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Published online before print February 1, 2002, 10.1148/radiol.2223010456
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(Radiology 2002;222:699-708.)
© RSNA, 2002

Pediatric Imaging

Posttransplantation Lymphoproliferative Disorder: Manifestations in Pediatric Thoracic Organ Recipients1

Gye Yeon Lim, MD2, Beverley Newman, MD, Geoffrey Kurland, MD and Steven Alan Webber, MD

1 From the Departments of Radiology (G.Y.L., B.N.) and Pediatrics (G.K., S.A.W.), Children’s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, 3705 Fifth Ave at DeSoto St, Pittsburgh, PA 15213-2583. Received February 13, 2001; revision requested March 20; revision received July 3; accepted July 26. Address correspondence to B.N. (e-mail: newmanb@chplink.chp.edu).


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
PURPOSE: To describe and correlate the clinical and imaging features of posttransplantation lymphoproliferative disorder (PTLD) in young thoracic organ transplant recipients.

MATERIALS AND METHODS: The authors retrospectively reviewed the medical and imaging records of 31 PTLD episodes in 27 patients with PTLD out of 183 young patients who survived for at least 1 month after thoracic organ transplantation: 18 (14%) heart transplant recipients and nine (16%) lung or heart-lung transplant recipients. Four patients had two separate PTLD episodes. The distribution, timing, and imaging features of the disease were analyzed.

RESULTS: Seventeen (55%) of 31 episodes involved intrathoracic PTLD manifesting as multiple pulmonary nodules (n = 10), a solitary nodule (n = 3), alveolar consolidation (n = 3), and/or mediastinal adenopathy (n = 8). Extrathoracic PTLD occurred in 21 (68%) of 31 episodes and involved the abdomen (n = 15), head and neck (n = 11), and/or central nervous system (n = 3). The imaging findings of these episodes included bowel wall thickening, lymphadenopathy, and focal masses. Intrathoracic PTLD occurred more commonly in lung transplant recipients (89%) than in heart transplant recipients (44%); no cases of lymphoma involved the thorax. The frequency of extrathoracic manifestations was higher in heart transplant recipients (83%) than in lung transplant recipients (33%). In lung transplant recipients, the prevalence of early-onset PTLD was significantly greater than that in heart transplant recipients (P < .05). Intrathoracic PTLD tended to manifest early.

CONCLUSION: PTLD in young thoracic transplant recipients involves the lungs and extrathoracic organs, tends to have an early onset, and manifests predominantly in the thorax in lung transplant and heart-lung transplant recipients, as opposed to heart transplant recipients.

© RSNA, 2002

Index terms: Heart, CT, 51.12111, 51.12112 • Heart, transplantation, 51.45 • Hodgkin disease, 60.34 • Lung, CT, 60.12111, 60.12112 • Lung, transplantation, 60.45 • Lymphatic system, diseases, 60.342, 60.343


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Posttransplantation lymphoproliferative disorder (PTLD) is a serious complication of chronic immunosuppression that is related to solid-organ transplantation (1,2). The frequency of PTLD varies with the type of organ transplant (1–3). The higher rate of PTLD in lung transplant and heart-lung transplant recipients, as compared with the frequency of this disease in other solid-organ transplant recipients, is thought to be due in part to the more aggressive immunosuppressive regimen required to prevent lung allograft rejection (2–4). With increasing numbers of children with thoracic organ transplants and their longer survivals, the cases of PTLD in pediatric patients have increased (5–7). In addition, PTLD is thought to occur with greater frequency in pediatric recipients than in adult recipients because of children’s lack of exposure to Epstein-Barr virus before transplantation and the consequent higher prevalence of posttransplantation seroconversion (2,8).

When PTLD is detected early and treated with reduction of immunosuppressive agents, the majority of cases resolve completely (9,10). Because the presenting clinical symptoms are often vague and confusing, recognition of the imaging features of PTLD might facilitate earlier diagnosis and treatment (4). Although the most common computed tomographic (CT) findings of PTLD in adults have been described, similar information on children with thoracic organ transplants is not readily available. The objective of our study was to describe and correlate the clinical and imaging features of PTLD in these young patients.


   MATERIALS AND METHODS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
DISCUSSION
 REFERENCES
 
From January 1982 through December 1999, 183 young patients survived for at least 1 month after thoracic organ transplantation at our institution. Thirty-one episodes of PTLD were diagnosed in 27 of these patients: 18 (14%) of 127 heart transplant recipients and nine (16%) of 56 lung or heart-lung transplant recipients. Thirteen of the 27 patients were male, and 14 were female, and their mean age at the time of diagnosis of PTLD was 10 years (age range, 9 months to 20 years). Four of the 27 patients—two heart transplant recipients and two lung/heart-lung transplant recipients—had two separate episodes of PTLD. The posttransplantation survivals prior to PTLD ranged from 4 to 141 months (median, 64 months) for the heart transplant recipients and from 3 to 87 months (median, 35 months) for the lung/heart-lung transplant recipients.

The organs transplanted included 17 hearts, one heart-kidney combination, five lungs, and four heart-lung combinations. The small numbers of lung transplant and heart and lung transplant recipients were combined into a single group. This was done, in accordance with the protocol used in several other studies (6,11), because heart-lung transplant recipients mimic lung transplant recipients more closely than they mimic heart transplant recipients and require higher doses of immunosuppressive medication.

Three authors (G.Y.L., B.N., S.A.W.) retrospectively reviewed the medical records of all patients to determine the clinical features, including type of transplant, time from transplantation to diagnosis of PTLD, symptoms at presentation, involved sites, histologic classification, and patient outcome. PTLD was proven at percutaneous or surgical biopsy in 29 of the 31 cases, and autopsy was performed in three of these cases. Two episodes were diagnosed and treated on the basis of clinical and imaging findings with no pathologic diagnosis. PTLD was frequently clinically suspected on the basis of symptoms, physical examination results, and/or evidence of Epstein-Barr virus seroconversion.

The pathologic diagnosis of PTLD was based on previously established histologic criteria and classified as polymorphous, monomorphous, or lymphoma. We distinguished malignant lymphoma such as Burkitt lymphoma from monomorphous PTLD by confirming the cytogenetic abnormalities in malignant lymphoma.

Whenever possible, tissue was obtained from multiple potentially involved sites with upper and/or lower gastrointestinal endoscopy and biopsy, core-needle biopsy with CT guidance, or excisional biopsy since different histologic findings could be present at different disease sites. Multiple samples and stains were analyzed to exclude other pathologic entities such as infection or rejection.

The initial and follow-up images obtained in all patients, including radiographs and cross-sectional imaging studies, were retrospectively reviewed. All patients underwent chest radiography. The cross-sectional imaging studies that were performed initially to evaluate PTLD varied. CT was performed in 28 of 31 cases: of the chest in five cases; of the abdomen in two cases; of the chest and abdomen in 11 cases; of the chest and neck in two cases; of the chest, neck, and abdomen in two cases, of the neck and abdomen in one case; of the chest, abdomen, and brain in two cases; and of the brain in three cases. Magnetic resonance (MR) imaging of the brain was performed in three of 31 cases. Ultrasonography of the abdomen was used as an adjunct to CT or biopsy. In all 29 proven cases, pathologic biopsy was performed within 1–14 days (mean, 4.5 days) after primary imaging.

The images were reviewed and a consensus was reached by two pediatric radiologists (G.Y.L., B.N.). All imaging studies in a given patient were evaluated together. Specifically, the thoracic images were evaluated for the presence of pulmonary parenchymal nodules or airspace consolidation, pleural disease, and hilar or mediastinal mass or adenopathy. In addition, the number, size, distribution, margin, and attenuation of pulmonary nodules and mediastinal lesions were characterized. We evaluated all abdominal studies for the presence of visceral, nodal, and extranodal disease. These abdominal lesions were analyzed on the basis of distribution, number, size, and attenuation characteristics. The head and neck images were evaluated for abnormalities of the oropharyngeal lymphatic tissues, the cervical lymph nodes, and other involved sites. The central nervous system CT or MR images were evaluated for the presence or absence of parenchymal, soft-tissue, or bone abnormalities. Individual lesions were characterized on the basis of distribution, enhancement pattern, and attenuation or signal intensity.

We ascribed imaging findings to PTLD when there was a corresponding direct pathologic correlation or when at least one of the following criteria was met: pathologic proof in the same organ or anatomic region of the body or lesions that responded to therapy depicted on follow-up images along with no clinical or pathologic evidence of other concurrent disease. The distribution of disease was determined after the evaluation of all medical records and imaging findings. The disease sites were subdivided into intrathoracic (with lung lesions or hilar or mediastinal adenopathy), extrathoracic, or both intra- and extrathoracic. At these sites, diffuse disease was defined as involvement of more than four organ systems. Early onset of PTLD was defined as a diagnosis made within 1 year following transplantation.

Statistical analysis was performed to compare the differences in distribution of disease and time from transplantation to diagnosis of PTLD according to type of transplant. Categorical data among groups were compared by using the Fisher exact test, with P values of less than .05 indicating a significant difference. For statistical evaluation, we randomly chose one episode of each of the four patients who had two separate PTLD episodes because multiple events in these patients should not be considered as independent variables. The Spearman rank correlation test was used to determine the correlation between the timing of PTLD and the distribution of PTLD as codependent variables.

This study was approved by the hospital’s human rights committee; the need for individual informed consent was waived.


   RESULTS
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Clinical Findings
The patient data are summarized in Table 1. Among the 31 episodes of PTLD, six involved diffuse disease. The tissue analyzed for pathologic diagnosis was obtained at intrathoracic (n = 8), extrathoracic (n = 14), or both (n = 7) locations. The intrathoracic biopsy locations included lung parenchymal lesions (n = 14), mediastinal lymph nodes or masses (n = 3), and the pleura (n = 1). The extrathoracic biopsy sites included the alimentary tract (n = 8), mesenteric lymph nodes or masses (n = 2), retroperitoneal lymph node (n = 1), inguinal lymph node (n = 1), liver (n = 1), kidney (n = 1), abdominal wall mass (n = 1), head and neck (n = 8), and central nervous system (n = 2).


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  		TABLE 1. Clinical and Pathologic Data on 31 PTLD Episodes in 27 Patients

 
It was particularly interesting that all five episodes of pathologically proven lymphoma occurred in heart transplant recipients in whom PTLD manifested late (>4 years after transplantation). None of these lymphomas involved the lung. One child had two separate episodes of lymphoma, and each case of lymphoma was pathologically distinct. There were no cases of lymphoma in patients with early-onset PTLD. Among 15 episodes of early-onset PTLD, 10 (67%) were associated with polymorphous histologic findings; and two, with monomorphous histologic findings. In one patient, the biopsy material obtained was insufficient to classify the PTLD. In two patients, no biopsy material was obtained, because no readily accessible biopsy site was available. Their diagnoses were based on the resolution of findings (ie, multiple pulmonary nodules) on follow-up CT scans and on clinical improvement after the discontinuation of immunosuppressive drugs.

Treatment resulted in the resolution of PTLD in 25 of 31 cases. PTLD directly contributed to death in six patients 1 week to 3 months (median, 5 weeks) after the diagnosis was established. Among these patients who died, one had respiratory failure, three had disseminated multiorgan failure, and two had concurrent opportunistic infections. An additional six patients died 4–28 months (median, 18 months) after the diagnosis of PTLD: two with severe rejection, one with obliterative bronchiolitis, one with graft failure, one with infection, and one with obliterative bronchiolitis and aspergillosis. These patients did not have active PTLD at the time of death. At the time this article was written, only four thoracic organ transplant recipients had died since 1997, and in only one case, the death was directly attributable to PTLD.

The results of comparing the prevalence of PTLD in the heart transplant recipients with that in the lung and heart-lung transplant recipients according to PTLD location are presented in Table 2. Eight (89%) of nine lung transplant recipients had intrathoracic PTLD, as compared with eight (44%) of 18 heart transplant recipients. In contrast, the prevalence of extrathoracic PTLD was greater in the heart transplant recipients (15 [83%] of 18 patients) than in the lung recipients (three [33%] of nine patients) (P > .05). In the transplant recipients with extrathoracic PTLD, most of the abdominal involvement (15 [94%] of 16 cases) occurred in heart transplant recipients, but one (6%) case of abdominal involvement occurred in a lung transplant recipient.


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  		TABLE 2. Prevalence of PTLD Compared between Lung Transplant Recipients and Heart Transplant Recipients according to Location of PTLD

 
The time from transplantation to diagnosis of PTLD ranged from 2 months to 11 years (mean, 36.6 months). The different transplant types were compared according to the early versus late onset of PTLD, and the results are presented in Table 3. The prevalence of early PTLD in the lung transplant recipients (seven [78%] of nine patients) was greater than that in the heart transplant recipients (six [33%] of 18 patients) (P < .05). There was a significant correlation between location of PTLD and timing of disease (r = 0.49; P < .05). Intrathoracic PTLD was more likely to manifest early (<1 year) after transplantation (in 11 [69%] of 16 cases) than extrathoracic PTLD (in eight [44%] of 18 cases). Seven of eight extrathoracic episodes of early-onset PTLD occurred in the abdomen, and five of these episodes involved the alimentary tract. Two cases involved the neck. All statistical data and the data presented in Tables 2 and 3 were based on findings in the 27 patients. Imaging findings were analyzed by using the 31 episodes of PTLD, including those in four patients who had two separate episodes each.


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  		TABLE 3. Transplant Recipient Groups Compared according to Early versus Late Onset of PTLD

 
Imaging Findings
Intrathoracic disease.—Of the 17 episodes of intrathoracic PTLD, all were examined with chest radiography and 16 were examined with CT. Chest radiography helped to identify an abnormality in 14 (93%) of 15 patients with lung parenchymal lesions and in three (43%) of seven patients with hilar and mediastinal adenopathies. One patient with normal radiographic findings had small (<8-mm) nodules at CT. In seven patients, CT depicted additional nodules that were not seen on chest radiographs. In four of seven patients with hilar and mediastinal adenopathies, the abnormalities were identified only at CT and were not suspected at chest radiography.

Fifteen (94%) of the sixteen patients who underwent chest CT had abnormalities involving lung parenchyma. Ten (67%) of these patients had multiple nodules, three (20%) had patchy consolidation, and one (7%) had a combination of both findings. Three patients (20%) had solitary nodules.

In the patients with multiple nodules (n = 81), 65 (80%) of the lesions were well circumscribed with an ovoid to round shape, and they ranged in size from 3.0 mm to 5.2 cm (mean, 1.6 cm). Sixteen (20%) of the 81 nodules had shaggy margins with a surrounding halo (Fig 1a). The 62 (76%) nodules larger than 1 cm had well-circumscribed margins, and 53 (85%) of these nodules showed central low attenuation, which possibly represented necrosis (Fig 1b). In nine (90%) of 10 patients with multiple nodules, the nodules were diffusely scattered throughout both lungs; however, in one patient, who had a single lung transplant, extensive PTLD involvement was noted in the allograft lung, with sparing of the native lung (Fig 2). In one patient, multiple isolated nodules progressed to patchy consolidation with areas of central necrosis within 2 weeks after treatment (Fig 3a, Fig 3b).



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  		Figure 1a. Patient 2. Transverse contrast material-enhanced CT scans obtained in a 17-year-old girl who presented with symptoms of respiratory distress and developed multiple pulmonary nodules 2 months after double-lung transplantation. (a) CT scan (lung window) shows multiple pulmonary parenchymal nodules, the two largest of which are in the superior segment of the left lower lobe abutting the pleura. One of these nodules (white arrows) has discrete well-defined margins, whereas the other nodule (arrowheads) has shaggy indistinct margins. Postthoracentesis air (black arrow) is seen in the right pleural fluid collection. (b) CT scan (mediastinal window) obtained at a more caudal level shows central low attenuation (arrowheads) of a large pulmonary nodule with marginal enhancement. Homogeneous soft-tissue attenuation (arrows) in the subcarinal region suggests lymphadenopathy. Polymorphous PTLD was confirmed pathologically in the lung, pleura, and tonsils.

 


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  		Figure 1b. Patient 2. Transverse contrast material-enhanced CT scans obtained in a 17-year-old girl who presented with symptoms of respiratory distress and developed multiple pulmonary nodules 2 months after double-lung transplantation. (a) CT scan (lung window) shows multiple pulmonary parenchymal nodules, the two largest of which are in the superior segment of the left lower lobe abutting the pleura. One of these nodules (white arrows) has discrete well-defined margins, whereas the other nodule (arrowheads) has shaggy indistinct margins. Postthoracentesis air (black arrow) is seen in the right pleural fluid collection. (b) CT scan (mediastinal window) obtained at a more caudal level shows central low attenuation (arrowheads) of a large pulmonary nodule with marginal enhancement. Homogeneous soft-tissue attenuation (arrows) in the subcarinal region suggests lymphadenopathy. Polymorphous PTLD was confirmed pathologically in the lung, pleura, and tonsils.

 


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  		Figure 2a. Patient 7. Transverse contrast-enhanced CT scans obtained in a 15-year-old girl 2 months after a single left lung transplantation. (a) CT scan (lung window) demonstrates both airspace consolidation (arrows) and nodular opacities with hazy margins (arrowheads) in the left upper lobe. The right lung is clear. (b) CT scan (mediastinal window) demonstrates areas of confluent airspace consolidation with patchy low attenuation (black arrows) in the posterior left lower lobe, as well as a discrete nodule (white arrow) more anteriorly. Diagnosis of PTLD was confirmed at open-lung biopsy.

 


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  		Figure 2b. Patient 7. Transverse contrast-enhanced CT scans obtained in a 15-year-old girl 2 months after a single left lung transplantation. (a) CT scan (lung window) demonstrates both airspace consolidation (arrows) and nodular opacities with hazy margins (arrowheads) in the left upper lobe. The right lung is clear. (b) CT scan (mediastinal window) demonstrates areas of confluent airspace consolidation with patchy low attenuation (black arrows) in the posterior left lower lobe, as well as a discrete nodule (white arrow) more anteriorly. Diagnosis of PTLD was confirmed at open-lung biopsy.

 


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  		Figure 3a. Patient 11. Transverse contrast-enhanced CT scans obtained 3 months after heterotopic heart transplantation in a 7-year-old boy with a history of diarrhea and in whom there was extensive PTLD involvement in the lung and alimentary tract. (a) Chest CT scan (lung window) shows multiple well-defined nodules throughout both lungs. The patient was treated with intravenous ganciclovir, and immunosuppressive medication was withheld. (b) Chest CT scan (mediastinal window) obtained 2 weeks after a demonstrates progression of PTLD and the development of confluent bilateral patchy airspace consolidation with central patchy low attenuation (arrows). This lesion proved to be polymorphous PTLD with necrotic areas. (c) Abdominal CT scan shows focal wall thickening involving several small-bowel loops (arrows). PTLD was confirmed at endoscopy and biopsy of the esophagus, stomach, duodenum, and colon.

 


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  		Figure 3b. Patient 11. Transverse contrast-enhanced CT scans obtained 3 months after heterotopic heart transplantation in a 7-year-old boy with a history of diarrhea and in whom there was extensive PTLD involvement in the lung and alimentary tract. (a) Chest CT scan (lung window) shows multiple well-defined nodules throughout both lungs. The patient was treated with intravenous ganciclovir, and immunosuppressive medication was withheld. (b) Chest CT scan (mediastinal window) obtained 2 weeks after a demonstrates progression of PTLD and the development of confluent bilateral patchy airspace consolidation with central patchy low attenuation (arrows). This lesion proved to be polymorphous PTLD with necrotic areas. (c) Abdominal CT scan shows focal wall thickening involving several small-bowel loops (arrows). PTLD was confirmed at endoscopy and biopsy of the esophagus, stomach, duodenum, and colon.

 


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  		Figure 3c. Patient 11. Transverse contrast-enhanced CT scans obtained 3 months after heterotopic heart transplantation in a 7-year-old boy with a history of diarrhea and in whom there was extensive PTLD involvement in the lung and alimentary tract. (a) Chest CT scan (lung window) shows multiple well-defined nodules throughout both lungs. The patient was treated with intravenous ganciclovir, and immunosuppressive medication was withheld. (b) Chest CT scan (mediastinal window) obtained 2 weeks after a demonstrates progression of PTLD and the development of confluent bilateral patchy airspace consolidation with central patchy low attenuation (arrows). This lesion proved to be polymorphous PTLD with necrotic areas. (c) Abdominal CT scan shows focal wall thickening involving several small-bowel loops (arrows). PTLD was confirmed at endoscopy and biopsy of the esophagus, stomach, duodenum, and colon.

 
The solitary lung nodules ranged in size from 1.4 to 5.0 cm (mean, 2.9 cm), and all of these lesions had discretely lobulated margins with internal low attenuation (Fig 4).



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  		Figure 4a. Patient 10. Transverse contrast-enhanced CT scans obtained in a 4-year-old girl with clinical symptoms of pneumonia. PTLD manifested in the lung as a solitary nodule that developed 3 years after heart transplantation. (a) CT scan (lung window) shows a large lobulated mass (arrows) with discrete margins in the posterior right lower lobe abutting the pleura and adjacent pleural thickening. (b) CT scan (mediastinal window) shows heterogeneous enhancement with some central low attenuation (arrows) in the mass. Monomorphous PTLD was confirmed at CT-guided biopsy of the lesion. Adenoid biopsy revealed polymorphous histologic features of PTLD.

 


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  		Figure 4b. Patient 10. Transverse contrast-enhanced CT scans obtained in a 4-year-old girl with clinical symptoms of pneumonia. PTLD manifested in the lung as a solitary nodule that developed 3 years after heart transplantation. (a) CT scan (lung window) shows a large lobulated mass (arrows) with discrete margins in the posterior right lower lobe abutting the pleura and adjacent pleural thickening. (b) CT scan (mediastinal window) shows heterogeneous enhancement with some central low attenuation (arrows) in the mass. Monomorphous PTLD was confirmed at CT-guided biopsy of the lesion. Adenoid biopsy revealed polymorphous histologic features of PTLD.

 
One of three cases of patchy airspace consolidation involved concomitant multiple nodules, and PTLD was pathologically confirmed in both processes (Fig 2). Another child who presented with a cough and fever and patchy airspace consolidation was found pathologically to have diffuse PTLD with concomitant cytomegalovirus disease (Fig 5).



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  		Figure 5. Patient 14. Frontal chest radiograph obtained in a 5-year-old girl who presented with a fever and abdominal pain 4 months after heart transplantation shows patchy alveolar opacities throughout both lung fields. Pathologic examination results demonstrated PTLD with concomitant cytomegalovirus infection, which was also confirmed in gastric ulcerative lesions at endoscopic biopsy.

 
Hilar and mediastinal adenopathies were present in seven (41%) of the 17 episodes of intrathoracic PTLD. Four (36%) of 11 episodes in the lung transplant recipients and three (15%) of 20 episodes in the heart transplant recipients involved the mediastinum, with no significant difference in the prevalence of mediastinal disease according to transplant type (P > .05). All four lung transplant recipients and one heart transplant recipient with mediastinal adenopathy also had associated lung parenchymal lesions (Fig 1b). Two of three heart transplant recipients had a hilar or mediastinal adenopathy as an isolated feature of intrathoracic PTLD without lung parenchymal abnormality. The involved nodal sites included paratracheal (n = 4), subcarinal (n = 4), prevascular (n = 3), hilar (n = 3), and azygoesophageal recess (n = 1) regions. Adenopathy typically consisted of 4.0-mm to 4.3-cm (mean, 1.6 cm) discrete or confluent areas of soft-tissue attenuation without internal necrosis.

One of the patients with PTLD had a large paravertebral mediastinal mass, presumably adenopathy, in conjunction with multiple parenchymal nodules. PTLD was pathologically confirmed in both sites.

Pleural involvement with PTLD was noted radiologically in three patients. One of these patients had moderate bilateral pleural effusions and pleural thickening (Fig 1b), and two had nonspecific pleural effusions without discernible thickening or nodularity. No patient in our series had an isolated pleural effusion without parenchymal manifestations of PTLD.

Combined intra- and extrathoracic involvement.—Seven (41%) of 17 episodes of intrathoracic PTLD involved associated extrathoracic PTLD in the alimentary tract (n = 3), mesenteric lymph nodes (n = 2), abdominal wall (n = 1), adenoids and tonsils (n = 2), and brain (n = 1). Five (71%) of the seven patients were heart transplant recipients, and two (29%) were lung transplant recipients.

Extrathoracic disease: abdomen.—The most commonly involved sites at imaging in 16 cases of abdominal PTLD were the alimentary tract (n = 6), lymph nodes (n = 5), liver (n = 4), kidney (n = 2), and spleen (n = 2). Involvement of the adrenal gland, pancreas, mesentery, lesser sac, and abdominal wall was identified in one case each.

Alimentary tract involvement was confirmed histopathologically in eight (50%) of 16 cases of abdominal PTLD. Tumor was identified histopathologically in the stomach (n = 5), small bowel (n = 3), colon (n = 2), and esophagus (n = 1). One child had extensive involvement of the bowel from the esophagus to the colon, along with multiple pulmonary nodules (Fig 3c).

Abnormal findings were identified at CT in six patients. These findings included localized circumferential bowel wall thickening (n = 5), eccentric nodular thickening of the gastric wall (n = 1), and multiple polypoid intraluminal gastric masses with low attenuation (n = 1) (Fig 6a). CT results were negative in two patients: one with PTLD of the stomach and the other with PTLD of the colon, both confirmed at endoscopic and colonoscopic biopsy.



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  		Figure 6a. Patient 27. Transverse contrast-enhanced CT scans obtained in a 5-year-old boy who presented with a neck mass 4 years after heart transplantation. (a) Abdominal CT scan shows multiple hypoattenuating nodular polypoid masses (arrows) in the stomach. This patient also had bilateral multiple renal masses (not shown). (b) CT scan of the neck obtained at the same time as a shows a destructive mass (black arrows) in the right mandible and a right mandible submandibular soft-tissue mass (white arrows). Burkitt lymphoma in the stomach and mandibular mass were confirmed.

 


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  		Figure 6b. Patient 27. Transverse contrast-enhanced CT scans obtained in a 5-year-old boy who presented with a neck mass 4 years after heart transplantation. (a) Abdominal CT scan shows multiple hypoattenuating nodular polypoid masses (arrows) in the stomach. This patient also had bilateral multiple renal masses (not shown). (b) CT scan of the neck obtained at the same time as a shows a destructive mass (black arrows) in the right mandible and a right mandible submandibular soft-tissue mass (white arrows). Burkitt lymphoma in the stomach and mandibular mass were confirmed.

 
In five patients, PTLD appeared at imaging as nodal disease, including retroperitoneal (n = 5), gastrohepatic ligament (n = 1), portacaval (n = 1), porta hepatis (n = 1), splenic hilar (n = 1), mesenteric (n = 2), and inguinal lymph node (n = 1) lesions. The CT appearance of adenopathy due to PTLD was that of multiple discrete or confluent enlarged and mildly enhancing lymph nodes with homogeneous soft-tissue attenuation and without evidence of necrosis (Fig 7b). The sizes of the nodes ranged from 1.3 to 5.0 cm (mean size, 2.8 cm).



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  		Figure 7a. Patient 24. Transverse contrast-enhanced CT scans obtained in a 12-year-old boy who presented with a fever 9 years after heart transplantation. (a) Chest CT scan shows bilateral hilar (straight arrows) and subcarinal (curved arrow) adenopathies. Multiple small prevascular and paratracheal lymph nodes with homogeneous attenuation also were demonstrated on other images (not shown). There was no abnormality in the lung parenchyma. (b) Abdominal CT scan shows multiple discretely enlarged mesenteric lymph nodes (arrows) with homogeneous attenuation. PTLD in the mesenteric and subcarinal masses was confirmed at CT-guided biopsies. MR images of the brain (not shown) in this child were normal, but meningeal PTLD was found at lumbar puncture.

 


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  		Figure 7b. Patient 24. Transverse contrast-enhanced CT scans obtained in a 12-year-old boy who presented with a fever 9 years after heart transplantation. (a) Chest CT scan shows bilateral hilar (straight arrows) and subcarinal (curved arrow) adenopathies. Multiple small prevascular and paratracheal lymph nodes with homogeneous attenuation also were demonstrated on other images (not shown). There was no abnormality in the lung parenchyma. (b) Abdominal CT scan shows multiple discretely enlarged mesenteric lymph nodes (arrows) with homogeneous attenuation. PTLD in the mesenteric and subcarinal masses was confirmed at CT-guided biopsies. MR images of the brain (not shown) in this child were normal, but meningeal PTLD was found at lumbar puncture.

 
In the liver, tumors were seen as solitary (n = 2) or variable-sized multiple (n = 1) discrete nodules with low attenuation (Fig 8). A poorly marginated region of low attenuation in the liver of one patient was thought to possibly represent PTLD. This area was not proven pathologically, but subsequent images obtained after therapy showed the lesion to be resolved. Splenomegaly without a discrete focal mass was noted in two patients.



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  		Figure 8. Patient 22. Transverse contrast-enhanced CT scan obtained in a 7-year-old boy who developed PTLD with multiple solid abdominal organ involvement 6 years after heart transplantation shows multiple discrete low-attenuating hepatic nodules (curved arrows) and intraperitoneal (short arrows) and retroperitoneal (long arrows) adenopathies. Multiple renal lesions, as well as a low-attenuating intrapancreatic lesion (arrowhead), are seen. Multiple biopsies of the kidneys and cervical lymphadenopathy confirmed Burkitt lymphoma. This patient had a prior history of polymorphous PTLD with alimentary tract involvement and gastrointestinal bleeding 4 months after transplantation.

 
Probable pancreatic PTLD appeared at CT as an intrapancreatic low-attenuating mass (Fig 8), and potential adrenal involvement appeared as unilateral diffuse enlargement of the gland. PTLD was not proved histologically in these areas; however, it was confirmed at biopsy to exist in close proximity elsewhere in the abdomen, and follow-up scans obtained after therapy showed it to be resolved. Renal involvement appeared on CT images as bilateral, multiple, low-attenuating masses with nephromegaly (Fig 8).

One child with PTLD had a large mesenteric mass with intramural extension into the adjacent bowel; this lesion produced obstruction (Fig 9). In another child, marked mesenteric adenopathy was present (Fig 7b).



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  		Figure 9. Patient 19. Transverse contrast-enhanced abdominal CT scan obtained in a 13-year-old boy who presented with severe abdominal pain 11 years after heart transplantation and 4 years after kidney transplantation shows a heterogeneous mesenteric mass that has internal low attenuation (arrowheads) and focal areas of hyperattenuation (white arrow) that are suggestive of calcification. This lesion extended intraluminally into the small bowel (black arrows). The markedly distended proximal small bowel on the left and the decompressed distal small bowel and colon on the right suggest a high grade of obstruction. Monomorphous PTLD in an ileocecal mass was confirmed at colonoscopic biopsy.

 
Extrathoracic disease: head and neck.—In five of the 11 cases of PTLD involving the head and neck, the patients underwent neck CT: Cervical lymphadenopathy was present in three of these cases; enlarged tonsils and adenoids, in two; and mandibular bone involvement with a large soft-tissue mass extending into the inferior orbital wall, in one (Fig 6b).

Cervical adenopathy was noted as the sole manifestation in one of three patients; another patient had associated enlarged abdominal lymph nodes, and the remaining patient had alimentary tract involvement. The two patients with enlarged tonsils and adenoids had lung involvement.

Extrathoracic disease: central nervous system.—Two of three patients with pathologically proven central nervous system PTLD underwent imaging studies. Brain MR imaging findings were normal in one patient, in whom meningeal PTLD was confirmed by means of lumbar puncture. MR imaging in the other patient depicted several enhancing nodular lesions involving the basal ganglia and the right temporal and frontoparietal regions; some of these regions had rim enhancement with central low signal intensity. The third patient had diffuse PTLD involvement, including central nervous system disease that was detected only at autopsy.


   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
REFERENCES
 
PTLD is believed to be induced by Epstein-Barr virus infection, which causes infectious mononucleosis and is a major coexisting factor in the development of Burkitt lymphoma (10–13). This virus selectively infects B lymphocytes and induces proliferation. This proliferation is normally controlled by T lymphocytes. T-cell function is reduced in the immunosuppressed patient who has undergone transplantation, however, and this reduction results in uncontrolled B-cell proliferation that ranges from benign lymphoid hyperplasia with preservation of the lymphoid architecture to polymorphous or monomorphous proliferation and ultimately malignant monoclonal lymphoma (2,3). This spectrum is referred to as PTLD, although, as observed in our series, lymphoid hyperplasia is not usually included in established PTLD.

PTLD is reported to occur in approximately 1%–10% of organ transplant recipients, depending on the organ transplanted, the recipient’s age, and the immunosuppressive regimen (2,3). The prevalence of PTLD with heart-lung transplants and lung transplants is greater than that with other transplanted organs (10,14). Boyle et al (15), in an earlier series from our institution that included 14 of the cases reported herein, reported that PTLD was diagnosed in 7.7% of the heart transplant recipients and in 19.5% of the heart-lung transplant and lung transplant recipients (versus 14% and 16%, respectively, in the current study); these are higher than the prevalences of 3.4% and 7.9% previously reported for adult heart transplant recipients and adult lung transplant recipients, respectively (16). The reason for the higher prevalence of PTLD in heart transplant recipients (14%) reported in the current study is probably related to the longer follow-up period.

PTLD can have a variable distribution and involve many organ systems. The most commonly affected sites are the tonsils, cervical nodes, gastrointestinal tract, and thorax (10,17). However, in patients with solid-organ transplants, a statistically significant correlation exists between the location of the organ transplant and the distribution of disease (4,18). In the series reported by Donnelly et al (18), there was a tendency for PTLD to occur in the anatomic region of the transplant organ as well as in the allograft itself. Our cases generally support these data.

Intrathoracic PTLD involvement was present in eight (89%) of nine patients among the lung transplant recipients; these data are comparable to the frequencies of 100% reported by Montone et al (3) and 69% reported by Pickhardt et al (19). In addition, a unilateral lung transplant recipient in our series had PTLD that was localized to the allograft lung. Heart transplants appear to be the exception to the predilection for PTLD to involve the allograft and adjacent regions. Among the heart transplant recipients with PTLD in our series, none had allograft involvement and 44% had PTLD with intrathoracic involvement.

In our young study patients, the prevalence of mediastinal involvement with thoracic PTLD was not substantially different between the lung transplant and heart transplant recipients. However, isolated mediastinal involvement without lung parenchymal abnormalities occurred in the heart transplant recipients, but not in the lung transplant recipients. Similar to Pickhardt and Siegel (20), we found that abdominal involvement with PTLD was more frequent in heart transplant recipients than in lung transplant recipients.

The timing of PTLD also differs between heart transplant and lung transplant recipients. In the lung transplant recipients in our study, PTLD tended to occur in the 1st year following transplantation. The heart transplant recipients, on the other hand, tended to develop PTLD more than 1 year after transplantation. These findings are similar to those reported by Armitage et al (16). Intrathoracic PTLD tended to have an earlier presentation than extrathoracic PTLD. Two lung transplant recipients had early-onset PTLD in the lung allograft; both had late recurrent episodes of extrathoracic PTLD involving the cervical lymph nodes only. Interestingly, five (62%) of eight extrathoracic sites involved with early-onset PTLD occurred in the alimentary tract.

Pickhardt et al (19) noted that the thoracic PTLD in children, unlike that in adults, was less likely to manifest as a solitary nodule at chest radiography and was more likely to have alveolar infiltrates. However, the imaging features of thoracic PTLD in our series were not substantially different from those reported in solid-organ transplant recipients, including children and adults, by Dodd et al (21). The most common finding of thoracic PTLD in our study cases was multiple discrete nodules with or without mediastinal lymphadenopathy (Fig 1). Less common findings were solitary pulmonary nodules (Fig 4) or confluent patchy alveolar consolidation (Fig 2). PTLD nodules, especially larger lesions, as well as confluent alveolar opacities, tended to exhibit central low attenuation (Figs 1b, 2b, 3b).

PTLD, which manifests as nodules or diffuse alveolar pulmonary infiltrates, can be confused with opportunistic infections. In these cases, correlation of the imaging findings with the clinical history is important. Thoracic PTLD is sometimes clinically undetectable, whereas pulmonary infection often produces clinical symptoms. Frequently, biopsy is needed to make a firm diagnosis; however, it may be helpful to search for evidence of other sites of tumor involvement because thoracic PTLD can occur with extrathoracic involvement, especially in the alimentary tract, tonsils and adenoids, and cervical lymph nodes. Diffuse disease is more likely with heart transplant recipients than with lung transplant recipients. An organized approach to imaging for suspected PTLD is recommended. Our data support the use of CT of the neck, chest, and abdomen as part of the initial evaluation.

Although PTLD can involve any solid organ, hollow viscera, or abdominal-pelvic lymph node, the most common sites of involvement in the abdomen are the alimentary tract, abdominal lymph nodes, and liver (22–25). It has been reported that abdominal PTLD is characterized by a relatively high frequency of extranodal disease and a lower frequency of nodal disease in patients with PTLD, as compared with the imaging features of non-Hodgkin lymphoma that occur in the general population (26). Our study results are similar to these findings, with extranodal involvement (73%) occurring more frequently than lymph node disease (33%). Although extranodal disease is the classic manifestation of abdominal PTLD, lymph node involvement is not unusual and is occasionally seen in isolation. There are some differences in the distribution of disease between our young thoracic organ transplant recipients and the solid-organ transplant recipients in a previous study by Pickhardt and Siegel (27). In their study, hepatic involvement (53%) predominated, whereas in our series, there was a low frequency of hepatic involvement (27%). This difference is likely secondary to differences in the types of transplants. Alimentary tract PTLD involvement has been identified in the bowel from the esophagus to the rectum, with the highest frequency in the distal small bowel, proximal colon, and stomach in a previously published article (20). In contrast, the stomach was the most frequently involved organ in our study patients (Fig 6).

The findings of PTLD in the abdomen are more specific than those in the chest. Although infection and some neoplasms may mimic PTLD, they occur less frequently in the abdomen and thus present less of a diagnostic problem (28). We therefore suggest that discrete homogeneously enlarged lymph nodes, localized circumferential wall thickening of the bowel, or any focal abdominal mass in the pediatric thoracic organ transplant recipient should be considered highly suspicious for PTLD.

Upper airway obstruction due to tonsil and/or adenoid enlargement or lymphadenopathy may be an acute presenting symptom of PTLD (10,29). Usually, immunosuppressed individuals have very small or absent adenoidal tissue on lateral neck radiographs (30). If CT of the neck depicts diffuse adenoidal or tonsillar enlargement or there is a cervical adenopathy in a pediatric transplant recipient, then PTLD should be suspected.

In conclusion, PTLD causes substantial morbidity and mortality involving many extrathoracic organs as well as the lungs in pediatric thoracic organ transplant recipients. In lung transplant recipients, PTLD tends to manifest predominantly in the thorax and occurs earlier than it does in heart transplant recipients. The imaging features in our young study patients were not markedly different from those in other pediatric and adult solid-organ transplant recipients. The specific imaging findings of thoracic PTLD included (a) multiple pulmonary nodules, which were the most common; (b) large pulmonary nodules or confluent alveolar consolidation that frequently showed central necrosis; and (c) isolated mediastinal involvement, which was rare, occurring only in heart transplant recipients. The diagnosis of PTLD should also be considered in patients who have localized thickening of bowel loops, discretely enlarged abdominal lymph nodes with homogeneous attenuation, and cervical adenopathy or enlarged oropharyngeal lymphatic tissues. Abdominal PTLD is rare in lung transplant and heart-lung transplant recipients. Biopsy of the most readily accessible sites is usually required for pathologic confirmation of disease.


   ACKNOWLEDGMENTS
 
The authors thank Ricki Smith for her assistance in preparing this article.


   FOOTNOTES
 
2 Current address: Department of Radiology, St Mary’s Hospital, Catholic University of Korea, School of Medicine, Seoul. Back

Abbreviation: PTLD = posttransplantation lymphoproliferative disorder

Author contributions: Guarantors of integrity of entire study, G.Y.L., B.N.; study concepts and design, G.Y.L., B.N.; literature research, G.Y.L.; clinical studies, G.K., S.A.W.; data acquisition, G.Y.L., S.A.W.; data analysis/interpretation, G.Y.L., B.N.; statistical analysis, G.Y.L.; manuscript preparation and definition of intellectual content, all authors; manuscript editing, B.N., G.K., S.A.W.; manuscript revision/review, G.Y.L., B.N., S.A.W.; manuscript final version approval, B.N.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 

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