O'Connor, Judith A.; Cogley, Catherine; Burton, Mark*; Lancaster-Weiss, Kristen*; Cordle, Richard A.
San Antonio Military Pediatric Center, San Antonio, Texas; Department of Pathology, Wilford Hall Medical Center, San Antonio, Texas, U.S.A.
Received May 24, 1999;
revised September 1, 1999, and March 6 and July 10, 2000; accepted August 4, 2000.
Address correspondence and reprint requests to Judith A. O'Connor, Dept of Pediatrics/MMNP, Wilford Hall Medical Center, 2200 Bergquist Drive, Suite 1, Lackland AFB, TX 78236-5300, U.S.A. (e-mail: Judith.Oconnor@59mdw.whmc.af.mil).
The views expressed in this article are those of the authors and do not reflect the official policy of the Department of Defense or any other Department of the United States government.
Background: posttransplantation lymphoproliferative disorder (PTLD) may manifest a variety of nonspecific symptoms and must be suspected in the patient who undergoes solid organ transplantation. Common sites of occurrence include the gastrointestinal tract, the central nervous system, and lymphoid tissue of the oral pharynx, mediastinum, and mesentery. The large incidence of gastrointestinal involvement provides an opportunity for endoscopic diagnosis. This is the description of a characteristic endoscopic finding in patients who have undergone liver transplantation who are under evaluation for suspected PTLD.
Methods: During a 2-year period, 27 liver transplantations were performed in 24 pediatric patients. Fourteen patients underwent endoscopic evaluation. Indications for endoscopy included abdominal pain, vomiting, hematemesis, irritability, growth failure, anemia, occult blood loss, and suspected PTLD. Biopsy specimens were obtained from any endoscopically detected abnormality and from the duodenum, gastric antrum, esophagus, terminal ileum, cecum, and rectum. Specimens with suspected PTLD were evaluated with Epstein–Barr virus latent membrane stain.
Results: Six patients were found to have a characteristic lesion, which was raised, rubbery, and erythematous, with a central ulceration. Lesions were singular or multiple and ranged from 5 to 15 mm in diameter. Microscopic evaluation revealed a monotonous proliferation of lymphocytes. All specimens were positive for Epstein–Barr virus latent membrane protein stain. Stains for cytomegalovirus were negative. Biopsy specimens from the eight patients without identified characteristic lesions were negative for PTLD.
Conclusions: Panendoscopy is a useful tool for the diagnosis and treatment of gastrointestinal PTLD. Endoscopy is easily accomplished, may provide an instantaneous result if the characteristic lesion is identified, and provides tissue for disease classification. Patients with unexplained gastrointestinal signs or symptoms should undergo panendoscopy for suspected PTLD.
Posttransplantation lymphoproliferative disorder (PTLD) is responsible for significant morbidity and mortality in transplant recipients. It represents a spectrum of abnormalities ranging from benign polyclonal B-cell hyperplasia to monoclonal malignant lymphoma. This disorder is due to an abnormal host response to infection with Epstein–Barr virus (EBV) and is related to immunosuppressive regimens required for graft survival in patients who undergo transplantation (1–3).
Early diagnosis is essential for successful treatment of PTLD. Unfortunately, PTLD may have a variety of nonspecific signs and symptoms, making diagnosis difficult. Diagnosis is dependent on high clinical suspicion and confirmed with histology. Recent data suggesting a high incidence of gastrointestinal involvement highlights the gastrointestinal tract as a reservoir for PTLD (4). In this study, we observed the efficacy of endoscopy in the diagnosis and management of PTLD.
SUBJECTS AND METHODS
All patients evaluated were from one solid organ transplant center. Twenty-four children underwent 27 orthotopic liver transplantations during a 2-year period. The age of the patients at transplantation ranged from 6 months to 17 years. The primary indication for liver transplantation was biliary atresia, accounting for 60% of the patient population. Cystic fibrosis, tyrosinemia, α1-antitrypsin deficiency, congenital hepatic fibrosis, autoimmune hepatitis, primary sclerosing cholangitis, Crigler–Najjar syndrome, Wilson's disease, fulminate hepatic failure, and hemangioendothelioma of the liver each accounted for a single patient.
Immunosuppression induction was achieved with a uniform regimen of prednisone, 6-mercaptopurine (6-MP), and oral tacrolimus. Prednisone (3.0 mg/kg per day) was rapidly tapered for 5 days to 0.4 mg/kg per day and then slowly tapered for the next 6 months to 0.05 mg/kg per day. The initial dose of 6-MP was 1 mg/kg per day, which was tapered and discontinued by 6 months after transplantation. A mean serum drug level for tacrolimus of 18 ng/mL was maintained during the first 2 weeks and then tapered to a mean level of 10 ng/mL by 1 month after transplantation. Acute rejection was treated with methylprednisolone bursts. One patient received OKT3. Six months after transplantation, maintenance immunosuppression consisted of oral prednisone (0.05 mg/kg day) and tacrolimus at a mean serum drug level of 10 ng/mL. Prednisone was discontinued 1 year after transplantation. Patients who were Epstein–Barr virus (EBV)–positive or EBV-negative and received an organ from an EBV-positive donor were maintained indefinitely by oral acyclovir (10 mg/kg) given four times a day. Immunoprophylaxis was not routinely used for cytomegalovirus (CMV). Acute CMV infection was treated with intravenous ganciclovir (5 mg/kg) twice daily, until viremia resolved.
Fourteen patients underwent endoscopic evaluation. Indications for endoscopy included abdominal pain, diarrhea, vomiting, hematemesis, irritability, growth failure, anemia, occult blood loss, and suspected PTLD. Thirteen patients underwent both an esophagogastroduodenoscopy (EGD) and colonoscopy with retrograde ileoscopy. One child with hematemesis who was medically fragile underwent EGD alone. Biopsy specimens were obtained from any endoscopic abnormality and from the duodenum, gastric antrum, and esophagus during an EGD and the terminal ileum, cecum, and rectum during colonoscopy. Biopsy specimens were stained with hematoxylin and eosin for microscopic evaluation. Special staining for CMV was performed on all specimens. Specimens suggestive of PTLD were evaluated for the presence of EBV with latent membrane protein stain. Specimens with positive latent membrane stains were confirmed for the presence of EBV with in situ EBV early RNA (EBER)-1 RNA hybridization. All specimens were reviewed by the department of pathology.
Routine surveillance of bone marrow or liver tissue for the presence of PTLD was not used. Two patients identified with gastrointestinal PTLD underwent percutaneous liver biopsy due to elevated serum aminotransferases or evidence of synthetic dysfunction. These tissue specimens revealed no pathologic diagnosis and were negative for EBV by both latent membrane stain and EBER hybridization.
Six patients were found to have a characteristic lesion that was located predominately in the colon or stomach. The lesion was raised, rubbery, and erythematous, with a central ulceration (Fig. 1). The lesions were singular or multiple and ranged from 5 to 15 mm in diameter. These lesions were distinct in appearance from nodular lymphoid hyperplasia. Microscopic examination showed a diffuse infiltrate of lymphoid cells with displacement of normal underlying structures (Fig. 2). The infiltrate was composed of B-lymphocytes with a spectrum of maturation, including immunoblasts, plasma cells, and small-and medium-sized lymphocytes. The polymorphic nature of the process was appreciated on higher magnification (Fig 3). Mitotic activity was present. Immunohistochemical analysis for EBV latent membrane protein showed positive in some of the lymphoid cells of all specimens (Fig 4). Stains for CMV were negative in specimens positive for PTLD.
Biopsy specimens from the eight patients without identified characteristic lesions were negative for PTLD. Four patients had CMV gastritis-enteritis, two had nonspecific gastritis, one had esophagitis, and one had Helicobacter pylori– associated gastritis. Vomiting or diarrhea was a universal symptom. Four patients, three with CMV and one with H. pylori, were Hemoccult positive (SmithKline Diagnostics, San Jose, CA, U.S.A.).
In the six patients in whom gastrointestinal PTLD was ultimately diagnosed, two had nonbilious, nonbloody emesis, one with an infectious mononucleosis-like illness and hematemesis, and one with irritability and growth failure. Two children were evaluated for anemia, occult blood loss, and serologic EBV reactivation as measured by EBV anti-immunoglobulin (Ig)M. All patients were Hemoccult positive.
The incidence of PTLD in pediatric patients is many times higher than in the adult transplantation population (5). The risk for PTLD correlates with primary EBV infection. Pediatric patients are more likely to be EBV naive before organ transplantation than the adult population. PTLD can also develop after reactivation of a latent infection, most commonly during the first posttransplantation year or during episodes of graft rejection, when immunosuppression is intensified. T-cell immunosuppressive agents inhibit the natural host response to eliminate latent-phase EBV-transformed lymphocytes. Left unabated, these cells can proliferate into a spectrum of abnormalities ranging from benign polyclonal B-cell hyperplasia to monoclonal malignant lymphoma with chromosomal abnormalities and gene rearrangement. The risk of PTLD is increased with more potent immunosuppressive regimens. Agents such as OKT3 and antithymocyte globulin have been associated with an increased incidence of PTLD (5). The use of tacrolimus instead of cyclosporine has been implicated in an increased incidence of PTLD, but this is controversial (5–7). It may represent a cumulative effect of the dose and duration of the immunosuppressive regimen used to prevent graft rejection. Therapy is intended to decrease T-cell immunosuppression to allow the natural host elimination of transformed lymphocytes.
Prognosis and treatment vary depending on the classification of PTLD. Tissue specimens are required for diagnosis and classification of PTLD. Benign B-cell hyperplasia has responded to immunosuppression reduction and anti-viral agents such as acyclovir or ganciclovir (3). Patients with polyclonal lymphoma have a less favorable prognosis but have responded to complete removal of immunosuppression in addition to ganciclovir, and in some case α-interferon (8,9). Unfortunately, immunosuppression reduction or withdrawal often precipitates graft rejection. Monoclonal PTLD is an extremely aggressive lymphoma with a uniformly poor prognosis. Antiviral drugs are not indicated, as the tumors are not dependent on viral replication. Some cases have responded to chemotherapy, surgical resection, and/or radiation. Ongoing experimental studies are being conducted using infusions of T lymphocytes and anti-B-cell antibody (10).
Posttransplantation lymphoproliferative disorder (PTLD) may present with a variety of nonspecific signs and symptoms (1–3). Pharyngitis, fevers, diarrhea, irritability, and growth failure or weight loss all suggest the diagnosis. Lymphoproliferative disorder can masquerade as acute graft rejection or sepsis. In our patient population there was no reliable sign or symptom that distinguished PTLD from other gastrointestinal disorders. Although all patients with PTLD had occult blood loss and anemia, these signs were also present in 50% of patients without PTLD. Younes et al. (4) recently reported that hypoalbuminemia, gastrointestinal bleeding, and weight loss were the most specific findings in gastrointestinal PTLD. In their study, using this criteria for gastrointestinal PTLD, all patients had positive histology. We report two asymptomatic patients with characteristic endoscopic PTLD lesions who were evaluated based solely on laboratory abnormalities of EBV-IgM seroconversion, occult blood loss, and anemia. The subtlety of this indication emphasizes the often elusive nature of early disease recognition.
Endoscopic recognition of gastrointestinal involvement in solid organ PTLD has been described (1,4,11). The preponderance of gut-associated lymphoid tissue (GALT) appears to be an obvious and easily accessible source for histology specimens. The results of Younes et al. (4) and our observations suggest panendoscopy may be a useful diagnostic tool for PTLD, even in the absence of definitive gastrointestinal symptoms. Endoscopy is easily accomplished, may provide instantaneous results if the characteristic lesion is identified, and has the added benefit of providing tissue for disease classification. All pediatric patients who undergo transplantation and have unexplained gastrointestinal signs or symptoms meet standard criteria for endoscopy and should be evaluated. Such patients with minimal or absent gastrointestinal symptoms and weight loss, hypoalbuminemia, anemia, EBV seroconversion, or gastrointestinal bleeding should undergo panendoscopy for suspected PTLD. Once PTLD is identified, endoscopy can be used to guide therapy. Persistence of PTLD lesions despite moderate reduction of immunosuppressive agents mandates cessation of immunosuppression. Resolution of the lesions allows for immunosuppression intensification in the face of organ rejection. Identification of monoclonal lesions suggests a need for chemotherapy.
Lymphoproliferative disorder remains one of the most feared complications after solid organ transplantation. The high mortality rate mandates early recognition. A high clinical suspicion is required for the diagnosis of PTLD. Panendoscopy has been shown to be a useful tool for the diagnosis and treatment of gastrointestinal PTLD. Additionally, endoscopy may be beneficial in monitoring the response to therapy.
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