B-Cell lymphoproliferative disorder not associated with Epstein-Barr Virus in a child with relapsed acute lymphoblastic leukemia

Lymphoproliferative disorder (LPD) is described in only a few children receiving chemotherapy for cancer. In all of them, an association between LPD and EBV (Epstein-Barr Virus) was found. We report on a patient who developed LPD not associated with EBV while receiving chemotherapy for relapsed acute lymphoblastic leukemia (ALL). Despite discontinuation of chemotherapy, administration of intravenous immunoglobulins and surgery the patient died. Growing experience with this disorder may allow better treatment options in the future and will show whether LPD not associated with EBV requires different therapeutic strategies.     

Central nervous system EBV lymphoproliferative disorder in a patient with rhabdomyosarcoma

Epstein–Barr virus associated lymphoproliferative disorder (EBV‐LPD) occurs in patients with immunodeficiency, but it has not been well described in patients who have received chemotherapy for solid tumors. We describe a child with rhabdomyosarcoma who developed isolated central nervous system (CNS) EBV‐LPD during combination chemotherapy with vincristine, actinomycin D and cyclophosphamide. The patient was treated with high‐dose methotrexate (HD‐MTX) for CNS EBV‐LPD and then treated with rituximab in addition to HD‐MTX because of the emergence of LPD in the liver. I.v. rituximab combined with HD‐MTX might be effective therapy for CNS EBV‐LPD.     

Facial manifestations of Epstein–Barr virus‐related lymphoproliferative disease in childhood acute lymphoblastic leukemia in remission: Two atypical presentations

Epstein–Barr virus‐related lymphoproliferative disease (EBV‐LPD) rarely occurs in patients with acute lymphoblastic leukemia (ALL), who have not received hematopoietic transplantation. We describe EBV‐LPD manifesting as facial lesions in two children with ALL in remission. One patient was a 16‐year‐old male with T‐cell ALL with an EBV‐positive angiocentric polymorphous lip lesion presenting as right‐sided facial swelling. The other patient was a 12‐year‐old male with B‐cell ALL with an EBV‐positive polymorphous lymphoplasmacytic infiltrate presenting as bilateral dacryoadenitis. Neither patient had known primary immunodeficiencies. Both cases improved with immunosuppressant de‐escalation. These cases suggest that immunosuppression induced by maintenance chemotherapy is sufficient to promote EBV‐LPD.     

Epstein-Barr Virus Polymerase Chain Reaction and Serology in Pediatric Post-Transplant Lymphoproliferative Disorder: Three-Year Experience

To assess whether the semiquantitative peripheral blood Epstein-Barr virus (EBV) polymerase chain reaction (PCR) test correlates with post-transplant lymphoproliferative disorder (LPD), we compiled the results of the test done over a 3-year period ending July 1997. Six hundred seventy-six tests were done on 185 patients. Four hundred-thirty tests (63%) were negative, 167 (25%) were weak positive, 67 (10%) were moderate positive, and 12 (2%) were strong positive. Twelve of the patients developed a lymphoproliferative disorder (LPD) during this time. The EBV PCR tests proximate to the diagnosis of LPD in the 12 patients with EBV-positive LPD were 6 strong positive, 5 moderate positive, 1 weak positive. No patient with LPD had a negative result at diagnosis. Stated another way, 6/12 (50%) of strong-positive PCR tests, 5/67 (7%) moderate-positive tests, and 1/167 (.6%) of weak-positive tests correlated with LPD. Serologic evaluation for EBV done on 7 patients at the time of LPD showed low serologic responses in 5 of the 7 patients. The EBV PCR temporally associated with the serology indicated moderate to large viral burdens. In each patient evaluated serially, the EBV PCR test rose before the diagnosis of LPD and fell with treatment for the disorder. In conclusion, the EBV PCR test may be used as an adjunct to the diagnosis of patients with LPD and may be used to monitor response to therapy for the disorder. Received August 26, 1997; accepted January 13, 1998.     

Concomitant Presentation of Hemophagocytic Lymphohistiocytosis and Posttransplant Lymphoproliferative Disease‐Like Lymphoma in a Mildly Immunosuppressed Leukemia Patient: An Unusual Association

We describe a 4‐year‐old female with pre‐B‐cell acute lymphoblastic leukemia on maintenance chemotherapy, who developed hemophagocytic lymphohistiocytosis (HLH) secondary to Epstein–Barr virus (EBV) infection, complicated by an aggressive lymphoproliferative disorder. Although there was no history of bone marrow transplant or underlying immunodeficiency, EBV triggered a post‐transplant lymphoproliferative disease (PTLD)‐like lymphoma. Multiple regimens of chemotherapy failed to induce remission and patient developed multiorgan failure. The association of HLH with EBV‐related PTLD‐like lymphoproliferative disorder is rare. We present this case to highlight this unusual association so that this highly fatal disease can be recognized and promptly addressed.     

Successful treatment of a classic Hodgkin lymphoma‐type post‐transplant lymphoproliferative disorder with tailored chemotherapy and Epstein–Barr virus‐specific cytotoxic T lymphocytes in a pediatric heart transplant recipient

CHL type is the least common major form of EBV‐related PTLD but rarely occurs in pediatric recipients; development of CHL subsequent to other PTLD subtypes in the same transplant recipient is even more unusual. Because of its rarity, indications on the best treatment strategy are limited. Patients have been mostly treated with standard HL chemotherapy/radiotherapy, and prognosis seems more favorable than other monomorphic PTLDs. Herein, we describe a pediatric case of EBV‐associated, stage IV‐B, CHL arising in a heart allograft recipient eight yr after diagnosis of B‐cell polymorphic PTLD. The patient was successfully treated with adjusted‐dose HL chemotherapy and autologous EBV‐specific CTL, without discontinuation of maintenance immunosuppression. At two yr from therapy completion, the patient is in CR with stable organ function. With this strategy, it may be possible to reproduce the good prognostic data reported for CHL‐type PTLD, with decreased risk of organ toxicity or rejection.     

EBV‐directed viral‐specific T‐lymphocyte therapy for the treatment of EBV‐driven lymphoma in two patients with primary immunodeficiency and DNA repair defects

Children with ataxia telangiectasia (AT), a primary immunodeficiency caused by mutations in ATM, which is critical for repairing DNA defects, are at risk for the development of hematologic malignancy, frequently driven by infection with Epstein‐Barr virus (EBV). Conventional chemotherapy is poorly tolerated by patients with AT, with excessive toxicity even when doses are reduced. Here, we report on two patients with AT and EBV‐positive neoplasms who were treated with EBV‐targeted viral‐specific T cells (VST). One patient had a prolonged complete response to VSTs while the other had a partial response. Therapy was well tolerated without infusion toxicity or graft‐versus‐host disease.     

The role of allogeneic hematopoietic stem cell transplantation and Epstein‐Barr virus infection on the treatment for child primary hemophagocytic lymphohistiocytosis patients with X‐linked lymphoproliferative disease: A rare case report and family survey study

XLP‐2 is known as a rare primary immunodeficiency disease, which is characterized by the susceptibility to EBV infection and potential development into the pHLH. The existing studies believe that the dysfunction of XIAP represents one of the most significant pathogenic mechanisms of XLP‐2, and allo‐HSCT is regarded as a crucial treatment for the long‐term survival in XLP‐2 patients. In our present study, a 2‐year‐old male patient was diagnosed with XLP‐2. After receiving chemotherapy by using HLH‐2004 without allo‐HSCT, he reached a complete remission, and his EBV load was brought under control. Our family survey revealed a novel frameshift mutation in the XIAP gene in this patient, as well as in his cousin and grandfather. Until now, the patient has been followed up for 22 months with no recurrence reported yet. Based on these findings, it is believed that for child pHLH patients with XLP‐2, the treatment by controlling symptoms alone without allo‐HSCT and with regular monitoring of EBV load could be conducive to a long‐term survival.     

Post‐transplant lymphoproliferative disorder resembling Wilms tumor. Diagnostic dilemma: Renal biopsy or nephrectomy?

Cheng E, Fustino N, Klesse L, Chinnakotla S, Sanghavi R. Post‐transplant lymphoproliferative disorder resembling Wilms tumor. Diagnostic dilemma: Renal biopsy or nephrectomy?
Pediatr Transplantation 2011: 15: E187–E191. © 2010 John Wiley & Sons A/S. Abstract: Post‐transplant lymphoproliferative disorder is a life‐threatening neoplasm that can occur after orthotopic liver transplant. We report a 14‐month‐old female status‐post OLT with an atypical presentation of PTLD as a solitary renal mass. At eight‐wk post‐transplant, she presented with elevated transaminases, CMV counts (73 000 copies/mL), and EBV counts (35 000 copies/mL). CT scan revealed a solid heterogeneously enhancing right renal mass measuring 2.6 × 2.4 × 3.3 cm. The radiological diagnosis was Wilms tumor, although PTLD could not be excluded. Complete resection of a Wilms tumor is potentially curative. A needle biopsy would upstage the malignancy and result in radiochemotherapy that is deleterious to a liver graft. The mass was not amenable to partial nephrectomy. A total nephrectomy, given life‐long nephrotoxic immunosuppressants, was an unfavorable option. Thus, needle biopsy was performed. Histology confirmed monoclonal, EBV‐associated PTLD and diffuse large B‐cell lymphoma. Her therapy included immunosuppression reduction, cyclophosphamide, steroids, and anti‐CD20 monoclonal antibody. Concomitantly, she received Cytogam and gancyclovir. Complete remission was achieved three months after chemotherapy. This case illustrates that young age, CMV infection, and EBV infection are strong risk factors for PTLD. With such risk factors present, any mass or lesion in a solid organ transplant patient should be considered PTLD until proven otherwise.     

Treatment response with sirolimus for a pediatric patient with an EBV‐associated smooth‐muscle tumor after bone marrow transplantation

Epstein–Barr virus–associated smooth‐muscle tumors (EBV‐SMTs) are unique and rare neoplasms described in immunocompromised patients. The case describes a nine‐year‐old female with a history of acute lymphoblastic leukemia with relapse and subsequent allogeneic bone marrow transplantation who presented with multiple EBV‐SMTs of the liver. EBV utilizes the mammalian target of rapamycin (mTOR) pathway for tumor growth, and sirolimus, a mTOR inhibitor, has shown to result in a short‐term response. We now report an extended treatment response with sirolimus in a pediatric patient with an EBV‐SMT.     

Spontaneous resolution of Epstein–Barr virus‐associated hemophagocytic lymphohistiocytosis

Secondary hemophagocytic lymphohistiocytosis (sHLH) is a reactive, proliferative disorder of the immune system resulting in lymphohistiocytic proliferation, hemophagocytosis, and cytokine dysregulation. The most common infectious trigger in sHLH is Epstein–Barr virus (EBV‐HLH). Current treatment protocols for EBV‐HLH have a cure rate of approximately 75%; however, there are significant toxicities associated with these therapies. We present two patients with EBV‐HLH who experienced spontaneous resolution of their disease prior to the initiation of therapy, suggesting there may be a subgroup of patients with EBV‐HLH who do well with conservative management and can avoid potentially toxic therapies. Pediatr Blood Cancer. 2010;55:754–756. © 2010 Wiley‐Liss, Inc.     

Pediatric patient with end‐stage kidney disease secondary to Eagle‐Barrett syndrome and metastatic unresectable hepatoblastoma treated successfully with chemotherapy and liver‐kidney transplant

HBL is the most common malignant liver neoplasm in children. The etiology of HBL is largely unknown but there are certain syndromes, such as Beckwith‐Wiedemann syndrome, that have been clearly associated with an increased incidence of this malignancy. EBS, also known as prune belly syndrome, is a congenital anomaly characterized by lax abdominal musculature, bilateral cryptorchidism requiring, in some cases, hemodialysis due to significant kidney and urinary tract dysfunctions. Despite an improvement on the survival rates of patients with advanced‐stage HBL, the presence of concomitant end‐stage renal disease that occurs in patients with EBS constitutes a therapeutic challenge for the clinician not only due to the use of nephrotoxic chemotherapy but also due to the potential need for multi‐organ transplant. We report case of a 2‐year‐old male patient with EBS diagnosed with stage IV, metastatic HBL successfully treated with multi‐agent chemotherapy while on dialysis whom then underwent a simultaneous liver‐kidney transplant followed by adjuvant chemotherapy. Ultimately, the patient achieved cancer remission with normalization of his renal function. Our report emphasizes that patients with HBL in the setting of EBS will not only require careful kidney function monitoring while receiving chemotherapy, but they might also need to undergo multi‐organ transplantation in order to achieve adequate cancer control and also normalization of their kidney function. Awareness of this unusual association calls for further investigation to potentially establish a genetic association between these two disease processes.     

Epstein-Barr-virus-related post-bone-marrow-transplant lymphoproliferative disease: association with cytomegalovirus infection and Down syndrome donor marrow

We describe the development of Epstein-Barr-virus (EBV)-related lymphoproliferative disease (LPD) in the recipient of a histocompatible bone marrow transplant (BMT). Although this rare complication is more common in recipients of mismatched bone marrow, several distinguishing features of our case may have contributed to the development of LPD in the recipient of a matched bone marrow transplant. The patient had received marrow from a sibling with Trisomy 21, a syndrome associated with variable cellular and humoral immune defects. Our patient also was infected with cytomegalovirus and was treated with immunosuppressant therapy for graft versus host disease. Although development of LPD in transplant recipients is a multifactorial process, either acquired or congenital immunosuppression/dysregulation is a common prerequisite for the process. Our case suggests that subtle immune defects in individuals with Down syndrome may contribute to the immunosuppressed setting in which EBV-related LPD can develop.     

Post‐transplant EBV‐related lymphoproliferative disorder complicating umbilical cord blood transplantation in patients of adrenoleukodystrophy

EBV‐associated post‐transplant lymphoproliferative disorder (PTLD) is a well‐recognized complication following solid organ transplantation and hematopoietic stem cell transplantation (HSCT) using bone marrow or peripheral blood as stem cell sources, but rarely reported in umbilical cord blood transplantation (UCBT). We report two cases in unrelated UCBT setting and added the following new information to the literature: (i) EBV‐related PTLD can be presented late in recipients of unrelated UCBT; (ii) in contrast to reported literatures that PTLD is a serious complication with unfavorable outcome, especially in monomorphic form, our cases showed that the clinical course may be relatively benign if treatment is initiated promptly. Pediatr Blood Cancer 2009; 53:1329–1331. © 2009 Wiley‐Liss, Inc.     

Hemophagocytic lymphohistiocytosis is a sign of poor outcome in pediatric Epstein‐Barr virus‐associated post‐transplant lymphoproliferative disease after allogeneic hematopoietic stem cell transplantation

EBV‐related PTLD developing after HSCT is a potentially life‐threatening disease. HLH is uncommon after allogeneic HSCT. Data on outcome of patients with PTLD and concomitant HLH after allogeneic HSCT are limited. In this retrospective study, we collected demographic, clinical, laboratory, and outcome data for 408 patients who underwent allogeneic HSCT from 2006 to 2015. Graft source included CB (n = 135; 33.1%), PBSCs (n = 34; 8.3%), and BM (n = 239; 58.6%). Eight out of 408 patients (2%) developed EBV‐PTLD with a median age at HSCT of 5.9 years (range: 2.3‐17.3). All eight patients received ATG as part of the conditioning regimen. Graft source was PBSC in three patients (37.5%), BM in four patients (50%), and CB in one patient (12.5%). Donors were matched unrelated in five patients (62.5%) and matched sibling in three patients (37.5%). Seven out of eight patients developed EBV‐PTLD within the first 100‐day post‐HSCT. Lymph node biopsy revealed early lesions in three patients, polymorphic in three patients, and monomorphic PTLD in two patients. Three patients (37.5%) died within 1 month of EBV‐PTLD diagnosis. All deceased patients developed HLH manifestations with two of them meeting HLH diagnostic criteria and one having an incomplete workup. PTLD after allogeneic HSCT with manifestations of HLH is associated with high mortality. Early identification and treatment of EBV‐PTLD seems imperative to control the disease, especially if signs of HLH are evolving.     

EBV‐positive low‐grade marginal zone lymphoma in the breast with massive amyloid deposition arising in a heart transplant patient: A report of an unusual case

According to the 2008 World Health Organization classification, low‐grade lymphomas arising in transplant recipients are not considered as specific types of PTLD. Most such cases are not associated with EBV infections, although rare reports of post‐transplant marginal zone lymphoma have been described. We describe the case of an 18‐yr‐old female with history of heart transplant who developed a breast mass, but was otherwise completely asymptomatic. Surgical excision of the mass and histopathologic examination showed a low‐grade B‐cell lymphoma most consistent with marginal zone lymphoma with massive amyloid deposition; furthermore, numerous tumor cells were positive for EBV by in situ hybridization for EBV‐encoded RNA. The patient was treated with reduction in immunosuppression, and no additional lesions developed. This case describes an atypical presentation of post‐transplant low‐grade B‐cell lymphoma, unusual in its location, histopathologic features, and association with EBV, thereby adding to the rare previous accounts of such an entity, suggesting the need to include post‐transplant marginal zone lymphomas in the current classification of PTLD, and helping in determining the optimal treatment modalities for such tumors.     

Rituximab for lymphoproliferative disease prior to haematopoietic stem cell transplantation for X-linked severe combined immunodeficiency

Lymphoproliferative disease (LPD) is a complication of congenital and acquired immunodeficiency states. There are a number of treatment options for LPD arising after haematopoietic stem cell or solid organ transplantation including reduction of immunosuppression, targeted therapies, such as the anti-CD20 monoclonal antibody, rituximab, and EBV specific cytotoxic lymphocytes. Treatment of LPD in children with congenital immunodeficiency syndromes remains unsatisfactory and is associated with a high mortality rate. We recently managed an infant found to have polymorphic LPD concurrent with X-linked severe combined immunodeficiency (SCID). Haematopoietic stem cell transplantation (HSCT) had to be deferred because of progressive LPD. Treatment with rituximab resulted in regression of the LPD following which the patient received a 5/6 HLA matched umbilical cord blood (UCB) transplant. The patient remains well 20 months following transplantation. Rituximab treatment may have a useful role in the control of LPD associated with congenital immunodeficiency prior to HSCT.     

CD56‐negative extranodal nasal type NK/T‐cell lymphoma

Extranodal natural killer (NK)/T‐cell lymphoma, nasal type, is a rare lymphoma that occurs predominantly in Asian adults. In this report, we describe the clinical and pathologic features of an unusual aggressive lymphoid neoplasm in a child and review the literature on NK/T‐cell lymphoma in children. The patient was a 4‐year‐old Native American male with facial swelling, lymphadenopathy, and fevers. Biopsy demonstrated neoplastic lymphoid cells that expressed CD3, CD8, TIA‐1, and EBV‐encoded RNA without CD56. The patient failed multiagent chemotherapy and died of therapy‐related complications. This case represents an extranodal NK/T‐cell lymphoma, nasal type, with an unusual lack of CD56. Pediatr Blood Cancer 2010;55:186–189. © 2010 Wiley‐Liss, Inc.     

De novo hepatocellular carcinoma post‐multivisceral transplantation in a child

De novo hepatocellular carcinoma (HCC) post‐transplantation in patients without viral hepatitis is extremely rare, with only three reported adult cases in the English literature. Here, we present a case of de novo HCC that developed in a 7‐year‐old female, who at 8 months of age received a liver, small bowel, spleen, and pancreas transplantation 6.5 years ago for gastroschisis and total parenteral nutrition (TPN)‐related cirrhosis. The post‐transplant course was complicated by Epstein‐Barr virus (EBV) infection, post‐transplant lymphoproliferative disease, and subsequent development of multifocal EBV‐associated post‐transplant smooth muscle tumors (EBV‐PTSMT) in the small bowel 1 year and 10 months after transplantation, respectively. This was managed by reducing immunosuppression with rituximab and EBV‐specific cytotoxic T‐cell therapy. She was noted to have a new lesion in her transplanted liver graft 6.5 years post‐transplantation that was diagnosed as HCC. The HCC was resected, and the patient remained clinically stable for 7 months. At that time, recurrence of the HCC was discovered on MRI. She passed away 6 months after. To the best of our knowledge, this is the first reported occurrence of de novo HCC post‐transplantation in the pediatric population that is unrelated to viral hepatitis in either recipient or donor.