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1 Mallinckrodt Institute of Radiology, Washington University School of Medicine,
510 S. Kingshighway Blvd., St. Louis, MO 63110.
2 Department of Pediatrics, Division of Pulmonary Medicine, Washington
University School of Medicine, St. Louis Children's Hospital, St. Louis, MO
63110.
Received February 18, 2003;
accepted after revision April 16, 2003.
Address correspondence to M. J. Siegel
(siegelm{at}mir.wustl.edu).
Abstract
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MATERIALS AND METHODS. We reviewed the medical records and CT examinations of 260 lung transplantations in pediatric patients and found 26 recipients who had 29 episodes of histologically proven posttransplantation lymphoproliferative disorder. The clinical and CT features of the disease, the time to diagnosis, and the outcomes were assessed.
RESULTS. The clinical presentation of posttransplantation lymphoproliferative disorder varied from asymptomatic pulmonary nodules (14/29 [48%]) detected on chest CT to specific (organ-related) and nonspecific symptoms (15/29 [52%]). Intrathoracic posttransplantation lymphoproliferative disorder occurred in 20 (69%) of 29 cases and manifested as multiple pulmonary nodules (n = 17), alveolar infiltrates (n = 2), and combined nodules and infiltrates (n = 1). In eight (28%) of 29 cases, there was extraparenchymal disease, including adenopathy, pleural effusion, and esophageal thickening and erosions. Extrathoracic posttransplantation lymphoproliferative disorder occurred in 13 cases and involved the abdomen (n = 10), paranasal sinuses (n = 2), and brain (n = 1). In the abdomen, extranodal disease was more common than nodal disease and presented as bowel wall thickening, focal mass lesions, and splenomegaly. In 18 of 29 episodes of posttransplantation lymphoproliferative disorder, the histologic diagnosis was lymphoma. The median time to diagnosis after transplantation for the 29 episodes of posttransplantation lymphoproliferative disorder was 10 months. Thirteen of the 26 patients died. The median time of survival after the diagnosis of posttransplantation lymphoproliferative disorder was 17 months.
CONCLUSION. Posttransplantation lymphoproliferative disorder in pediatric lung transplant recipients occurs with relatively high frequency in both the chest and abdomen, tends to have lymphomatous features, and results in substantial mortality rates.
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Underlying lung diseases leading to transplantation in the 26 patients included cystic fibrosis (n = 22), pulmonary hypertension (n = 3), and factor V Leyden deficiency. All 26 patients underwent bilateral lung transplantation.
Diagnosis of posttransplantation lymphoproliferative disorder in the 29 study cases was made by open surgical biopsy in 20 cases, percutaneous biopsy in four cases, endoscopic biopsy in four cases, and autopsy in one case. The time interval between radiologic diagnosis and tissue diagnosis was less than 1 week in all cases. Results from immunohistochemical testing of the specimens for Epstein-Barr virus were positive in 14 patients (54%) and negative in 12 patients (46%). Samples were examined to exclude other pathology, such as rejection and infection.
Histopathologic diagnosis of posttransplantation lymphoproliferative disorder in the 29 study cases was based on the criteria described by the Society of Hematopathology [8]. Lesions having a monomorphic appearance or possessing histologic features of malignant lymphoma were classified as monomorphic. The lymphomas were further subdivided by histologic features using standard nomenclature for lymphomas. Lesions possessing histologic features that lacked a repetitive morphologic appearance were classified as polymorphic.
Our standard protocol for surveillance of asymptomatic pediatric lung allograft recipients requires chest radiography and CT at 3, 6, and 12 months after transplantation and then yearly. Additional images are acquired at any time if patients become symptomatic or there is evidence of Epstein-Barr virus seroconversion. In symptomatic patients with measurable (i.e., obvious) disease, tissue sampling of one of the lesions is performed. In asymptomatic patients or symptomatic patients with tiny lesions that are too small to be characterized at CT, scanning at more frequent intervals, usually at 4- to 6-week intervals, is performed. If disease persists or increases in volume, tissue sampling is performed to obtain a definitive diagnosis (e.g., distinguishing between posttransplantation lymphoproliferative disorder and infection). Once thoracic or abdominal posttransplantation lymphoproliferative disorder is documented, the abdomen in patients with thoracic posttransplantation lymphoproliferative disorder or the chest in patients with abdominal posttransplantation lymphoproliferative disorder is examined on CT to stage the extent of disease.
For the purpose of our analysis, baseline posttransplantation CT was compared with CT performed at the time of diagnosis of lymphoproliferative disorder to assess for interval change. The baseline study was defined as a CT study performed after transplantation that showed normal or near normal findings and minimal postoperative changes. Chest CT was performed with a conventional or helical technique using 4- to 10-mm collimation with contiguous intervals, a pitch of 1.5, and IV contrast medium. Differences in collimation were related to patient size and the use of two different CT scanners. High-resolution (2-mm-thick) scans at 2-cm intervals were obtained in all patients. Oral contrast medium was given for all abdominal examinations. Follow-up CT examinations were performed approximately 1 month after institution of therapy. All CT studies in this series except the baseline and follow-up studies were performed within 1 week of the diagnosis of lymphoproliferative disorder.
All CT scans were reviewed by two radiologists. Diagnosis of disease was based on the consensus interpretation. Thoracic CT was evaluated for pulmonary parenchymal nodules and infiltrates, pleural and pericardial disease, and mediastinal and hilar lymphadenopathy. The distribution and size of nodules, infiltrates, and lymph nodes were recorded. Abdominal CT was evaluated for nodal, solid-organ, or hollow-organ abnormalities and for mesenteric or omental abnormalities. The head and neck were evaluated for nodal, extranodal soft-tissue, or bone lesions. Abdominal and head and neck lesions were analyzed for number, size, distribution, and attenuation characteristics. CT findings were attributed to posttransplantation lymphoproliferative disorder when pathologic proof of the diagnosis in the same anatomic area was available or when the lesions decreased in size or resolved on follow-up imaging studies.
Medical records of the 26 patients were reviewed to determine the time to diagnosis of posttransplantation lymphoproliferative disorder, clinical features and immunosuppressive therapy at the time of diagnosis of posttransplantation lymphoproliferative disorder, histopathologic diagnosis, subsequent treatment, and survival rates.
Statistical Analysis
Descriptive statistics were calculated for the time to onset of
posttransplantation lymphoproliferative disorder and survival time for two
groups of lung allograft recipients: those who developed thoracic
posttransplantation lymphoproliferative disorder and those who developed
extrathoracic posttransplantation lymphoproliferative disorder. Shapiro-Wilk W
tests were used to test the normality of distributions. Equality of variances
was tested with O'Brien, Brown-Forsythe, Leven, and Bartlett tests. Data for
time to diagnosis after transplantation for the two groups were compared with
a median test. A Fisher's exact test was used to test for differences in
survival (living or dead) between the two groups. Alpha was set at 0.05.
Analyses were performed with JMP statistical software (SAS, Cary, NC) and
StatXact 5 statistical software for exact nonparametric inference (Cytel,
Cambridge, MA).
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Posttransplantation lymphoproliferative disorder limited to the chest occurred in 16 (55%) of the 29 cases. Seven (44%) of 16 cases were asymptomatic, and the disease was detected on surveillance CT. Two patients presented with symptoms and serology results consistent with primary Epstein-Barr virus infection. The remaining patients had nonspecific respiratory symptoms, including cough and mild dyspnea.
Posttransplantation lymphoproliferative disorder limited to the abdomen occurred in eight (28%) of the 29 cases. In all eight cases, there were abdominal symptoms, including pain, fever, and abnormal results on liver function tests. In two cases, combined chest and abdominal disease was present. The presenting findings in these two cases were abdominal pain and weight loss. One patient had both brain and lung disease and presented with headaches. Another patient had esophageal and sinus disease and presented with dysphagia and sinusitis. The final patient had disease isolated to the paranasal sinuses and presented with sinusitis. Thus, posttransplantation lymphoproliferative disorder involved the chest in 20 cases and the abdomen in 10 cases.
At the time of diagnosis, all patients except one received triple immunosuppression with corticosteroids, cyclosporine, and azathioprine. Additional drugs in some patients included antithymocyte or antilymphocyte globulin, tacrolimus, and murine monoclonal antihuman CD3 antibody. Antilymphocyte globulin was used for induction immunotherapy before 1994 in our program, and antithymocyte globulin was used thereafter. Antithymocyte globulin and murine monoclonal antihuman CD3 antibody were used for steroid-refractory allograft rejection. Tacrolimus was used in place of cyclosporine in two patients who received second solid-organ engraftments.
Treatment for lymphoproliferative disorder consisted of primarily reduction of immunosuppression (n = 20 cases), occasionally chemotherapy (n = 6), and rarely surgery (n = 1). Two cases were not treated. Fifteen (58%) of 26 patients died 0 days–7 years after the diagnosis of lymphoproliferative disorder. Of these 15 patients, death was attributed directly to lymphoproliferative disorder in six patients (40%); to bronchiolitis obliterans, sepsis, cardiac failure, and sarcoma in two patients each (53%); and to unrelated causes in one patient (7%). The time of survival after the diagnosis of posttransplantation lymphoproliferative disorder in the remaining patients ranged from 4 to 105 months, with a median of 36 months. Two (8%) of 26 patients developed bronchiolitis obliterans after reduction of immunosuppression and underwent repeated transplantation.
For statistical analysis of survival rates, only the second episode of posttransplantation lymphoproliferative disorder was analyzed in the three patients with recurrent disease. Two patients had thoracic disease at the time of the first episode, and the third had abdominal disease. One of the two patients with lung disease had recurrent lung disease but at different sites in the chest. The second patient with lung disease had an abdominal recurrence. The patient with abdominal disease at initial presentation had recurrent disease in the esophagus and sinuses. Nine (56%) of the 16 patients presenting with isolated thoracic disease on CT versus three (30%) of the 10 patients with all other presentations of posttransplantation lymphoproliferative disorder were alive 2 years after the diagnosis of posttransplantation lymphoproliferative disorder (p = 0.25).
Histopathologic Findings
Eighteen cases were monomorphous disease, usually B-cell lymphoma or
non-Hodgkin's lymphoma and less commonly Hodgkin's disease, and seven cases
were polymorphous disease. In four cases, lymphocyte proliferation was noted
on histologic section, but these findings were not further classified as
monomorphous or polymorphous disease and the histologic specimens were not
available for further analysis.
CT Findings
Posttransplantation lymphoproliferative disorder limited to the chest was
found in 16 cases and combined intra- and extrathoracic involvement in four
cases. Seventeen (85%) of 20 patients had multiple pulmonary nodules
(Fig. 1), ranging from 2.0 mm
to 4.0 cm (mean, 1.4 mm). The nodules were typically of homogeneous
soft-tissue attenuation (110/118 [93%]); however, in seven patients (35%), the
nodules exhibited central low attenuation suggestive of necrosis. In four
patients, the nodules were surrounded by a hazy rim or halo of infiltrate
(Figs. 1 and
2). All nodules were randomly
distributed throughout the lung allografts. Two (10%) of 20 cases had
multifocal alveolar infiltrates on CT (Fig.
3), and one patient (5%) had a combination of both nodules and
air-space infiltrates. Alternative or concomitant causes of infiltrates or
nodules, such as aspergillus or cytomegalovirus, were excluded by a
combination of negative biopsy findings for infection, clinical course, and
response of the lesions to immunomodulation.
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Extraparenchymal intrathoracic involvement by lymphoproliferative disorder was present in eight (28%) of 29 cases at CT and was associated with allograft involvement in seven of the eight cases. Hilar and mediastinal lymph node enlargement was noted in two patients. The nodes ranged from 5 mm to 4 cm in diameter (mean, 1.6 mm) (Fig. 4). One patient had associated parenchymal nodules, and the other had parenchymal infiltrates (Fig. 3). One of these two patients also had a small pericardial effusion. Axillary lymphadenopathy was not present in any patient. Five (25%) of 20 cases had small pleural effusions (Fig. 1), all occurring in association with parenchymal disease. One patient had esophageal involvement, which manifested as wall thickening and ulcerations on CT. This patient had no allograft disease.
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Extrathoracic involvement occurred in 13 cases, four of which also had thoracic involvement. Intraabdominal involvement by lymphoproliferative disorder was pathologically proven in 10 (34%) of 29 cases. Nodal disease was present in six cases and extranodal disease in nine cases. Most patients had more than one site of intraabdominal involvement. Specific sites included abdominal lymph nodes (n = 6), bowel (n = 5), liver (n = 4), kidney (n = 1), and spleen (n = 3). The nodes were typically of homogeneous soft-tissue attenuation and showed minimal to no visible enhancement. Nodal disease involved the mesenteric, retroperitoneal, porta hepatis, portacaval, and presacral nodes; the nodes ranged from 4 mm to 3.5 cm (Figs. 5 and 6). Bowel involvement appeared as wall thickening; the small bowel was involved in four patients (Fig. 7) and the cecum in one patient. Hepatic involvement most often, in three of four patients, appeared as focal low-attenuation masses; however, in one patient, diffuse hepatic infiltration, consisting of geographic or ill-defined regions of low attenuation, was detected. The focal hepatic lesions ranged from 1 to 4 cm in diameter (Fig. 8) and from one to more than 20 in number. Renal involvement appeared as a focal parenchymal mass. Splenic involvement produced diffuse enlargement without focal lesions. Two cases of extrathoracic posttransplantation lymphoproliferative disease involved the paranasal sinuses, and one case involved the brain.
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Posttransplantation lymphoproliferative disorder is thought to result from an Epstein-Barr virus–induced proliferation of B lymphocytes. This proliferation is normally opposed by a functioning T-cell system in immunocompetent patients [11, 12]. In contrast, in transplant recipients who are immunosuppressed, T lymphocyte function is reduced, which results in an unregulated B-cell proliferation referred to as posttransplantation lymphoproliferative disorder. Posttransplantation lymphoproliferative disorder represents a spectrum of lymphoid expansion that ranges from polyclonal hyperplasia to monoclonal malignant lymphoma [13–15]. Knowledge of the various clinical and imaging appearances of posttransplantation lymphoproliferative disorder is important because posttransplantation lymphoproliferative disorder is a substantial problem in children who have undergone transplantation and early diagnosis and treatment can affect outcome.
Posttransplantation lymphoproliferative disorder is estimated to occur in 2–3% of all solid-organ transplants including both children and adults [13, 15]. It can occur in any transplant setting, and the incidence varies with the type of graft [16–18]. In an earlier study of adult and pediatric lung allograft recipients that included 10 of the cases described in this study, posttransplantation lymphoproliferative disorder occurred in 7% of lung transplants (a 3.7% frequency in adults and an 8.3% frequency in children) [18]. The incidence of posttransplantation lymphoproliferative disorder was 11% for young lung transplant recipients. This incidence contrasts with the 16–19.5% incidence reported in two studies of pediatric heart–lung and lung transplant recipients from the University of Pittsburgh [4, 5]. The reason for the lower incidence in our study may be related to differences among the patient populations. We studied pediatric lung transplant recipients, whereas other investigators studied both young heart–lung recipients and young lung recipients and then analyzed them as a single group [4, 5]. Differences in immunosuppression regimens also may be an explanation for the incidence differences.
In our lung transplant recipients, posttransplantation lymphoproliferative disorder tended to occur within the first year after transplantation. The time interval from organ transplantation to diagnosis ranged from 7 weeks to 9 years 6 months in our pediatric population (median, 10 months), with approximately 60% of cases occurring within the first year after transplantation. These findings of an early onset are similar to those reported by Boyle et al. [4], Lim et al. [5], and Armitage et al. [19].
Involvement of the allograft by posttransplantation lymphoproliferative disorder is not rare, with the frequency varying by the type of graft. In a group of pediatric transplant recipients who underwent transplantations involving many organ systems, Donnelly et al. [20] reported that posttransplantation lymphoproliferative disorder tended to involve the allograft and the area around the transplant. Lim et al. [5] showed similar findings in their heart–lung and lung transplantation series. Our findings support the results of these groups. In our experience with young lung transplant recipients, the overall distribution of posttransplantation lymphoproliferative disorder in descending frequency was the thorax (69% [20/29 cases]), abdomen (34% [10/29]), head (7% [2/29]), and brain (3% [1/29]). The 69% frequency of intrathoracic involvement in this series is lower than the 89% (8/9 cases) frequency among young heart–lung and lung recipients reported by Lim et al. [5], but it is comparable with the 69% frequency reported by Pickhardt et al. [18].
The clinical manifestations of posttransplantation lymphoproliferative disorder are protean. Other studies have shown that affected patients can present with nonspecific constitutional symptoms of fever, malaise, weight loss, an infectious mononucleosis-like syndrome, and palpable lymphadenopathy [21]. Posttransplantation lymphoproliferative disorder can also be an incidental finding on routine surveillance imaging studies or at autopsy. Occasionally, children present with a fulminant course characterized by sepsis and multiorgan failure from disseminated abdominal and thoracic involvement by posttransplantation lymphoproliferative disorder [2]. In our experience, children with abdominal posttransplantation lymphoproliferative disorder were more symptomatic than those with thoracic posttransplantation lymphoproliferative disorder, which is similar to data reported in other investigations [22–24]. In our series, most children with abdominal posttransplantation lymphoproliferative disorder presented with fever and abdominal pain or abnormal results on liver function tests. Clinical presentations reported in other series include hepatomegaly; splenomegaly; and symptoms referable to solid- or hollow-organ involvement including gastrointestinal bleeding, intussusception, and diarrhea [23, 24].
Unlike abdominal posttransplantation lymphoproliferative disorder, pulmonary involvement was often asymptomatic (44% [7/16 cases]), and the diagnosis was suspected first from imaging findings. The reason for the lower frequency of symptoms in lung transplant recipients with intrathoracic involvement can be explained by the fact that CT was used as a surveillance tool in the chest but not in the abdomen, presumably enabling identification of preclinical disease.
We found that multiple new soft-tissue nodules in the allograft is the most common CT presentation of intrathoracic lymphoproliferative disorder after lung transplantation, occurring in 85% (17/20) of thoracic posttransplantation lymphoproliferative disorder cases. This frequency is slightly higher than that in adult lung transplant recipients (75% [6/8 patients]) reported by Rappaport et al. [25] and the 67% frequency reported among pediatric heart–lung recipients [5]. Our findings differ from those in an earlier series from our institution that evaluated the sensitivity of chest radiography for the diagnosis of posttransplantation lymphoproliferative disorder [14]. In that study, posttransplantation lymphoproliferative disorder in a small subset of children was more likely to manifest as alveolar infiltrates. The reason for the higher frequency of pulmonary nodules in our study is likely related to the use of CT in this study and its greater sensitivity for detecting parenchymal nodules. Pulmonary nodules tended to be randomly distributed throughout the allograft and were usually homogeneous and well-defined. Occasionally, they exhibited central necrosis or a rim of hazy infiltrate on CT. Alveolar infiltrates, hilar and mediastinal adenopathy, and pleural effusions were less common CT findings of posttransplantation lymphoproliferative disorder.
Distinguishing allograft involvement by posttransplantation lymphoproliferative disorder from infection can be difficult on the basis of clinical findings alone. Pulmonary posttransplantation lymphoproliferative disorder should be suspected when pulmonary infiltrates fail to respond to antibiotic therapy. In our experience, biopsy remains the only reliable method of distinguishing lymphoproliferative disorder from opportunistic infection. A high index of suspicion for the diagnosis of posttransplantation lymphoproliferative disorder is critical so that prompt and appropriate therapy can be instituted. Left untreated, posttransplantation lymphoproliferative disorder will invariably progress and ultimately become widespread.
We observed a relatively high rate of abdominal involvement by posttransplantation lymphoproliferative disorder. Abdominal involvement was present in 34% (10/29) of patients with lymphoproliferative disorder in our series, which is similar to the 33% frequency (3/9 cases) among the heart–lung and lung transplant recipients reported by Lim et al. [5]. The distribution of abdominal disease also did not significantly differ between the two populations. In both series, extranodal involvement was more common than nodal disease. In our experience with lung allograft patients, bowel involvement occurred in 50% (5/10 cases) of abdominal posttransplantation lymphoproliferative disorder cases and hepatic involvement occurred in 40% (4/10 cases). The mid and distal small bowel was the most frequently involved part of the gastrointestinal tract. In heart–lung and lung transplant recipients with abdominal posttransplantation lymphoproliferative disorder, alimentary tract and liver involvement were reported to occur in 50% and 27% of the cases, respectively. In that population, posttransplantation lymphoproliferative disorder tended to involve the stomach [5].
The mainstay of treatment for posttransplantation lymphoproliferative disorder has consisted of reduction or cessation of immunosuppression [2, 3, 9, 26]. A survival rate of 43% (6/14 patients) after immunosuppression reduction was reported for heart–lung transplantation in children [4]. Of the 26 patients with posttransplantation lymphoproliferative disorder in our series, 50% (13/26) were alive more than 2 years after posttransplantation lymphoproliferative disorder was diagnosed. No significant difference was noted in survival rates among patients with isolated intrathoracic disease (9/16 [56%]) and those with other presentations (3/10 [30%]) (p = 0.25). The relatively low survival rates may reflect the predominance of monomorphic features at histology. Prior studies have suggested that patients who have monomorphic features or lymphomatous findings at histology have a poorer outcome than those who do not [1, 27, 28].
In this series, we found that CT is a simple and reliable surveillance method for detecting lymphoproliferative disorder in lung transplant recipients. In our study, patients whose lesions were detected on CT were often asymptomatic; thus, the disease was detected earlier than it would have been if the CT examinations had been prompted by symptoms.
In summary, our preliminary results suggest that both thoracic and abdominal posttransplantation lymphoproliferative disorder are not rare in pediatric lung transplant recipients. This disease usually has its onset within the first year after transplantation, is commonly associated with a monomorphic appearance at histology, and results in substantial mortality rates. CT can reveal thoracic disease before it becomes symptomatic. Future investigations are warranted to determine the potential usefulness of increased surveillance with CT to identify patients with abdominal disease that may be early in the course of posttransplantation lymphoproliferative disorder.
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