This is the first reported case of lymphoproliferative disease presenting with adrenal insufficiency after liver transplantation.
A 38-year-old white man was admitted 8 months after transplantation for cryptogenic cirrhosis with fever (38-39°C), chills, cough, and dyspnea. His blood pressure was 100/70 mm Hg, there was pallor of the conjunctiva, and a lymph node was palpable in the left groin. Laboratory analyses revealed the following values: serum sodium concentration (112 mmol/L), potassium (5.4 mmol/L), hemoglobin (7.8 g/L), white blood cell count (7.7 x 109/L), glucose 3.9 (mmol/L), and mildly elevated liver functions. Abdominal ultrasound showed multiple hypoechoic solid-appearing lesions throughout the liver and spleen. Results of a biopsy specimen of the groin node confirmed polymorphic B-cell lymphoma. A negative Epstein-Barr virus screen before transplant became positive. The patient’s fever increased to 40°C. He subsequently developed sepsis and later, multiple organ failure. Autopsy confirmed extensive abdominal disease. The adrenal glands had been completely replaced by the tumor.
Primary Epstein-Barr virus infection is associated with posttransplant lymphoproliferative disease. Replacement of the adrenal glands with a tumor produces a clinical picture of adrenal insufficiency.
Key words : Liver transplantation, Epstein-Barr virus, B-cell lymphoma
Transplantation of solid organs owes its success to the development of effective immunosuppressive regimens. While rejection has become a rare cause of allograft loss, the incidence of opportunistic infections and malignancies has increased . Posttransplant lymphoproliferative disorder (PTLD) can be considered, for the most part, as an opportunistic infectious complication that arises after transplantation due mostly to Epstein-Barr virus (EBV) infection . PTLD can manifest as a spectrum of presentations varying from localized to disseminated involvement, nodal to extranodal disease, and it may include the allograft organ itself . The reported incidence varies between 1%-7.3% for liver transplant recipients . It is almost invariably of B-cell origin .
We present a case of a young man with an advanced malignant lymphoma less than 1 year after liver transplantation presenting with adrenal insufficiency due to bilateral adrenal infiltration with lymphoma cells. To our knowledge, this is the first case of PTLD presenting with adrenal insufficiency.
A 38-year-old white man was admitted to our hospital 8 months after transplantation for cryptogenic cirrhosis, with fever (38ºC-39ºC), chills, cough, and dyspnea. He was found to have left lung infiltrates consistent with pneumonia on chest roentgenogram, anemia, and hyponatremia. His past history included paranoid schizophrenia and seizure disorder. The patient’s immunosuppression regime included tacrolimus (5 mg b.i.d.) and prednisone (2.5 mg q.d.). He had received a 1 gram methylprednisone at induction, which was rapidly tapered to 20 mg q.d. prednisone after the first week. After the first 2 months, prednisone was tapered over 5 months to 2.5 mg q.d. He had no rejection episodes after transplantation and hence, had not received any steroid boluses or OKT3. Tacrolimus level was checked weekly for the first month, biweekly for the next 3 months, and then monthly until presentation. The mean tacrolimus level (calculated using the mean for each month) was 17.3 pg/mL (SD, 4.7) (Figure 1).
Physical examination revealed an obese gentleman, alert and oriented, in minimal distress. He was afebrile, with a pulse rate of 122 beats/minute, BP of 102/70 mm Hg, and a respiratory rate of 20/minute. Conjunctivae were pale, and the extremities showed minimal edema. The lungs had normal vesicular breath sounds bilaterally, and there was a II/VI ejection systolic murmur in the precordium. The abdomen was soft with hepatomegaly. Rectal examination was trace positive for occult blood. A nontender lymph node lump was palpable in the left groin, without evidence of any other lymphadenopathy.
Laboratory analyses revealed the following values: WBC, 7.7 x 109/L; Hb, 7.8 g/dL; hematocrit, 23 mm; platelet count, 357 x 109/L; serum sodium, 120 mmol/L; potassium, 5.4 mmol/L; bicarbonate, 24 mmol/L; and chloride, 83 mmol/L. Initial tacrolimus level was 39.2 pg/mL (normal range, 5-20 pg/mL) and fell rapidly after the drug was withheld. Serum creatinine was 1.6 µmol/L. Liver enzymes were mildly deranged (total bilirubin, 14.0 µmol/L; AST, 121 IU/L; ALT, 108 IU/L; alkaline phosphatase, 174 IU/L), which prompted an ultrasound that subsequently showed normal flows in the portal veins and hepatic artery. There were, however, multiple hypoechoic solid-appearing lesions throughout the liver as large as 2.5 cm and multiple tiny (< 1 cm) lesions throughout the spleen. There were also aggregates of enlarged lymph nodes in the right iliac region. There was a small amount of ascites and a small left pleural effusion. These findings were confirmed by computed tomography scan.
A biopsy specimen of the groin node was resected, the result of which demonstrated a large B-cell lymphoma with immunoblastic features. Flow cytometric analysis of the node showed no light chain restriction. These studies were consistent with polymorphic large cell lymphoma. Immunohistochemical staining for EBV latent membrane protein was positive (stained red), fulfilling the criteria for PTLD (Figure 2). With this diagnosis, his tacrolimus and prednisone were withheld, and he was started on intravenous ganciclovir.
The patient’s temperature rose to 40°C on the fifth day of admission, and he became hypotensive. He was transferred to the intensive care unit, and broad-spectrum antibiotics and fluconazole were started. He deteriorated further, developing a gastrointestinal bleed, worsening renal function, and he required ventilatory support. Addisonian crisis also was considered in view of hyponatremia, hyperkalemia, hypoglycemia, and acidosis. The following day, a radiograph of the chest showed a left lower lobe infiltrate and worsening renal failure, low platelet counts, and altered liver function tests. Bronchoalveolar lavage was negative for Pneumocystis carinii, and results of fungal cultures and viral isolation studies were negative. Blood culture grew coagulase-negative staphylococcus. Cytomegalovirus serology was reported as positive (IgG), and the EBV antibody was also positive at 1:160. EBV profile in the lymph node showed the viral capsid antigen IgG was 1:160, while viral capsid antigen IgM was less than 1:10, and the Epstein-Barr nuclear antigen was 1:640. Kappa Bence-Jones proteins also were reported in the urine. Clostridium difficile toxin was positive in stool. A Tc-99m–labeled red blood scan showed multiple points of intestinal hemorrhage. His condition continued to deteriorate, and he succumbed to multiple organ failure after 7 days in the intensive care unit.
Autopsy confirmed lymphomatous involvement of the liver, spleen, peripancreatic nodes, and small and large bowel, with areas of ulceration and hemorrhage. There was also involvement of the mesentery, omentum, and peritoneum. Multiple nodules were also found in the lungs and heart and in both kidneys. The adrenals were studded with lymphomatous nodules (Figure 3), showing large areas of necrosis and infiltration with lymphoma cells on histopathology.
Most cases of PTLD occur within a year of transplantation, and nearly all cases are of B-cell origin. PTLD is strongly associated with EBV infection, although there are exceptions that suggest alternate oncogenic pathways . After primary infection, usually in early childhood, the virus persists in the host for life in the B cells of the peripheral blood. In immunosuppressed patients, PTLD is believed to result from inadequate T-cell control over EBV-driven B-cell proliferation.
The risk factors for EBV-related PTLD include primary EBV infection (EBV- seronegative recipients, where the risk is 10- to 76-fold higher than it is in seropositive recipients), transmission of donor EBV in a seronegative recipient, and postoperative symptomatic CMV infection [6,7]. At least 2 out of 3 risk factors were present in this patient, as he had a positive EBV screen on this admission as well as CMV antigen positivity at the time of presentation. The donor EBV screen could not be determined and could have been the source of transmission of EBV.
Eagan and coworkers  have suggested that an absence of prospective HLA matching, leading to chronic antigenic stimulation (with resultant increased immunosuppression), may contribute to greater incidence of PTLD in lung transplant recipients. Whether this logic would apply to liver transplantation is not known. In the current case, the donor was a 30-year-old pregnant woman of the same blood group as the recipient. Younger donors tend to be more immunogenic and also, younger recipients mount a greater immune response. Hence, these patients are kept at a higher level of immune suppression. While tacrolimus levels around 15 pg/mL are well tolerated and contribute to lower incidences of acute rejection than do levels between 5 and 10 pg/mL, the higher mean tacrolimus level in our patient (17.3 pg/mL) is likely to have contributed to his disease and its rapid progression.
Malignant lymphoma after transplantation behaves in a particularly aggressive fashion, with a far greater incidence of extranodal presentation and invasion of the central nervous system, a lesser likelihood of response to chemotherapy, and poorer outcome . One radiologic study  reported involvement of the adrenal glands in 8% of patients having abdominal PTLD. However, adrenal insufficiency was not reported as a presentation. In our case, presentation of relative hypotension, hyponatremia, hyperkalemia, and relative hypoglycemia was likely caused by near total replacement of the adrenal glands. A low serum cortisol level would have confirmed the diagnosis; however, the patient had been given exogenous steroids at the referring hospital and subsequently, serum cortisol levels sent 24 hours after admission were noted to be at the upper limit of the normal range. The patient went on to develop bleeding from the gut and possibly sepsis, causing more severe hypotension and worsening renal failure, which proved to be terminal.
Treatment of PTLD remains controversial. Early stages may respond to reduction of immunosuppressive therapy and administration of antiviral agents and anti-CD-20 monoclonal antibodies, but advanced disease is often fatal despite additional aggressive radio/chemotherapy . In terms of aggressiveness, this patient’s disease would be classified as grade II on the scale of I-IV of the Society of Hemopathology, and revised by the European-American Lymphoma Group . The sheer bulk of disease at presentation dissuaded the oncologists against more-aggressive interventions.
PTLD is a known complication of transplantation and should be considered in the differential diagnosis of transplant patients presenting with a picture of adrenal insufficiency.
Volume : 3
Issue : 1
Pages : 341 - 348
Albert Einstein Medical Center, Departments of 1Surgery and 2Pathology, Philadelphia, PA
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Figure 1. Tacrolimus Levels after OLT (mean: 17.6, SD 4.7)
Figure 2. Non-Hodgkin’s large cell lymphoma, B-cell type. These cells were positive for intracellular EBV proteins (stained red).
Figure 3. Figure showing gross involvement of kidneys and adrenals with tumor deposits.