First published online March 28, 2007
British Journal of Radiology (2007) 80, 337-346
© 2007 British Institute of Radiology
doi: 10.1259/bjr/63272556
Post-transplant lymphoproliferative disease in liver transplantation
M S Dhillon, MRCS, FRCR1,
J K Rai, MRCP1,
B K Gunson, BA2,
S Olliff, MRCP, FRCP1 and
J Olliff, MRCP, FRCP1
1 Radiology Department, 2 Liver Unit, University Hospital Birmingham, Birmingham, UK
Correspondence: Dr Manpreet Dhillon, Radiology Department, University Hospital Birmingham (QE), Vincent Drive, Edgbaston, Birmingham B12 2TH, UK. E-mail: mandhon{at}hotmail.com
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Abstract
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Post-transplant lymphoproliferative disease (PTLD) is a well recognized complication of solid organ transplantation and therapeutic immunosuppression, first reported in 1968. PTLD incorporates a spectrum of abnormalities ranging from a benign infectious mononucleosis-like illness to non-Hodgkin's lymphoma with nodal and extranodal site involvement. The first liver transplant was performed at our institution in January 1982. This retrospective study examined the incidence of PTLD, reason for the original transplants, presenting symptoms, radiological findings, immunosuppression regimens and outcomes of these patients. From a total of 2005 adult liver transplants, 23 patients (1.1%) were identified with PTLD. The average age of these patients at the time of transplant was 46.5 years, with a ratio of female-to-male of 14:9. Indication for transplant ranged from primary biliary cirrhosis (eight patients) to epitheloid haemangioendothelioma (one patient). The average time interval between transplant and diagnosis of PTLD was 50 months. Imaging abnormalities identified included generalized lymphadenopathy, liver and portal masses, splenic enlargement, bowel, eye, cerebral and neck involvement; and in two patients, no radiological abnormality. The most common histological findings ranged from B-cell non-Hodgkin's lymphoma (five patients) to early PTLD in one patient. Our rate of PTLD is lower compared with published literature and demonstrates a much longer time interval from transplant to occurrence of PTLD than previously appreciated. This could be secondary to a low immunosuppression therapy followed at our institution. From a few months to several years after liver transplantation, the radiologist needs to be alert to the possibility of PTLD and thorough imaging is required to detect the wide variety of potential presentations.
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Introduction
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A large part of the success of solid organ transplantation is due to immunosuppressive therapy preventing rejection of the allograft. Cyclosporin, one of the most common agents, acts by T-lymphocyte suppression and this and other agents have made rejection a rare cause of allograft loss [1]. The "trade off" for this non-specific immunosuppression is the increased risk of the patient contracting opportunistic infections (i.e. viral, fungal and protozoal organisms) and increased risk of malignancies [2]. In 1968, lymphoid tumours were first described in transplant patients with a subgroup of these termed "pseudolymphomas" in recognition of their ability to undergo regression after reduction of immunosuppression [3–5]. "post-transplant lymphoproliferative disease" (PTLD) is now a well recognized complication of solid organ transplantation and therapeutic immunosuppression. PTLD incorporates a spectrum of abnormalities ranging from a benign infectious mononucleosis-like illness to non-Hodgkin's lymphoma with nodal and extranodal site involvement [3, 6–10]. There is also a strong association identified between PTLD and the Epstein–Barr virus (EBV) with up to 80% of patients affected at the time of diagnosis [6, 10–13]. The overall incidence of PTLD after liver transplantation has been quoted as 2–8.4% [7, 10, 14–17]. The first liver transplant was performed at our institution in January 1982. This study examined the incidence of PTLD, indication for the original transplants, presenting symptoms, radiological findings and outcomes of these patients.
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Methods and materials
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A database survey of adult liver transplants from January 1982 to December 2003 was performed and any patients with PTLD identified. Patients' notes, radiological images and pathological reports were retrospectively examined. The patients' age, gender, indication for liver transplant, time interval to diagnosis of PTLD and survival were recorded. Radiological imaging was reviewed and where none was available old reports were used. Pathology reports confirmed final diagnosis and EBV status. Available literature is reviewed and comparison made with our study group.
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Results
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From a total of 1755 adult liver transplants in addition to 250 re-grafts, 23 patients (1.1%) were identified as having PTLD. The average age of these patients at the time of transplant was 46.5 years (range 26–67 years), with a ratio of female-to-male patients of 14:9. The average median age for the whole transplant population is 50 years (range 16–73 years) with a female-to-male ratio of 13:12. Owing to the countrywide referral for transplantation and long study period, imaging was available for only 15 patients. The rest were analysed from the patient's notes and reports.
Our current guidelines for investigation of patients suspected of having PTLD are included (Table 1
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Table 1. Current guidelines for investigation of patients suspected of having post-transplant lymphoproliferative disease
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Indications for liver transplantation ranged from primary biliary cirrhosis (eight patients) to epitheloid haemangioendothelioma (one patient) (Table 2).
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Table 2. Indication for original transplant(number of patients) and comparison with incidence of disease prevalence in whole of transplant cohort
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The average time interval between the transplant and the diagnosis of PTLD was 50 months (range 5–140 months). Early onset disease, defined as diagnosis within 1 year post-transplantation, was identified in four patients. Two deaths occurred within the early onset group at 1 month and 14 months, respectively, after the diagnosis of PTLD. Late onset PTLD was identified in 19 cases of our 23. Twelve deaths occurred within this group, ranging from within 1 month to 26 months (mean 7.5 months). Of the 14 deaths, 11 patients died within 1 year of diagnosis of the disease. The association between age and time to development of lymphoma was examined by Spearman's rank correlation test (Figure 1). No statistically significant correlations were found either overall or in individual disease groups (p>0.5) – however, the number of patients in each group is extremely small.
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Figure 1. Comparison of age at transplantationvs time interval to PTLD vs primary pathology (Spearman's rank correlation test – p>0.5). PBC, primary biliary cirrhosis; Hep C, hepatitis C cirrhosis; Hep B, hepatitis B cirrhosis; NonA/B, non A/B hepatitis cirrhosis; Scl Ch, sclerosing cholangitis.
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The clinical presentation of most of the patients was non-specific including general malaise, lymphadenopathy, fevers, anaemia, or worsening liver function tests. Portal masses as expected presented relatively late as obstructive jaundice. Small bowel obstruction was the presenting feature of a patient with lymphoma of the terminal ileum. Lymphoma within the cerebrum had signs of focal neurology and raised intracranial pressure.
Imaging abnormalities identified included generalized lymphadenopathy, liver and portal masses, splenic enlargement, bowel, cerebral and neck involvement (Table 3; Figures 2–6). 10 patients were found to have more than one organ and/or area affected. Abdominal abnormalities were seen in 16 patients. Seven patients had isolated extraabdominal disease of which two had systemic bone marrow disease in isolation, i.e. no imaging abnormality.
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Table 3. Age, gender, primary diagnosis, time to diagnosis of post-transplant lymphoproliferative disease (PTLD) from transplantation, Epstein–Barr virus (EBV) status and imaging abnormalities of the individual cases in our series
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Figure 2. Allograft involvement– 6 years post-transplant for primary biliary cirrhosis. (a) Abnormal ultrasound of liver allograft identified multiple hypoechoic parenchymal lesions. (b) CT confirmed multiple low attenuation lesions within the liver and the presence of ascites. (c) Concurrent pleural effusions and lung collapse noted. Final diagnosis – B-cell non-Hodgkin's lymphoma; the patient is still alive 2 years post-chemotherapy.
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Figure 3. Portal mass– patient presented with obstructive jaundice 5 months post-transplant for primary biliary cirrhosis. (a) Ultrasound identified the presence of a portal hilar mass confirmed on CT. (b) CT – note the distortion of the portal vein (arrow) and the intrahepatic duct dilatation (broken arrow). Final diagnosis – non-Hodgkin's lymphoma. Tumour responded after several cycles of chemotherapy and one of radiotherapy. The patient is alive 5 years post-treatment.
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Figure 4. Portal stricture– patient presented 11 months post-transplant for hepatitis C cirrhosis. (a) CT identifies low attenuation area around porta hepatitis causing stricturing. (b) Confirmed at endoscopic retrograde cholangiopancreatography. (c) Second CT image post stent placement after 1 month; notice the increase in size of the mass. Final diagnosis: B-cell lymphoma; treated with re-transplantation. The patient is still alive 4 years later.
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Figure 5. Small bowel involvement: barium follow-through for a patient 3 years post-transplant for hepatitis C cirrhosis presenting with small bowel obstruction with an extensive stricture within the terminal ileum which was resected. Final diagnosis: Burkitt's lymphoma; treated further with chemotherapy. Patient is still alive 9 years post-treatment.
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Figure 6. Cerebral mass 5.5 years post-transplant for hepatitis C cirrhosis, patient presented with increasing confusion and signs of raised intracranial pressure. CT head identified a deep right frontal space-occupying lesion demonstrating marked surrounding oedema. The tumour bled post biopsy (arrow) and the patient died within 2 weeks of the biopsy. Final diagnosis was lymphoma.
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Lymphadenopathy was identified in 11 patients with a total of 13 areas involved (i.e. abdominal, thoracic and cervical regions). Two patients demonstrated lymphadenopathy in two or more areas.
The most common abdominal abnormalities seen were liver masses (seven patients – including portal masses), followed by abdominal lymphadenopathy (five patients), splenic abnormalities (nine patients) and bowel lymphoma in three patients. Splenic abnormalities presented in the form of generalized splenomegaly (six patients) or focal lesions (three patients). Ascites was present in three patients. The liver masses were single or multifocal. Portal masses measured up to several centimetres in length, hypoechoic on ultrasound, with resultant biliary obstruction and dilatation. Bowel lymphoma was imaged by barium follow-through in one patient after presenting with symptoms of small bowel obstruction. In the other two patients it was an incidental finding on abdominal CT of large bowel thickening and one of these also had pre-existing ulcerative colitis.
Extraabdominal findings included cervical and chest hilar lymphadenopathy. In addition two patients had pleural effusions and another two had cerebral and spinal involvement.
Pathological review of specimens revealed that the most common lymphoma type was of the B-cell variety in at least 13 patients ranging from B-cell non-Hodgkin's lymphoma (5 patients) to one with early PTLD (Table 4). Nine patients expressed the EBV antigen (39%).
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Table 4. Final pathology of post-transplant lymphoproliferative disease (PTLD) (number of patients). The first three groups are all B-cell related, but in the remaining groups the pathology reports did not specify cell lineage, although in practice most are B-cell related
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Discussion
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Our incidence of PTLD for liver transplantation at 1.1% is lower than the published rates of 2–8.4% [7, 10, 14–17]. This may be may partially explained by our adult group compared with paediatric liver transplant recipients with PTLD rates of up to 7.3–8.4% [7, 17]. Some of the other studies combined children and adults with a higher overall incidence [10, 18]. Children tend to have a higher incidence of PTLD in other solid organ transplants. One explanation for this may be the higher incidence of EBV infections among paediatric liver transplant recipients.
The mean time to onset of PTLD of 50 months is much longer than the reported intervals of 7–14 months [10, 16]. In one of the largest studies of 4000 liver transplant patients over a 25 year period, there was an incidence of 4.3% (170 patients) with a mean onset at 10 months. When this was re-analysed looking only at the adults, the interval increased to 15 months [18]. It is possible that the lower rate and longer time interval to development of PTLD in our study reflects a lower level of immunosuppressive therapy compared with other groups. Unfortunately, consistent accurate documentation of the immunosuppression used in our patients could not be obtained. However, at our institution, we follow a recognized lower immunosuppression strategy whereby monoclonal antibodies are not used and withdrawal from steroids occurs as soon as possible [19].
The development of PTLD has a strong association with EBV, although the incidence in this study group at 39% was lower than in others with quoted rates up to 80%. This virus is known to cause infectious mononucleosis in the general population and also has a strong association with the development of Burkitt's lymphoma. EBV infection induces a diffuse intranodal and extranodal polymorphic B-cell proliferation, which is held in check by T-cell immunosuppression. In the immunosuppressed liver this initially leads to polyclonal and then to a monoclonal proliferation which can eventually result in non-Hodgkin's lymphoma, the most severe end of the PTLD spectrum [3, 6, 8, 9, 13, 17]. The final histology in one case in our series was "early PTLD", a condition seen more frequently in the paediatric population reflecting polyclonal B-cell hyperplasia – the more benign end of the PTLD spectrum [18]. Most cases of PTLD are believed to begin as a benign lymphoproliferative process from which the more aggressive forms of PTLD develop. Therefore, PTLD generally is of B-cell lymphocyte origin, though up to 11% may arise from T-cell lymphocytes [20].
EBV titres have been shown to be sensitive to adjustments of immunosuppressive therapy, and it has been suggested that immunosuppressive therapy could be reduced when a rising titre is observed, thus pre-empting the development of PTLD [21]. Studies examining this have concentrated on the paediatric population where it is thought that EBV exposure occurs at the time of transplantation so that PTLD is most frequently observed during the first post-transplant year [21]. However, in adults, there is often pre-transplant EBV immunity and this is reflected in the later development of PTLD. 4 out of our study group of 23 patients developed PTLD during the first 12 months after transplantation [22]. It is therefore unlikely that EBV titres during the early period will identify patients who will develop PTLD and for this reason EBV titres are not performed routinely in our adult practice [23].
Mortality due to PTLD ranges from 22% to 70% [6, 14, 16, 17] and the mortality rate in our study is comparable. Of 14 who died, 11 deaths occurred within 1 year of diagnosis of PTLD. The mortality rate within the early onset group, that is PTLD occurring within 1 year of transplantation, was two of four (50%). The relationship of early onset disease to mortality has been variable with some suggesting that early onset disease may have a better prognosis than late onset disease [19], whereas other studies suggest the converse [6, 10, 17, 24, 25]. Our results would suggest a tendency for a higher rate of mortality within the late onset group compared with the early onset group (63% vs 50%).
The single most frequent imaging finding was lymphadenopathy seen in 11 (48%) patients. Two of these cases had more than two areas affected (i.e. abdominal, thoracic or cervical) with the abdomen, as expected, being the most common region involved. Previous studies have reported lymphadenopathy between 55% and 74% [3, 10, 15, 17]. Pickhardt and Siegel reported a lower incidence of 34%, but only concentrated on intraabdominal abnormalities [26]. Of our patients with intraabdominal pathology lymphadenopathy was seen in 31% (5 of 16) – a similar figure to this latter study.
Overall, as in previous studies abdominal findings were the most common manifestation [10], with isolated extraabdominal disease occurring in only eight (35%) patients. After splenic abnormalities, PTLD within the liver allograft was the next most common abnormality (six patients). Affinity for allograft involvement by PTLD has been described in solid organ transplant series [6], with the liver affected in 6 of 10 adult and in 12 of 25 paediatric patients, respectively [16, 17]. Other series' of 4 and 5 adult patients have identified no allograft disease [3, 27] and a more recent study by Wu et al [10] only found allograft disease in 1 of 20 patients. Our rate of allograft disease lies within the range between these two groups. Portal masses have been reported as hypoechoic lesions on ultrasound demonstrating low attenuation masses on CT [10, 28] – a finding repeated in this study. These have sometimes initially been treated as abscesses until the diagnosis of PTLD was made [10, 28]. These lesions often present with mass effect and intrahepatic bile duct dilatation [10, 28–30].
PTLD affecting the bowel was found in three of our cases, two within the large bowel and one within the terminal ileum. Other studies have reported higher rates of 50% and 30% and have found it to be associated with a high perforation rate [3, 15]. A more recent study quoted an incidence of 15% for bowel PTLD which is similar to our result (13%) [10]. No patient in the current series suffered bowel perforation. Two out of three patients had large bowel pathology and one had pre-existing inflammatory bowel disease [10]. The latter raises the possibility of an association between inflammatory bowel disease and PTLD accelerated by immunosuppression. After transplantation the presence of gastrointestinal disturbances should alert the clinician to the potential diagnosis of PTLD as well as the more common complications of infection and inflammation.
PTLD is a relatively uncommon but important complication of solid organ transplants. Patients often present with vague symptoms. It has a high mortality in our series (61%) as in previous reports (22–70%) [3, 14, 16, 17]. The radiological abnormalities are diverse, with a longer time interval from the time of transplant to occurrence of PTLD than previously reported. The increased time interval and lower rate of PTLD compared with previous studies probably reflects the lower level of immunosuppression followed at our institution. Unfortunately our study lacks accurate detail of immunosuppressive regimens of the individual patients, but we do have a recognized low immunosuppression policy [19]. Obviously some of the imaging findings described in our series such as generalized splenomegaly, pleural effusions and lymphadenopathy are not specific for PTLD. However, in the context of a post-transplantation patient where there is clinical deterioration, it is not unreasonable to consider it and investigate the patient thoroughly; most of our patients had an imaging abnormality. Hence the radiologist needs to be alert to the possibility of the development and diverse nature of PTLD from a few months to several years after liver transplantation. When there is any clinical suspicion, cross-sectional imaging of the neck, chest, abdomen and pelvis (and head when focal neurology is present) should be performed to detect the wide range of potential abnormalities.
Received for publication February 7, 2005.
Revision received July 25, 2006.
Accepted for publication August 21, 2006.
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Abstract
Introduction
