Abstract
PTLD following hematopoietic stem cell transplantation has a very huge variability in clinical and biochemical presentation, making diagnosis often very challenging. Two typical presentation types have been observed, the former resembling a viral infection, whereas the latter often follows a more fulminant lymphoma-like course. Most but not all cases of PTLD after hematopoietic stem cell transplantation occur early after transplant and are Epstein-Barr virus-related.
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Keywords
- Epstein-Barr virus
- Hematopoietic stem cell transplantation
- Posttransplant lymphoproliferative disorder
- Presentation
- Symptoms
In contrast to lymphomas in immune-competent patients, presentation of PTLD in general is associated with a higher number of extranodal involvement and central nervous system invasion. In addition allograft localization is a peculiar finding in solid organ transplantation (SOT)-related PTLD, but seems to be observed less frequently in allogeneic hematopoietic stem cell transplantation (HSCT)-related PTLD. In allogeneic HSCT recipients, risk factors for PTLD development mainly include the degree of HLA matching and, hence, the need for T-cell depletion protocols before transplantation. In addition higher recipient age and underlying primary immunodeficiency disorders are also considered risk factors. PTLD following allogeneic HSCT typically is donor lymphocyte-derived, whereas SOT-related PTLD in most cases is recipient-derived [1].
Presentation of patients with PTLD after allogeneic HSCT may be highly variable due to the organs and structures involved [2, 3]. Often cases are preceded by a mainly asymptomatic phase of EBV reactivation or primary infection in peripheral blood. The lack of symptoms in these early stages may be attributable to the depletion of T cells, preventing typical symptoms of fever and enlarged lymph nodes. However, if left untreated, rapid disease progression finally leading to organ involvement may occur, causing a huge variety of organ-specific symptoms. Late onset PTLD has been described in a minority of patients and almost always results from ongoing immune-suppressive therapy for chronic graft versus host disease (GVHD) [2].
Based on this concept, there are mainly two forms of clinical presentation: a more classical nodal presentation with frequent involvement of Waldeyer’s ring, lymph nodes, liver, and spleen. Patients often present with lymph node, liver, or spleen enlargement or difficulties in swallowing and breathing. Involvement of lung is common and may represent a risk organ, and patients may suffer from gastrointestinal symptoms like abdominal pain, mucocutaneous ulcers, or diarrhea [3,4,5,6,7].
On the other hand patients may present with a fulminant course, resembling primary EBV-mononucleosis infectiosa or even hemophagocytic syndrome with high fevers, cytopenias, and organ dysfunction up to multi-organ failure. The latter is associated with high risk of fatal outcome [8]. Bone marrow examination should be done at least in all patients with blood count abnormalities [9]. A minority of patients (10–15%) presents with involvement of the central nervous system (CNS), which may be suspected in the case of neurological symptoms (headache, seizures, neurologic deficits) [8]. A lumbar puncture and, if symptoms are present, MRI imaging of the brain are advisable in all patients. Recently a new entity, EBV-positive mucocutaneous ulcer, was added to the revised WHO 2016 classification; thus, a thorough inspection of the oral cavity is mandatory in all patients [10].
As symptoms of PTLD are often unspecific, the clinician is challenged by sorting out several differential diagnoses (pathogen-induced sepsis, graft versus host disease, recurrence of the underlying disease, toxic organ failure). A biopsy and histologic evaluation are mandatory whenever deemed possible.
Few studies have compared the clinical presentation of PTLD following allogeneic HSCT and SOT. In a recent retrospective analysis, Romero et al. compared 82 cases of SOT-PTLD with 21 cases of HSCT-PTLD, showing differences in presentation. HSCT-PTLD was associated with a higher incidence of B symptoms and more advanced stage and of specific nodal (Waldeyer’s ring), splenic and extranodal (liver and CNS) involvement. In this series 91% of the cases had an early onset presentation [11]. In a large retrospective European Society for Blood and Marrow Transplantation (EBMT) study, extranodal involvement was seen in 42% of the patients [12].
Although most cases of PTLD following allogeneic HSCT are EBV-associated, a recent retrospective analysis of the Center for International Blood and Marrow Transplant Research (CIBMTR) showed 17% of PTLD cases were EBV-negative. Time of occurrence following transplantation, clinical features, and histology were not significantly different between EBV-positive and EBV-negative PTLD. Outcome was poor in both subtypes [13].
In conclusion, clinical presentation of PTLD following allogeneic HSCT may be very variable, often confronting transplant physicians with difficult but important differential diagnoses including several early and life-threatening transplant-related complications. In contrast to SOT-related PTLD, less information is available on clinical presentation, which is probably due to the relative limited number of transplantations (and hence cases) compared to SOT and to the widespread use of preemptive administration of rituximab following allogeneic HSCT.
References
Dierickx D, Habermann TM. Post-transplantation lymphoproliferative disorders in adults. N Engl J Med. 2018;378(6):549–62.
Landgren O, Gilbert ES, Rizzo JD, et al. Risk factors for lymphoproliferative disorders after allogeneic hematopoietic cell transplantation. Blood. 2009;113(20):4992–5001.
Rasche L, Kapp M, Einsele H, Mielke S. EBV-induced post transplant lymphoproliferative disorders: a persisting challenge in allogeneic hematopoietic SCT. Bone Marrow Transplant. 2014;49(2):163–7.
Sanz J, Andreu R. Epstein-Barr virus-associated posttransplant lymphoproliferative disorder after allogeneic stem cell transplantation. Curr Opin Oncol. 2014;26(6):677–83.
Chen DB, Song QJ, Chen YX, Chen YH, Shen DH. Clinicopathologic spectrum and EBV status of post-transplant lymphoproliferative disorders after allogeneic hematopoietic stem cell transplantation. Int J Hematol. 2013;97(1):117–24.
Hou HA, Yao M, Tang JL, et al. Poor outcome in post transplant lymphoproliferative disorder with pulmonary involvement after allogeneic hematopoietic SCT: 13 years’ experience in a single institute. Bone Marrow Transplant. 2009;43(4):315–21.
Deeg HJ, Socie G. Malignancies after hematopoietic stem cell transplantation: many questions, some answers. Blood. 1998;91(6):1833–44.
Sanz J, Arango M, Senent L, et al. EBV-associated post-transplant lymphoproliferative disorder after umbilical cord blood transplantation in adults with hematological diseases. Bone Marrow Transplant. 2014;49(3):397–402.
Llaurador G, McLaughlin L, Wistinghausen B. Management of post-transplant lymphoproliferative disorders. Curr Opin Pediatr. 2017;29(1):34–40.
Swerdlow SH, Webber SA, Chadburn A, Ferry JA. Post-transplant lymphoproliferative disorders. In: Swerdlow SH, Campo E, Harris NL, et al., editors. WHO classification of tumours of haematopoietic and lymphoid tissues. 4th ed. Lyon: IARC Press; 2017. p. 453–62.
Romero S, Montoro J, Guinot M, et al. Post-transplant lymphoproliferative disorders after solid organ and hematopoietic stem cell transplantation. Leuk Lymphoma. 2019;60(1):142–50.
Styczynski J, Gil L, Tridello G, et al. Response to rituximab-based therapy and risk factor analysis in Epstein Barr Virus-related lymphoproliferative disorder after hematopoietic stem transplant in children and adults: a study from the Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation. Clin Infect Dis. 2013;57(6):794–802.
Naik S, Riches M, Hari P, et al. Survival outcomes of allogeneic hematopoietic cell transplants with EBV-positive or EBV-negative post-transplant lymphoproliferative disorder, a CIBMTR study. Transpl Infect Dis. 2019;21(5):e13145.
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Maecker-Kolhoff, B., Dierickx, D. (2021). Clinical Presentations and Features of PTLD After HSCT. In: Dharnidharka, V.R., Green, M., Webber, S.A., Trappe, R.U. (eds) Post-Transplant Lymphoproliferative Disorders. Springer, Cham. https://doi.org/10.1007/978-3-030-65403-0_13
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DOI: https://doi.org/10.1007/978-3-030-65403-0_13
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