1. Top of page
  2. Abstract
  5. Acknowledgements

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.


  1. Top of page
  2. Abstract
  5. Acknowledgements

Patient 1

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).

thumbnail image

Figure 1. Polymorphic variant of posttransplantation lymphoproliferative disease in the colon of patient 1. Hematoxylin and eosin.

Download figure to PowerPoint

Table 1. Immunosuppression Regimens
DatePatient 1*Trough levels (ng/ml)DatePatient 2Trough levels (ng/ml)
Dose mg/dayDose mg/day
  1. Abbreviations: MMF, mycophenolate mofetil (MMF), CsA, Cyclosporine A (CsA). *Patient 1 received Basilixmab induction before transplantation.

IV 2002151000123.8VII 200115 9 10.3
VII 2002101000139.3X 20017.5 5 19
IX 20021010001312.6XI 20017.5 2  
I 2003510001314XI 20017.51000STOP200127
IV 2003510001110.8XII 20017.51000 225117
VI 2003510001011.5II 20027.5STOP 200169
IX 20035STOP10 VII 20027.5  12586
XI 20035 99.3I 20037.5  125109
I 20045 88.2VII 20037.5  125155
VI 20045 8 IX 20037.5  125114
IX 20045 812.4XII 20037.5  125120
I 20055 69.8VI 20045  10086
VII 20055 411.5II 20055  10087
X 20055 48XII 20055  10098
XI 20065 58.3XII 20062.5  100103

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.

thumbnail image

Figure 2. Polymorphic variant of posttransplantation lymphoproliferative disease in the right tonsil of patient 1. Mixed lymphoid infiltrate can be seen under the normal epithelium. Hematoxylin and eosin.

Download figure to PowerPoint

thumbnail image

Figure 3. Plasmacytic hyperplasia in the left tonsil of patient 1. Brown cells are positive for Epstein-Barr virus latent membrane protein 1 immunostaining.

Download figure to PowerPoint

Patient 2

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.

thumbnail image

Figure 4. Diffuse large B cell lymphoma in the right tonsil of patient 2 immunostained for CD20.

Download figure to PowerPoint

Table 2. Serological Markers of EBV Infection in Tonsillar PTLD in Patient 2
  • Abbreviations: EBV, Epstein-Barr virus; Ig, immunoglobulin; PTLD, posttransplantation lymphoproliferative disease; EBNA, Epstein-Barr nuclear antigen; VCA, viral capsid antigen.

  • *

    More than 20 AU/mL (positive).

  • Diagnosis of PTLD, reduction of cyclosporine, and initiation of ganciclovir.

September 11, 2003123.9121.543.1
December 6, 2006119.518939.8


  1. Top of page
  2. Abstract
  5. Acknowledgements

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.


  1. Top of page
  2. Abstract
  5. Acknowledgements

We thank Krzysztof Król for professional assistance in editing the figures.


  1. Top of page
  2. Abstract
  5. Acknowledgements
  • 1
    Mamzer-Bruneel MF, Bourquelot P, Hermine O, Legendre C, Kreis H. Treatment and prognosis of post-transplant lymphoproliferative disease. Ann Transplant 1997; 2: 4248.
  • 2
    Boubenider S, Hiesse C, Goupy C, Kriaa F, Marchand S, Charpentier B. Incidence and consequences of posttransplantation lymphoproliferative disorders. J Nephrol 1997; 10: 136145.
  • 3
    Swinnen LJ. Diagnosis and treatment of transplant-related lymphoma. Ann Oncol 2000; 11: 4548.
  • 4
    Young L, Alfieri C, Hennessy K, Evans H, O'Hara C, Anderson KC, et al. Expression of Epstein-Barr virus transformation-associated genes in tissues of patients with EBV lymphoproliferative disease. N Engl J Med 1989; 321: 10801085.
  • 5
    Yang J, Tao Q, Flinn IW, Murray PG, Post LE, Ma H, et al. Characterization of Epstein-Barr virus–infected B cells in patients with posttransplantation lymphoproliferative disease: disappearance after rituximab therapy does not predict clinical response. Blood 2000; 96: 40554063.
  • 6
    Opelz G, Dohler B. Lymphomas after solid organ transplantation: a collaborative transplant study report. Am J Transplant 2004; 4: 222230.
  • 7
    Aucejo F, Rofaiel G, Miller C. Who is at risk for post-transplant lymphoproliferative disorders (PTLD) after liver transplantation? J Hepatol 2006; 44: 1923.
  • 8
    Langrehr JM, Glanemann M, Guckelberger O, Klupp J, Neumann U, Machens C, et al. A randomized, placebo-controlled trial with anti–interleukin-2 receptor antibody for immunosuppression induction therapy after liver transplantation. Clin Transpl 1998; 12: 303312.
  • 9
    Dufour JF, Fey MF. What is the current treatment of PTLD after liver transplantation? J Hepatol 2006; 44: 2326.
  • 10
    Kremers WK, Devarbhavi HC, Wiesner RH, Kroma RAF, Macona WR, Habermann TM. Post-transplant lymphoproliferative disorders following liver transplantation: incidence, risk factors and survival. Am J Transpl 2006; 6: 10171024.
  • 11
    Leblond V, Davi F, Charlotte F, Dorent R, Bitker MO, Sutton L, et al. Posttransplant lymphoproliferative disorders not associated with Epstein-Barr virus: a distinct entity? J Clin Oncol 1998; 16: 20522059.
  • 12
    Leblond V, Choquet S. Lymphoproliferative disorders after liver transplantation. J Hepatol 2004; 40: 728735.
  • 13
    Loevner LA, Karpati RL, Kumar P, Yousem DM, Hsu W, Montone KT. Posttransplantation lymphoproliferative disorder of the head and neck: imaging features in seven adults. Radiology 2000; 216: 363269.
  • 14
    Wu L, Rappaport DC, Hanbidge A, Merchant N, Shepherd FA, Greig PG. Lymphoproliferative disorders after liver transplantation: imaging features. Abdom Imaging 2001; 26: 200206.
  • 15
    Shapiro NL, Strocker AM, Bhattacharyya N. Risk factors for adenotonsillar hypertrophy in children following solid organ transplantation. Int J Pediatr Otorhinolaryngol. 2003; 67: 151155.
  • 16
    De Diego JI, Prim MP, Hardisson D, Verdaguer JM, Jara P. Post-transplant lymphoproliferative disease in tonsils of children with liver transplantation. Int J Pediatr Otorhinolaryngol 2001; 27;58: 113118.
  • 17
    Koh BY, Rosenthal P, Medeiros LJ, Osorio RW, Roberts JP, Ascher NL, et al. Posttransplantation lymphoproliferative disorders in pediatric patients undergoing liver transplantation. Arch Pathol Lab Med 2001; 125: 337343.
  • 18
    Tsai DE, Hardy CL, Tomaszewski JE, Kotloff RM, Oltoff KM, Somer BG, et al. Reduction in immunosuppression as initial therapy for posttransplant lymphoproliferative disorder: analysis of prognostic variables and long-term follow-up of 42 adult patients. Transplantation 2001; 71: 10761088.
  • 19
    Rowe DT, Webber S, Schauer EM, Reyes J, Green M. Epstein-Barr virus load monitoring: its role in the prevention and management of post-transplant lymphoproliferative disease. Transpl Infect Dis 2001; 3: 7987.
  • 20
    Foroncewicz B, Mucha K, Usiekniewicz J, Chmura A, Kryst P, Soldacki D, Paczek L. Posttransplant lymphoproliferative disorder of the lung in a renal transplant recipient treated successfully with surgery. Transplant Proc 2006; 38: 173176.
  • 21
    Choquet S, Leblond V, Herbrecht R, Socie G, Stoppa AM, Vandenberghe P, et al. Efficacy and safety of rituximab in B-cell post-transplantation lymphoproliferative disorders: results of a prospective multicenter phase 2 study. Blood 2006; 107: 30533057.
  • 22
    Oertel SH, Verschuuren E, Reinke P, Zeidler K, Papp-Vary M, Babel N, et al. Effect of anti-CD 20 antibody rituximab in patients with post-transplant lymphoproliferative disorder (PTLD). Am J Transplant 2005; 5: 29012906.
  • 23
    Nouwen J, Smets F, Rombaux P, Hamoir M, Sokal EM. Acute tonsillitis as the first manifestation of post-transplant lymphoproliferative disorder. Ann Otol Rhinol Laryngol 2002; 111: 165168.
  • 24
    Kuppers R. B cells under influence: transformation of B cells by Epstein-Barr virus. Nat Rev Immunol 2003; 3: 801812.
  • 25
    Lazda VA. Evaluation of Epstein-Barr virus (EBV) antibody screening of organ donors for allocation of organs to EBV serostatus matched recipients. Transplant Proc 2006; 38: 34043405.
  • 26
    Shaknovich R, Basso K, Bhagat G, Mansukhani M, Hatzivassiliou G, Murty VV, et al. Identification of rare Epstein-Barr virus infected memory B cells and plasma cells in non-monomorphic post-transplant lymphoproliferative disorders and the signature of viral signaling. Haematologica 2006; 91: 13131320.
  • 27
    Scheenstra R, Verschuuren EA, de Haan A, Slooff MJ, The TH, Bijleveld CM, et al. The value of prospective monitoring of Epstein-Barr virus DNA in blood samples of pediatric liver transplant recipients. Transpl Infect Dis 2004; 6: 1522.
  • 28
    Wagner HJ, Wessel M, Jabs W, Smets F, Fischer L, Offner G, et al. Patients 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: 10121019.
  • 29
    Tursi A, Brandimarte G, Torello M. Disappearance of gastric mucosa-associated lymphoid tissue in hepatitis C virus–positive patients after anti–hepatitis C virus therapy. J Clin Gastroenterol 2004; 38: 360363.
  • 30
    Shpilberg O, Wilson J, Whiteside TL, Herberman RB. Pre-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.