungal infections such as invasive aspergillosis (78). Parenchymal nodules are usually of homogeneous soft-tissue attenuation but sometimes demonstrate central areas of low attenuation due to necrosis (25). Alveolar PTLD is often multifocal and mimics infection (Fig 11) (25).
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Figure 9a. Thoracic PTLD: pulmonary nodules. (a) Frontal chest radiograph obtained in a 17-year-old boy with fever 3 months after heart transplantation shows multiple right-sided pulmonary nodules and only one left-sided nodule (arrow). (b) Nonenhanced transverse chest CT scan redemonstrates the asymmetric distribution of the PTLD nodules and shows additional nodules not seen in a. Unsuspected abdominal PTLD also was present at CT (not shown). (c) Follow-up frontal chest radiograph obtained 6 months after immunosuppression was reduced shows resolution of the pulmonary nodules. A two-lead cardiac pacemaker was placed during the interval.
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Figure 9b. Thoracic PTLD: pulmonary nodules. (a) Frontal chest radiograph obtained in a 17-year-old boy with fever 3 months after heart transplantation shows multiple right-sided pulmonary nodules and only one left-sided nodule (arrow). (b) Nonenhanced transverse chest CT scan redemonstrates the asymmetric distribution of the PTLD nodules and shows additional nodules not seen in a. Unsuspected abdominal PTLD also was present at CT (not shown). (c) Follow-up frontal chest radiograph obtained 6 months after immunosuppression was reduced shows resolution of the pulmonary nodules. A two-lead cardiac pacemaker was placed during the interval.
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Figure 9c. Thoracic PTLD: pulmonary nodules. (a) Frontal chest radiograph obtained in a 17-year-old boy with fever 3 months after heart transplantation shows multiple right-sided pulmonary nodules and only one left-sided nodule (arrow). (b) Nonenhanced transverse chest CT scan redemonstrates the asymmetric distribution of the PTLD nodules and shows additional nodules not seen in a. Unsuspected abdominal PTLD also was present at CT (not shown). (c) Follow-up frontal chest radiograph obtained 6 months after immunosuppression was reduced shows resolution of the pulmonary nodules. A two-lead cardiac pacemaker was placed during the interval.
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Figure 10a. Thoracic PTLD: pulmonary nodules with CT halo sign. (a) Nonenhanced transverse chest CT scan in a 12-year-old asymptomatic boy 3 months after lung transplantation shows bilateral pulmonary nodules, several of which are surrounded by ill-defined halos (arrows) of soft-tissue attenuation. PTLD was unsuspected clinically. (b) Follow-up nonenhanced transverse CT scan obtained 1 month after the reduction of immunosuppression shows a decrease in the size of the pulmonary nodules, which now have a sharper margin.
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Figure 10b. Thoracic PTLD: pulmonary nodules with CT halo sign. (a) Nonenhanced transverse chest CT scan in a 12-year-old asymptomatic boy 3 months after lung transplantation shows bilateral pulmonary nodules, several of which are surrounded by ill-defined halos (arrows) of soft-tissue attenuation. PTLD was unsuspected clinically. (b) Follow-up nonenhanced transverse CT scan obtained 1 month after the reduction of immunosuppression shows a decrease in the size of the pulmonary nodules, which now have a sharper margin.
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Figure 11. Thoracic PTLD: pulmonary consolidation. Contrast-enhanced transverse CT scan obtained in a 6-year-old boy with a transplanted heart shows right-lower-lobe consolidation, with areas of decreased attenuation (arrowheads). Less extensive right-middle-lobe consolidation, small right-sided pleural effusion (solid arrows), and esophageal thickening (open arrow) are also present. The child presented with symptoms related to abdominal PTLD.
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Extrapulmonary intrathoracic involvement by PTLD is best evaluated with CT (25). Mediastinal lymphadenopathy usually consists of discrete nodal enlargement, but large coalescent masses are occasionally seen (Fig 12). Pericardial and pleural involvement usually manifest as nonspecific effusion (Fig 12).
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Figure 12. Thoracic PTLD: pulmonary and mediastinal disease. Nonenhanced transverse CT scan obtained in a 17-year-old girl 3 months after bilateral lung transplantation shows enlarged right paratracheal lymph nodes (arrow) posterior to the superior vena cava. A large right upper lobe pulmonary nodule ( ) and left-sided pleural effusion (arrowheads) are present, both of which were proved at tissue sampling to be due to PTLD.
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Neuroimaging
In our experience, PTLD involvement of the extracranial head and neck occurs in about 25% of children and is often associated with extranodal disease of the abdomen and thorax. Sites of disease include the cervical lymph nodes, pharynx, orbit, and sinonasal region (43). By comparison, brain involvement by PTLD is less common in children—it is seen in 1% to 6% of cases—and is usually an isolated process (17).
CT and MR imaging are both useful adjuncts to physical examination in evaluating the head and neck region for PTLD. Diffuse enlargement of the pharyngeal and palatine tonsils and cervical lymphadenopathy are common manifestations of head and neck disease (Fig 13a, 13b). Orbital involvement by PTLD usually appears as a soft-tissue mass within the lacrimal fossa (Fig 13c). Sinonasal involvement by PTLD can mimic rhinosinusitis or sinonasal polyposis both clinically and radiologically (Fig 13d). MR imaging may be useful in distinguishing tumor from benign inflammatory disease (43).
Hemorrhage and necrosis are seen more commonly with PTLD of the brain in allograft recipients than with primary central nervous system lymphoma in immunocompetent patients (43). PTLD lesions tend to be supratentorial, usually involving the periventricular and subcortical regions. Solitary lesions compose the majority of cases (43). The lesions may appear higher in attenuation than the surrounding brain parenchyma on nonenhanced CT images because of either hypercellularity or hemorrhage (Fig 14). MR imaging can reveal lesion hemorrhage with characteristic signal intensity changes and lesion necrosis with ring enhancement following contrast material administration (Fig 14).
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Figure 14a. PTLD of the brain in an 11-year-old boy who presented with seizures 4 months after lung transplantation. (a) Nonenhanced transverse head CT scan shows a high-attenuation subcortical lesion (arrow) in the right frontal lobe, with surrounding vasogenic edema (arrowheads). (b) Contrast-enhanced T1-weighted transverse MR image (100/30) shows ring enhancement of the lesion (arrow).
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Figure 14b. PTLD of the brain in an 11-year-old boy who presented with seizures 4 months after lung transplantation. (a) Nonenhanced transverse head CT scan shows a high-attenuation subcortical lesion (arrow) in the right frontal lobe, with surrounding vasogenic edema (arrowheads). (b) Contrast-enhanced T1-weighted transverse MR image (100/30) shows ring enhancement of the lesion (arrow).
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CONCLUSION
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PTLD represents a broad spectrum of lymphoid proliferation in the setting of immunosuppression. Currently, the role of imaging is the detection of PTLD and the assessment of disease extent. Awareness of the clinical and imaging findings of PTLD is important so that the radiologist can suggest the diagnosis and prompt appropriate management. However, imaging and clinical manifestations of PTLD are protean and are not reliably predictive of histopathologic subtype, which makes tissue sampling necessary. Future challenges include a greater insight into the appropriate timing of imaging studies, determination of the relative value of imaging versus molecular analysis for the diagnosis of PTLD, and an evaluation of the effect of surveillance imaging on patient outcome.
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FOOTNOTES
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2**. Multiple body systems 
Abbreviations: EBV = Epstein-Barr virus,
PTLD = posttransplantation lymphoproliferative disorder
The opinions and assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Department of Defense.
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ABSTRACT
INTRODUCTION
