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Posttransplantation Lymphoproliferative Disorders


Lymphoproliferative disorders (LPDs) can be parsed into the following 6 categories:

Hodgkin disease

Non-Hodgkin lymphoma

Histiocytosis X

Benign reactive lymphoproliferative disorders (including posttransplantation lymphoproliferative disorder [PTLD])

Plasma cell neoplasms

Cutaneous T-cell lymphoma (mostly in heart, pancreas and bone marrow transplantation; the first case linked to a liver transplant was reported in 2012)

This article focuses primarily on PTLD, which occurs in the context of solid organ and hematopoietic stem cell transplantation.

LPDs can occur in individuals infected with HIV, exclusive of LPDs that develop in transplant recipients treated with immunosuppressive drugs or radiotherapy.
In patients infected with HIV, LPDs are often linked to infection with Epstein-Barr virus (EBV). Adult Burkitt lymphoma is an EBV-linked LPD that occurs in the context of AIDS. Cutaneous T-cell lymphoma and pseudocutaneous T-cell lymphoma are also LPDs linked to HIV. See the image below.

Non-Hodgkin lymphoma of the terminal ileum. Note t

Non-Hodgkin lymphoma of the terminal ileum. Note the doughnut sign, ie, intraluminal contrast material surrounded by a grossly thickened bowel wall. This appearance is highly suggestive of small noncleaved cell lymphoma (Burkitt type).

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In addition, various LPDs (eg, Castleman disease, Kikuchi-Fujimoto disease, and Rosai-Dorfman disease) can occur in the head and neck in individuals who have not undergone transplantation.

Congenital LPDs, which usually occur in the setting of congenital immunodeficiencies,
are diseases associated with genetic defects and include the following:

Wiskott-Aldrich syndrome (WAS)

Severe combined immunodeficiency (SCID)

Common variable immunodeficiency (CVID; a heterogeneous syndrome characterized by various degrees of hypogammaglobulinemia)

Ataxia telangiectasia (AT)

X-linked lymphoproliferative disorder (XLP)

Hyper–immunoglobulin M (IgM) syndrome

The lymphomas and leukemias of AT mirror sporadic LPD but often manifest earlier in life.
EBV generally plays an important role in PTLD and particularly in the setting of congenital LPDs.

PTLDs are an uncommon but serious complication of immunosuppressive therapy after both solid organ and hematopoietic stem cell transplantation. PTLDs develop in approximately 2-3% of patients who undergo immunosuppressive therapy after solid organ transplantation. The precise rate of occurrence and incidence depends on the type of organ transplanted and the type and duration of immunosuppressive treatment. Studies evaluating large transplantation registries have shown an increase in the incidence of PTLD.
 This trend is postulated to be secondary to increased growth in transplantation, older age of donors and recipients, increased diagnosis and awareness of PTLD, and the use of novel, aggressive immunosuppressive regimens.

PTLDs are a varied class of abnormal lymphoid growths, including both hyperplasias and neoplasias, that are histologically and genetically heterogeneous disorders hallmarked by an abnormal lymphoid cell proliferation.

PTLD usually manifests with B-cell proliferation induced by EBV; this proliferation is left unopposed by the pharmacologically suppressed T-cell system. Abnormal lymphoproliferation ranges from a polymorphic form characterized by premalignant hyperplasia to a monomorphic form that is pathologically indistinguishable from non-Hodgkin lymphoma. The distinction between polymorphic and monomorphic PTLD significantly affects therapeutic decisions, as the monomorphic form is usually fatal. Genetic polymorphisms may predispose patients to the development of PTLD.

A few PTLDs are of T-cell origin, Hodgkin type, or, rarely, plasma cell neoplasms such as multiple myeloma. Patients with these types of PLTD are more likely to be EBV negative and usually present later in life (median onset, 50–60 mo posttransplantation); these disorders are generally more aggressive.

Nalesnik et al (2001) noted that PTLDs of T- or NK-cell origin have been described, and late-arising EBV-negative lymphoid tumors have become more frequently reported in patients with PTLD. Other lymphoid neoplasms, such as those that arise from mucosal-associated lymphoid tissue (MALTomas), have recently been recognized in transplant recipients, and their relationship to PTLD is uncertain.

Nalesnik and colleagues also noted that multicentric PTLD may represent either advanced-stage disease or multiple independent primary tumors. Likewise, recurrent PTLD may represent true recurrence or the emergence of a second primary tumor. Transplant recipients are also at risk for other opportunistic neoplasms, including EBV-associated leiomyosarcomas that may be seen alone or in conjunction with PTLD.

The risk of developing PTLD depends on the type of organ transplantation performed. PTLD develops least often in renal transplant patients (1-2% of cases) and liver transplant recipients (1.4% of cases). Heart-lung recipients have the highest prevalence of PTLD (4.6% of cases). In a large UK study of lymphoproliferative disorders in renal transplant recipients, PTLD occurred in 27 (1.95%) of the 1383 patients studied, with a mortality rate of more than 50%.

Studies report varying intervals prior to disease onset. Presentation can occur within the first year following transplantation. Loevner et al noted that the interval between transplantation and PTLD was 3.5-108 months (mean, 30 mo).
The mean time to onset in the UK study was 46 months. The longest interval between transplant and PTLD diagnosis was 232 months.

PTLD manifests in different areas of the body but occurs most commonly in the gastrointestinal tract. PTLD can develop in the head and neck and has rarely been noted to manifest as nodules of the skin or superficial soft tissues, several of which presented on the face. Central nervous system involvement is uncommon but, when present, occurs in isolation, sparing other organ systems. The central nervous system was the predominant site of disease prior to the use of cyclosporine, which has led to more frequent presentations in the thorax and abdomen. PTLD isolated to renal transplantation is a new manifestation of disease that may be due to immunosuppression with muromonab-CD3 (OKT3). Monomorphous PTLD is associated with a PTLD-related mortality rate of 78%. Polymorphous PTLD carried a PTLD-related mortality rate of 0%.

Hanasono et al (2004) noted that PTLD has diverse manifestations that can vary from mild febrile syndrome with pharyngitis and lymphadenopathy to aggressive lymphomas that involve nodal and extranodal sites.
PTLD of the head and neck has been described in the literature, with the Waldeyer ring being the most common site of disease involvement

Younger age and EBV seronegativity appear to increase the risk for PTLD. PTLD is also believed to be more common in children because many are EBV-naïve at the time of transplantation.

Lattyak et al (1998) believe that the incidence of head and neck PTLD in pediatric transplant recipients has been underappreciated.
Their experience suggests that almost 10% of pediatric patients who undergo liver transplantation eventually develop PTLD in the head and neck. Remarkably, head and neck involvement represents nearly two thirds of all cases of PTLD in the pediatric population, with the Waldeyer ring being the most common site of disease involvement.

The diagnosis of PTLD requires an evaluation of histopathologic appearance, cell phenotype, clonal status, and EBV status. Some suggest that the diagnosis of PTLD can be confirmed based on histologic evidence of invasive lymphoid hyperplasia along with positive tissue staining for EBV via either immunoperoxidase for latent membrane protein (LMP-1) or in situ hybridization for EBV-encoded messenger RNA (EBERs).

Walton et al (2007) reported on the examination of an 8-year-old boy, 3 months after bone marrow transplantation with bilateral enlarged gelatinous bulbar conjunctiva.
Conjunctival biopsy demonstrated a polymorphous infiltrate of lymphoid cells with large atypical immunoblastic lymphoma cells, plasmacytoid lymphocytes, and plasma cells. B-cell markers CD20 and CD79a were positive. Plasma cells showed restriction for kappa immunoglobulin light chain and were positive for CD79a. Most cells were positive for EBV-encoded ribonucleic acid. EBV-related polymorphic PTLD was diagnosed and treated with discontinuation of cyclosporine, reduction in prednisone dosage, and administration of EBV-specific cytotoxic T lymphocytes. The observed conjunctival lesions resolved over 5 weeks.

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