The first 2 authors contributed equally to this article.
Tonsil enlargement after liver transplantation in adults—reason enough for tonsillectomy? Two cases of tonsillar posttransplantation lymphoproliferative disease
Article first published online: 30 MAY 2007
Copyright © 2007 American Association for the Study of Liver Diseases
Volume 13, Issue 6, pages 918–923, June 2007
How to Cite
Mucha, K., Foroncewicz, B., Niemczyk, K., Ziarkiewicz-Wróblewska, B., Stanisławek-Sut, O., Zieniewicz, K., Krawczyk, M. and Pączek, L. (2007), Tonsil enlargement after liver transplantation in adults—reason enough for tonsillectomy? Two cases of tonsillar posttransplantation lymphoproliferative disease. Liver Transpl, 13: 918–923. doi: 10.1002/lt.21177
- Issue published online: 30 MAY 2007
- Article first published online: 30 MAY 2007
- Manuscript Accepted: 1 MAR 2007
- Manuscript Received: 16 DEC 2006
Posttransplantation lymphoproliferative disease (PTLD) is a well-known complication of solid organ and bone marrow transplantation. It is agreed that the main causes of PTLD are chronic infection with Epstein-Barr virus (EBV); the intensity, rather then the type, of immunosuppression used; and underlying recipient disease. Hepatitis C virus (HCV) and cytomegalovirus, as cofactors of EBV infection, have been suggested to increase the risk of PTLD. Use of calcineurin inhibitors, anti-CD3 monoclonal antibody (OKT3), and antithymocyte globulin may increase the risk of PTLD. On the other hand, mycophenolate mofetil, sirolimus, and the anti–interleukin-2 receptor monoclonal antibodies Daclizumab and basiliximab have not been demonstrated to increase the risk of PTLD. The incidence of PTLD after liver transplantation (LT) is estimated to be 1.5-3%, but a tonsillar location is extremely rare in adults. Thus, little is known about the best diagnostic tools for and treatment by LT recipients with tonsillar PTLD. Here, we report 2 cases of adult LT recipients with tonsillar PTLD. Tonsillectomy was used as a diagnostic tool and treatment option and resulted in complete remission for >2 years. Considering the high mortality and diagnostic difficulties of PTLD, together with the relatively low risks of tonsillectomy, we recommend tonsillectomy for treating tonsil enlargement of unknown cause and suspected PTLD in LT recipients. A larger series of patients and prospective studies comparing different treatment options will be needed to substantiate our recommendation. Liver Transpl 13:918–923, 2007. © 2007 AASLD.
Posttransplantation lymphoproliferative disease (PTLD) comprises a spectrum of clinically relevant lymphatic diseases that have resulted from the use of highly potent immunosuppressive drugs and progress in transplantation medicine. The reported incidence of PTLD is 1-20%1–3 and depends on the type of organ transplanted; the intensity of the immunosuppression; the occurrence of viral infections, particularly Epstein-Barr virus (EBV); underlying disease; and age. It has also been suggested that hepatitis C virus (HCV) and/or cytomegalovirus, as cofactors of EBV infection, may increase the risk of PTLD.4, 5 It was demonstrated that tacrolimus, cyclosporine A (CsA), anti-CD3 monoclonal antibody (OKT3), and antithymocyte globulin increased the risk of PTLD.6, 7 In liver recipients assessed during a 5-year period, the risk of lymphoma was comparable for patients treated with FK506 or CsA.6 The use of other immunosuppressants, such as mycophenolate mofetil (MMF), sirolimus, and anti–interleukin-2 receptor monoclonal antibodies was not directly linked to an increased risk of PTLD.7, 8 It is generally agreed that the intensity, rather then the type, of immunosuppression is a critical factor in PTLD development. The incidence of PTLD after LT is estimated to be 1.5-3% in the adult population.7 The majority of PTLD cases, especially those that occur early after liver transplantation (LT), are of B cell origin and are associated with EBV. The reason for this is that in immunosuppressed patients, EBV-infected B cells cannot be controlled by EBV-specific cytotoxic T cells.9 In several studies, it has been demonstrated that EBV-negative PTLD tends to occur later after transplantation and result in a worse prognosis compared with early-onset PTLD, which is observed during the first 18 months after LT and is predominantly EBV positive.6, 10–12
According to the Collaborative Transplant Study (CTS) database of approximately 200,000 organ transplant recipients, PTLD lesions occur primarily in the allografted organ, gastrointestinal tract, central nervous system, heart, lung, or lymph nodes, depending on the type of transplantation. In liver recipients, lymphomas localize preferentially in the graft.6 PTLD in the head and neck region of adult recipients of solid organ transplants is unusual.13, 14 In a series of 7 patients with histopathologically proven PTLD of the Waldeyer (lymphoid) ring or cervical lymph nodes, PTLD was observed in the unilateral oropharyngeal tonsil in 2 patients and in the bilateral oropharyngeal tonsils in 1 patient. Moreover, only 3 of these 7 PTLD patients were LT recipients.13 In another study of 20 adult patients diagnosed with PTLD, only one case of lymphadenopathy in the neck, without tonsil involvement, was observed.14 Nearly all reports of tonsillar PTLD are in children, in whom the Waldeyer ring is a common site of PTLD.15–17
Management of liver recipient PTLD patients is challenging. Once PTLD is diagnosed, the strategy is to take advantage of the special pathogenesis of lymphomas in immunocompromised hosts.18 Therefore, the first aim should be to minimize immunosuppression. Even though it carries the risk of graft rejection, restoring recipient immunity remains the most pathophysiologically sound option for controlling EBV-driven lymphoproliferation.9, 18, 19 Depending on the location and the aggressiveness of lymphoproliferation, conventional chemotherapy, surgery, and radiotherapy may be helpful.20 Recently, the mouse-human chimeric anti-CD20 monoclonal antibody rituximab was reported to be safe and effective in PTLD patients who did not respond to immunosuppression reduction.21, 22 The role of antiviral therapy remains controversial because of an increasing frequency of EBV-negative PTLD in adult LT recipients. This is probably a consequence of a long follow-up, and therefore of an increase in the incidence of late PTLD. Moreover, the number of EBV-negative PTLD is likely to increase in the future.10, 11
Because the tonsillar location of PTLD in adult LT recipients is rare, little is known about the best diagnostic tools and treatment choices. Here, we report 2 cases of LT recipients with tonsillar PTLD diagnoses on the basis of histopathology and immunostaining with commercially available antibodies against CD20, CD3, CD5, CD10, VS38c, CD15, immunoglobulin (Ig) kappa, Ig lambda, BCL2, BCL6, EBV latent membrane protein 1 (LMP1), and Ki67 (Dako, Glostrup, Denmark). In this report, we point out the essential role of prompt tonsillectomy in diagnosing and treating tonsillar PTLD after LT.
A 35-year-old woman who received a liver allograft was diagnosed with EBV-associated tonsillar PTLD. In April 2002, at the age of 31 years, she received a cadaveric LT to treat autoimmunologic hepatitis-related cirrhosis. Her immunosuppression consisted of glucocorticoids, MMF, tacrolimus, and basiliximab induction before transplantation. Recurrent diarrhea and Clostridium difficile infection, which began in December 2002, were the major medical problems and one of the reasons for MMF withdrawal in September 2003 and a colonoscopy in January 2004. Infiltrate containing variable-sized lymphoid cells of B (CD20+) and T (CD3) phenotypes, centrocyte-like cells, immunoblasts, and polyclonal lymphocytes (VS38c, Ig kappa, and Ig lambda positive) were observed in the colon biopsy sample. Mitotic activity was high (Ki67 = 50%). EBV LMP1 was not immunohistochemically detected. The polymorphic form of PTLD was diagnosed (Fig. 1). Immunosuppression consisted of 5 mg prednisone and tacrolimus with trough concentrations of 8.2 ng/mL (Table 1).
|Date||Patient 1*||Trough levels (ng/ml)||Date||Patient 2||Trough levels (ng/ml)|
|Dose mg/day||Dose mg/day|
|IV 2002||15||1000||12||3.8||VII 2001||15||9||10.3|
|VII 2002||10||1000||13||9.3||X 2001||7.5||5||19|
|IX 2002||10||1000||13||12.6||XI 2001||7.5||2|
|I 2003||5||1000||13||14||XI 2001||7.5||1000||STOP||200||127|
|IV 2003||5||1000||11||10.8||XII 2001||7.5||1000||225||117|
|VI 2003||5||1000||10||11.5||II 2002||7.5||STOP||200||169|
|IX 2003||5||STOP||10||VII 2002||7.5||125||86|
|XI 2003||5||9||9.3||I 2003||7.5||125||109|
|I 2004||5||8||8.2||VII 2003||7.5||125||155|
|VI 2004||5||8||IX 2003||7.5||125||114|
|IX 2004||5||8||12.4||XII 2003||7.5||125||120|
|I 2005||5||6||9.8||VI 2004||5||100||86|
|VII 2005||5||4||11.5||II 2005||5||100||87|
|X 2005||5||4||8||XII 2005||5||100||98|
|XI 2006||5||5||8.3||XII 2006||2.5||100||103|
At the beginning of May 2004, the patient had a sore throat, difficulty swallowing, and normal body temperature. Examination revealed 2 asymmetrically enlarged tonsils with no debris on their surface. The larger right tonsil reached the median line. The patient had no lymphadenopathy. Five days later, she underwent tonsillectomy. We did not change the immunosuppression protocol.
The diagnosis of PTLD in both tonsils was established by postoperative histopathology. The left tonsil showed a typical plasmacytic hyperplasia with preserved normal architecture (Fig. 2). We observed a large number of polyclonal plasmocytes (VS38c, Ig lambda, Ig kappa). The more advanced polymorphic variant of PTLD was diagnosed in the right tonsil. In PTLD, the infiltrate consisted of various cells, including small- and medium-sized lymphoid cells with irregular nuclei, centrocyte-like cells, immunoblasts, and plasmocytes. Immunohistochemistry revealed EBV LMP1 staining (Fig. 3). Because of the prohibitive cost of the procedure, EBV serostatus is not routinely checked in our adult patients before LT. Therefore, neither donor nor recipient pretransplant EBV serostatus was established. Control colonoscopy performed 4 months after tonsillectomy and again in 2005 revealed no signs of lymphoproliferative disorder. The patient has remained in complete remission for over 2 years. In September 2005, she delivered a healthy child.
A 51-year-old man with liver failure due to HCV infection received a LT in June 2001. Immunosuppression after the LT consisted of corticosteroids and tacrolimus. Five months after transplantation, the patient was switched from tacrolimus to CsA because he developed diabetes mellitus. Beginning in July 2003, the patient complained of difficulty swallowing. Two months later, a cyst in the lower lobe of the right tonsil was diagnosed, and a right tonsillectomy was performed.
Histopathological findings varied in different parts of the tonsil. In addition to areas of typical polymorphic PTLD, areas of diffuse large B cell lymphoma were observed (CD20+, BCL6+, BCL2+, CD10−, CD3−) (Fig. 4). The mitotic index in these areas was 60%. Tissue was negative for EBV LMP1, but infection was serologically confirmed. Subsequent investigations revealed no other PTLD sites. Immunosuppressive therapy was maintained minimally, and on the basis of positive serological EBV markers (Table 2), the patient was treated with ganciclovir. Like patient 1, pretransplant EBV serostatus was not established in the donor or the recipient. The patient has remained in complete remission for >3 years.
|Date||IgG EBNA*||IgG VCA*||IgM VCA*|
|September 11, 2003†||123.9||121.5||43.1|
|December 6, 2006||119.5||189||39.8|
We present 2 cases of PTLD located in the tonsils of adult LT recipients. Symptoms of tonsillar PTLD are usually nonspecific. Affected children can present with ear, nose, and throat manifestations, fever, malaise, and mononucleosis-like symptoms after LT.23 There is little information about adult PTLD symptoms. Both of our patients had difficulty swallowing and enlarged tonsils, symptoms that are typically related to tonsillitis rather than a lymphoproliferative disease.23 Therefore, diagnosis of tonsillar PTLD should be based on an objective examination that includes histopathology. Taking into account the difficulties in diagnosis, the still-high PTLD mortality, and the relatively low risks of tonsillectomy, we recommend tonsillectomy for enlargement of the tonsils of unknown cause in adult LT recipients.
It is well known that chronic immunosuppression is a risk factor for a variety of neoplastic diseases, including PTLD. Data from the CTS database indicated that the risk of malignant lymphomas in LT recipients over a 5-year period was 29.9-fold higher than that in a matched nontransplant population.6 Immunosuppression in patient 1 consisted of glucocorticoids, MMF, tacrolimus, and basiliximab. In patient 2, only glucocorticoids and CsA were provided. The drug protocols were tailored to underlying autoimmunologic hepatitis in patient 1 and HCV in patient 2. Prospective comparison of the lymphomagenic potential of CsA and FK506 in pivotal trials in liver and renal transplantation did not demonstrate differences after 3 or 5 years of follow-up.6 On the other hand, a retrospective study in pediatric LT recipients revealed a 5-fold increase in lymphoma in primary FK506-treated patients compared with a primary CsA-treated group.6 It was suggested that the intensity, rather than the type, of immunosuppression was a key determinant of lymphoma development.6 In the present report, both patients developed PTLD regardless of the immunosuppression treatment. In accordance with standard treatment protocols, immunosuppression was maintained at levels as low as possible once PTLD was diagnosed. Immunosuppression regimens, including trough levels, are presented in Table 1.
It is believed that EBV is a key factor in PTLD pathophysiology, especially in EBV-negative recipients, for whom the incidence of PTLD was reported to be as high as 24 times greater than for EBV-positive patients.7 The 2 patients we present in this report were seropositive for EBV, although in patient 2, a sample from the affected tonsil did not stain positive for EBV LMP1. Because EBV infects >90% of the population, and because of the prohibitive costs of testing, we did not establish pretransplant EBV serostatus in our patients.24 It has previously been reported that as many as 94% of organ donors are EBV IgG positive.25
Immunohistochemical staining for EBV LMP1 was not consistent across organ samples from patient 1. Staining was positive in the tonsils, but no staining was observed in the colon biopsy sample. EBV results also varied in patient 2. For instance, the patient was seropositive for EBV, but the tonsil samples did not stain positive for EBV LMP1. A possible explanation for the lack of EBV LMP1 staining in the colon of patient 1 is that in the polymorphic form of PTLD, only a small portion of cells express LMP1.26 Second, the tissue sample was small and damaged. Traces of reaction product could be seen, but it was not enough to establish positive staining. In patient 2, the size and quality of the material was satisfactory, but it did not stain positive for EBV LMP1. It may be that the tissue was improperly fixed, although the tissue stained positive for other antigens, and reactions were repeated many times in different buffers and concentrations.
The usefulness of monitoring EBV virus loads in LT recipients has not been clearly demonstrated. Some studies indicate that high EBV DNA copy number detected by polymerase chain reaction in peripheral blood is associated with a higher risk of PTLD, and others do not.27 It is generally agreed that a high EBV load does not predict PTLD, except for primary EBV infections. Virus load must be considered with other symptoms and PTLD risk factors, including primary EBV and HCV infection and/or intensity of immunosuppression.7, 27 Additionally, it should be remembered that unlike the case for children, EBV load monitoring in adults was reported to be associated with high specificity and low sensitivity.28 Therefore, in patient 2, we introduced ganciclovir therapy, although we did not establish the EBV load at the time of diagnosis. From a practical point of view, it is important to establish EBV load in order to determine whether to treat the patient with antiviral agents. The number of EBV-negative adult LT recipients has increased.10, 11 Available data suggest that despite the important role EBV plays in PTLD, antiviral drugs are limited in their treatment capabilities. For instance, acyclovir and ganciclovir are ineffective in preventing persistence of the episomal form of EBV associated with latency. They may be better as prophylactic treatments.9
It is important to emphasize the role of HCV in PTLD because it is the leading cause of end-stage liver disease in a large portion of the population and was the reason for transplantation in patient 2. HCV has a 10.5% frequency in LT PTLD patients. Although EBV and HCV infection appear to influence the risk of PTLD, it is unclear how they do so. HCV is an RNA virus with no DNA replication intermediates. Therefore, unlike EBV, HCV cannot integrate into the human genome. It is believed that chronic HCV infection may lead to the development of PTLD by lymphoid stimulation and clonal expansion of B cells.7 It deserves mention that treatment targeted to HCV can modulate PTLD in that cellular environment.29 Admittedly, other PTLD risk factors may be of more importance than HCV. For example, autoimmune disorders, such as autoimmune hepatitis or primary biliary cirrhosis, may predispose patients to PTLD.30 Autoimmunologic hepatitis was diagnosed in patient 1, who presented at the age of 16 years, and we assume it was a relevant risk factor.
Finally, we stress that prompt tonsillectomy, performed on the bases of a clinical suspicion of PTLD and combined with immunosuppression drug reduction, may be critical for successful treatment of tonsillar PTLD. Of course, conventional chemotherapy and radiotherapy may also be of great help, depending on the localization and the aggressiveness of the disease.
We thank Krzysztof Król for professional assistance in editing the figures.
- 28Patients at risk for development of posttransplant lymphoproliferative disorder: plasma versus peripheral blood mononuclear cells as material for quantification of Epstein-Barr viral load by using real-time quantitative polymerase chain reaction. Transplantation 2001; 72: 1012–1019., , , , , , et al.
- 30Pre-transplant immunological profile and risk factor analysis of post-transplant lymphoproliferative disease development: the results of a nested matched case-control study. The University of Pittsburgh PTLD Study Group. Leuk Lymphoma 1999; 36: 109., , , .