Posttransplant Lymphoproliferative Disorder Presenting as Multiple Cystic Lesions in a Renal Transplant Recipient

Authors


John Moir, john.moir@nuth.nhs.uk

Abstract

We report a case of a 67-year-old man who experienced allograft dysfunction following a renal transplantation from a donation after cardiac death. The postoperative course was initially complicated by episodes of E. coli urinary sepsis causing pyrexia and a raised creatinine level. Ultrasound scanning 5 weeks posttransplant revealed mild hydronephrosis with several parenchymal cystic areas measuring up to 2 cm with appearances suggestive of fungal balls. Aspirated fluid again grew Escherichia coli, and this was treated with the appropriate antimicrobial therapy. The patient continued to have episodes of culture-negative sepsis; therefore, a computed tomography scan was performed 6 months posttransplant, which revealed multiple lesions in the renal cortex as well as liver and spleen. Subsequent biopsy revealed an Epstein–Barr virus-driven lymphoproliferation consistent with a polymorphic posttransplantation lymphoproliferative disorder (PTLD). This rare case of PTLD presenting as multiple renal, hepatic and splenic lesions emphasizes the need for a high index of clinical suspicion for this condition. Abnormal para-renal allograft masses should be biopsied to allow swift and effective management of a disease that can disseminate and become significantly more challenging to manage.

Abbreviations: 
CHOP

Cyclophosphamide, Hydroxy-daunorubicin, Oncovin, Prednisolone

CMV

Cytomegalovirus

CT

computed tomography

EBV

Epstein–Barr virus

PCR

polymerase chain reaction

PTLD

posttransplant lymphoproliferative disorder

WHO

World Health Organization

Introduction

Posttransplant lymphoproliferative disorder (PTLD) is a severe and often fatal complication of solid-organ transplantation, affecting approximately 1% of renal allograft recipients (1). A strong association exists between PTLD and Epstein–Barr virus (EBV) infection of B-lymphocytes (2). We report a case of PTLD presenting as multiple cystic lesions in both renal allograft and liver in a patient 2 months posttransplantation. This is a rare mode of presentation and highlights the need for vigilance for this serious complication.

Case Report

A 67-year-old man with end-stage renal failure secondary to bladder outflow obstruction underwent renal transplantation from a donation after cardiac death. He had been maintained on hemodialysis for the preceding 2 years. The donated kidney was healthy, with a cold ischemic time of 12 h. Donor urine culture showed no abnormality. The donor was EBV negative, while the recipient was EBV positive. Surgery was performed without complication, with good initial perfusion seen, and a transplant ureteric stent was left in situ. HLA mismatching was 2:2:0 and a donor-positive, recipient-negative CMV mismatch was present; the patient was therefore treated with a 6-month postoperative prophylactic course of valgancyclovir. He received daclizumab (chimeric antihuman anti-CD25 monocolonal antibody) perioperatively. Initial maintenance immunosuppression consisted of mycophenolate mofetil and prednisolone.

Allograft function was slow to improve although he did not require further dialysis treatment; transplant biopsy on the 11th postoperative day revealed acute tubular necrosis, which was shown to be resolving when repeated 10 days later. Tacrolimus was introduced once his serum creatinine had fallen below 300 μmol/L.

His recovery was complicated by an Escherichia coli septicemia. Transplant ultrasound scanning showed no abnormalities, with good Doppler blood flows reported. There was no growth on culture of urine, wound swabs or from the central venous line. He responded, quickly, to treatment with intravenous aztreonam and was discharged on the 24th postoperative day with a serum creatinine of 280 μmol/L. His transplant ureteric stent was removed 5 weeks after discharge according to the unit protocol.

The patient was readmitted 1 week later with a pyrexia, transplant dysfunction (serum creatinine 400 μmol/L) and a growth of E. coli on urine culture. He was treated with a 7-day course of intravenous cefuroxime. Transplant ultrasound on the day of his readmission revealed a moderate hydronephrosis. At the time of percutaneous nephrostomy, later that day, multiple hypo-echoic areas were noted, suggestive of small abscess formation, with associated, generalized edema. A transplant ureteric stent was subsequently reinserted and his nephrostomy removed.

Follow-up ultrasound scanning on day 7 of his re-admission (Figure 1) showed several parenchymal cystic areas measuring up to 2 cm in diameter with appearances suggestive of fungal balls. Mild hydronephrosis remained with evidence of marked urothelial thickening. Doppler waveforms were normal and no liver lesions were seen. An ultrasound-guided cyst aspiration was therefore performed, with the fluid growing E. coli. A further course of intravenous cefuroxime was instituted but the patient remained pyrexial with repeat ultrasounds showed no significant change in the size or number of the transplant lesions. He improved enough clinically for discharge on the 11th day at which time he was afebrile.

Figure 1.

Ultrasound scan demonstrating several parenchymal cystic lesions (arrowed).

Unfortunately, the patient continued to suffer recurrent episodes of sepsis requiring further antibiotic therapy and hospital admission although no positive cultures were grown. At 6 months posttransplantation, a computerized tomography (CT) scan was performed (Figure 2), showing multiple cortical lesions and a prominent pelvicalyceal system. Multiple liver and splenic lesions were also seen, which were noted to be of higher density than the renal lesions. Around this time our patient suffered an unexpected gastrointestinal bleed although no culpable mass lesions could be identified on endoscopy or on the CT images.

Figure 2.

Computed tomography scan demonstrating multiple cortical lesions (i) and a prominent pelvicalyceal system (ii).

At 7 months posttransplantation, an ultrasound-guided transplant parenchymal biopsy was performed. Histological examination revealed a core of renal tissue with extensive necrosis. The viable parenchyma showed patchy infiltration by a mixed cellular infiltrate including small lymphocytes, plasma cells and scattered larger lymphoid cells (Figure 3A). The infiltrate included abundant CD20-positive B cells and lambda light chain restricted plasma cells. In situ hybridization studies for EBV showed numerous positive lymphoid cells (Figure 3B). The overall impression was therefore that of an EBV-driven lymphoproliferation consistent with a polymorphic PTLD. The necrotic tissue contained greater numbers of large CD20-positive cells, raising the possibility of a monomorphic PTLD (diffuse large B-cell lymphoma-like) but definitive diagnosis was not possible on the necrotic tissue.

Figure 3.

(A). Hematoxylin and eosin stained section (×400) showing renal transplant tissue infiltrated by a mixed lymphoid infiltrate, including plasma cells. (B) In situ hybridization for Epstein–Barr Virus (×400) showing abundant positive lymphoid cells (stained dark).

EBV PCR revealed 1.3 × 104 DNA copies/mL of blood. The patient demonstrated no neurological signs; hence no cerebrospinal fluid was obtained for investigation of CNS involvement. He was commenced on valacyclovir therapy and immunosuppressive treatment was reduced to minimal doses. Follow-up CT scanning showed a reduction in the size of the splenic lesion but not of the renal masses. The transplanted sister kidney showed no evidence of any similar lesions reducing the likelihood that this was donor-driven disease. Renal transplant function remained stable.

Ten months following transplant, the patient was admitted with confusion and evidence of posterior fossa compromise. Biopsy of an abnormal area in the right cerebellar hemisphere and vermis at MRI scanning revealed an EBV-positive, diffuse large B-cell lymphoma consistent with a monomorphic, posttransplant lymphoproliferative disorder although the procedure was complicated by a fatal bleed.

Discussion

Lymphoma is one of a number of neoplasms that occur more frequently in solid-organ transplant recipients. First described in a renal transplant recipient by Doak et al. in the late 1960s (3), the term “posttransplant lymphoproliferative disorder” only came into use in 1984 (4).

PTLD can involve any abdominal visceral organ although the transplanted kidney is the most common primary site (47–71%) (1,5) with presenting features including renal dysfunction, fever, and hydronephrosis secondary to ureteric obstruction. The next most common extranodal site is the gastrointestinal tract (13). Other sites PTLD has been reported to affect include the sino-nasal cavity, central nervous system, skin (14) and lymph nodes in isolation (12).

A strong association with the presence of the EBV is apparent with the combination of a sero-positive donor and previously sero-negative recipient carrying a 10- to 50-fold increased risk (2,9,10). An association with heavier overall levels of immunosuppression (although not with any specific agent) (7,8) might explain an increased risk in the first postoperative year although the condition can occur at any time following transplantation. Other possible risk factors include a CMV mismatch (11) and increased HLA mismatching (7).

Histological evaluation and classification (see WHO guidelines—Table 1) are essential, with other investigative modalities (imaging, endoscopy) being employed to target tissue for biopsy and assess spread. Blood should be sent for EBV PCR. Positron emission tomography scanning may be particularly useful in detecting extranodal disease (15,16) although PTLD is otherwise extremely difficult to diagnose prior to the development of any mass lesions.

Table 1.  Categories of PTLD according to WHO classification (6)
  1. 1Some mass-like lesions in the posttransplant setting may have the morphologic appearance of florid follicular hyperplasia or other marked but non-IM-like lymphoid hyperplasias.

  2. 2ICD-O codes for these lesions are the same as those for the respective lymphoid or plasmacytic neoplasm.

  3. 3Indolent small B-cell lymphomas arising in transplant recipients are not included among the PTLD.

Early lesions1
 Plasmacytic hyperplasia
 Infectious mononucleosis-like lesion
Polymorphic PTLD
Monomorphic PTLD2
(classify according to lymphoma they resemble)
 B-cell neoplasms
   Diffuse large B-cell lymphoma
   Burkitt lymphoma
   Plasma cell myeloma
   Plasmacytoma-like lesion
   Other3
 T-cell neoplasms
   Peripheral T-cell lymphoma, NOS
   Hepatosplenic T-cell lymphoma
   Other3
Classical Hodgkin lymphoma-type PTLD

Treatment is based on reducing the level of immunosuppression (18) and antiviral therapy, such as acyclovir, gancyclovir and valacyclovir. These latter agents, although frequently used to limit viral replication, are of debatable benefit as they do not affect the latent phase of EBV infection with which PTLD is associated (19). If the patient is found to have CD20-positive PTLD, then first-line monoclonal antibody therapy with, for instance, rituximab is often used (20). Polychemotherapy, such as the CHOP regime, is now only considered if other treatment options have failed.

Reported outcomes vary greatly with complete remission rates ranging from 28% to 75%, and 1-year survival from 44% to 73% (21–23). Negative prognostic indicators include poor performance status, monomorphic disease and graft involvement (24).

The presentation of PTLD with cystic lesions, as in our case, is rare. In the context of renal transplantation, Jukic et al. reported a case of PTLD arising in the wall of a lymphocoele surrounding a renal allograft (17). There was an accompanying history of B-symptoms and deterioration of graft function. The only other case in the literature was reported by Khan et al., concerning PTLD presenting as a symptomatic lymphocele 12 years after deceased donor renal transplantation (25).

To our knowledge, our case is the first reported presentation of PTLD with multiple cystic lesions, not only affecting the graft, itself, but also involving the liver and spleen. It is noteworthy that our initial assumption of microbiological disease may have been perpetuated by bacterial growths from the initial cyst aspirate-–only a failure to resolve despite intensive antibiotic therapy and the finding of the development of more widespread disease prompted histological evaluation. However, there is no doubt a septic process was occurring; a positive blood culture with no evidence of urinary infection indicated parenchymal involvement, and this was further supported by the biopsy showing extensive parenchymal necrosis, which is not a typical feature of PTLD. Nonetheless, an earlier appreciation of the possibility of PTLD as explaining this atypical presentation may have led to a more prompt tissue diagnosis.

In conclusion, we describe a case of PTLD presenting with multiple cystic lesions. A high index of suspicion for PTLD should be maintained when imaging patients posttransplantation and, if abnormal renal masses are found, early consideration for biopsy should be given to allow swift and effective management of a disease that can disseminate and become significantly more challenging to manage.

Disclosure

The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.

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