Posttransplantation Lymphoproliferative Disorders

Updated: Sep 08, 2016
  • Author: Noah S Scheinfeld, JD, MD, FAAD; Chief Editor: Arlen D Meyers, MD, MBA  more...
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Overview

Overview

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

  • Histiocytosis X
  • Benign reactive lymphoproliferative disorders (including posttransplantation lymphoproliferative disorder [PTLD])
  • Plasma cell neoplasms [1]
  • Cutaneous T-cell lymphoma (mostly in heart, pancreas and bone marrow transplantation; the first case linked to a liver transplant was reported in 2012) [2]

This article focuses mostly on PTLD, which occurs in the context of transplantation.

LPDs can occur in individuals infected with HIV, exclusive of LPDs that develop in transplant recipients treated with immunosuppressive drugs or radiotherapy. [3] 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).

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

Congenital LPDs, which usually occur in the setting of congenital immunodeficiencies, [4] 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. [4] EBV generally plays an important role in PTLD and particularly in congenital LPDs.

PTLDs are an uncommon but serious complication of immunosuppressive therapy after solid-organ 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.

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 pathologically indistinguishable from non-Hodgkin lymphoma. The distinction between polymorphic and monomorphic PTLD significantly affects therapeutic decisions because the monomorphic form is usually fatal. Genetic polymorphisms may predispose a patient 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 (median onset, 50–60 mo posttransplantation); these disorders are generally more aggressive.

Nalesnik (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. [5]

Nalesnik 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 (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 recent 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 in excess of 50%. [6]

Studies report varying intervals before onset. Presentation can occur within the first year following transplantation. Loevner et al noted that the interval between transplantation and PTLD onset was 3.5-108 months (mean, 30 mo). [7] The mean time to onset in the UK study was 46 months. The longest interval between transplant and diagnosis was 232 months (nearly 20 y).

PTLD manifests in different body areas but most commonly manifests 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 tissue, 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 the renal transplant 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%. [8]

Hanasono et al (2004) noted that PTLD has diverse manifestations that vary from mild febrile syndrome with pharyngitis and lymphadenopathy to aggressive lymphomas that involve nodal and extranodal sites. [9] PTLD of the head and neck has been described in the literature, with the Waldeyer ring being the most common site of 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 children 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. [10] 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 involvement.

The diagnosis of PTLD requires 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 (2007) reported on the examination of an 8-year-old boy, 3 months after bone marrow transplantation with bilateral enlarged gelatinous bulbar conjunctiva. [11] 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 Epstein-Barr virus (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 conjunctival lesions resolved over 5 weeks.

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Considerations in the Diagnosis of Posttransplantation Lymphoproliferative Disorder

Nalesnik notes that transplant recipients, like other patients with profound immunosuppression, may develop nonneoplastic mass lesions, or they may develop tumors other than those caused by posttransplantation lymphoproliferative disorder (PTLD). [5] Episodes of suspected allograft rejection can be manifestations of allograft-restricted PTLD or may be due to concurrent acute rejection and PTLD. Clinical recurrence of PTLD may reflect reemergence of the original neoplasm, development of a separate tumor clonal neoplasm, or the appearance of a completely unrelated neoplasm.

A study of 20 years of cases of posttransplantation lymphoproliferative disorders in renal transplant recipients at a referral center in Iran revealed that the prevalence of PTLD was 0.66%, which was less than reports from Western countries. [12]

In one series about lung transplantation patients with PTLD over a 15-year retrospective analysis, those with late-onset PTLD were Epstein-Barr virus (EBV) positive; most eventually died of treatment-related etiologies rather than disease progression. [13]

Examination using gene expression of PTLD profiling revealed distinct variations between EBV-positive and EBV-negative PTLD, perhaps accounting for the worse outcomes in PTLD when EBV infection coexists. [14]  (However, a study by Luskin et al indicated that in adults with PTLD, EBV status does not affect survival rate or treatment response. The investigators found that EBV-negative status did not lead to a worse prognosis than did having EBV-positive PTLD, while neither the response to initial therapy nor the likelihood of experiencing complete remission differed significantly between the two groups. The study included 176 adult solid organ transplantation recipients, 58 of whom were EBV negative and 118 of whom were EBV positive. [15] )

A series of 163 patients with monomorphic T-cell–related PTLD (T-PTLD), which is mostly linked to EBV infections, noted an association with hematopoietic stem cell transplantation in conjunction with rapid-onset T-PTLD. On the other hand, later-onset T-PTLD occurred post-immunosuppression without the administration of calcineurin inhibitors and with azathioprine and steroids. The major important independent favorable prognostic factors included T-PTLD involved with a subtype of large granular lymphocytic leukemia, youth, and combining radiochemotherapy/radiotherapy with a reduction of immunosuppression. On the other hand, a subtype of hepatosplenic T-cell lymphoma and patient with pathology of the graft, central nervous system, and bone marrow had worse outcomes. [16]

Another study of 127 children with PTLD found that early childhood PTLD and late childhood PTLD differ in their characteristics. While early PTLD appears to primarily be an EBV-related process facilitated by disease in particular with immunosurveillance, late childhood PTLD usually mimics tumors that have distinctive alterations in pathology and distinctive appearance in the nodes. [17]

The occurrence of EBV-associated PTLD involving the central nervous system, after autologous hematopoietic stem cell transplantation for neuroblastoma, was reported in 2014. [18]

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Etiology

Virus-induced B-cell proliferation is one of the theoretical and hypothesized bases for the development of posttransplantation lymphoproliferative disorder (PTLD). The immunosuppressive agents inactivate T cells, which normally suppress viral proliferation. Pretransplant seronegativity has been reported to be a significant risk factor, especially in pediatric patients who have not been exposed to the virus before transplantation. [19]

Etiologic factors include the following:

  • Epstein-Barr virus (EBV) is a factor. (Ninety percent of patients with PTLDs are EBV positive.)
  • Rearrangements of the c- myc protooncogene are present in some patients with PTLDs.
  • Molecular analysis of PTLD has demonstrated that the anomalies, mutations, and proto-oncogenic expressions described in standard lymphomas, such as TP53 or N- ras mutations or c-myc rearrangements, occur only in monomorphic PTLD, which is the category of PTLD that histologically resembles lymphomas. [20, 21]
  • At least 90% of PTLDs that develop following solid-organ transplantations arise from recipient cells.
  • Immunosuppressive medications are a factor.
  • BCL6 mutations are found in 40% of patients with polymorphic PTLDs.

Advances continue to be made defining the landscape of molecular changes in PTLD. [22]

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History

Patients with posttransplantation lymphoproliferative disorder (PTLD) may present with the following:

  • Cranial nerve palsies or a new onset of seizures
  • Focal neurologic deficits
  • Altered mental status
  • Febrile illnesses
  • Dysphagia
  • Odynophagia
  • Pharyngitis
  • Acute stridor with supraglottic involvement
  • Acute tonsillitis (should be assessed with a throat swab)
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Clinical Findings

Clinical findings may include the following:

  • Upper airway obstruction
  • Sinusitis
  • Otitis media
  • Cervical adenopathy
  • Large tonsils
  • Supraglottic mass
  • Prolapsing epiglottic mass
  • Pituitary involvement [23]
  • Skin involvement [24]
  • Multiple cystic nodules (in a recipient of a renal transplant) [25]

Rombaux et al state that, in the ENT area, tonsillar hypertrophy and adenoid enlargement are the most encountered features of PTLD in orthotopic liver transplantations. [26]

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Alternate Diagnoses

Invasive fungal disease

Sinusitis

Leiomyosarcoma

Lymphoma

Leukemia

Metastatic carcinoma

Tonsillar inflammation

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Histologic Findings and Evaluation

Pathologic interpretation of posttransplantation lymphoproliferative disorders (PTLDs) was predated by the clinical observation that transplant recipients appeared prone to develop lymphomatous growths. Based on the examination of proliferations that arose in renal transplant recipients, Frizzera et al defined the concept that a range of lymphoproliferations could occur in the posttransplant setting. [27]

Nalesnik (2001) stated that PTLD is best diagnosed with tissue biopsy. [5] Cytological preparations are useful, particularly in the analysis of effusions, and can provide adequate diagnostic material, particularly if ancillary studies such as phenotypic, clonal, and viral analyses are also obtained.

Nalesnik also noted that PTLDs may contain large necrotic areas and that excision of involved lymph node or tumor is preferred over a needle biopsy; however, in many cases, a needle biopsy sample may be the only source of tissue available. [5] If such specimens are compromised by extensive necrosis, examining the necrotic areas and identifying the cell as mononuclear in origin may still be possible. Usually, recuts show at least a few spared tumor cells that resemble the cell ghosts present in areas of coagulative necrosis. Epstein-Barr virus (EBV) stains can usually still be performed on such tissue.

PTLDs are categorized based on histopathological subtype and include the following: [28]

  • Early lesions
    • Hyperplastic (plasma cell hyperplasia)
    • Infectious mononucleosis–like
  • Polymorphic polyclonal
  • Polymorphic monoclonal
  • Monomorphic (lymphomatous)
    • B-cell lymphoma (diffuse large cell and Burkitt lymphoma–like)
    • T-cell lymphoma
  • Other
    • Plasmacytoma
    • Multiple myeloma
    • Hodgkin disease
    • T-cell─rich large B-cell lymphoma

Clonal analysis of immunoglobulin genes and tests to determine the presence of EBV may be used to support the diagnosis of PTLD. Clonal analysis may also be required to establish a diagnosis of lymphomatous PTLD of T-cell origin. Molecular analysis of oncogenes and tumor suppressor genes will probably play an important role in the definition of PTLD's behavior in the future.

Immunohistochemical marker analysis of PTLD can show positive results for the CD45, CD138, CD20, and CD79a markers and BCL-6.

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Radiographic Findings

Cross-sectional imaging can reveal complications after transplantation. The imaging features of non-Hodgkin lymphoma in immunocompetent persons differ from those of posttransplant lymphoproliferative disorders (PTLDs) in transplant recipients.

Scarsbrook et al (2005) compared the findings of non-Hodgkin lymphoma and PTLD, and the following data are adapted from their article: [29]

  • Non-Hodgkin lymphoma
    • The incidence of extranodal disease is low (25%).
    • The frequency of nodal disease is high.
    • Gastrointestinal involvement most commonly involves the stomach.
    • Non-Hodgkin lymphoma usually results from direct extension from the involved nodes.
    • Renal involvement is bilateral in 75% of cases.
    • Diffuse infiltration of the liver is the most common form of involvement; focal involvement occurs in less than 10% of patients.
    • Neck involvement usually manifests as a solid mass that grows exophytically into the airway lumen. Necrosis is rare.
  • PTLD in transplant recipients
    • The incidence of extranodal disease is high (80%).
    • The incidence of nodal disease is low (20%).
    • The small bowel is the predominant site of gastrointestinal involvement. Primary disease is more common.
    • Renal PTLD is usually unilateral and rarely bilateral.
    • Periportal lymphomatous infiltration after liver transplantation is unique to PTLD. Focal disease is more common.
    • Neck involvement is necrotic in up to 50% of patients and may mimic an abscess. This necrosis tends to extend submucosally into the parapharyngeal space.

Cervical lymphadenopathy is relatively common and is usually associated with generalized extranodal disease. An excessive number of slightly enlarged nodes should raise the suspicion of PTLD. Necrotic lymphadenopathy is uncommon but is more likely in solitary large nodal masses. Involvement of the pharyngeal tissues is relatively common. The Waldeyer ring, which consists of the lymphoid-rich adenoids and tonsils, is a site of predilection, particularly in children. The disease may be asymmetrical and necrotic, mimicking an abscess. PTLD occasionally involves the orbit, especially the lacrimal fossa, and can involve the paranasal sinuses, where it may mimic sinonasal polyposis. [29]

Loevner (2000) noted that all patients in his study had imaging abnormalities that involved the Waldeyer ring; also, focal 2- to 4.5-cm masses were present in 6 patients (unilateral oropharyngeal tonsil in 2, bilateral oropharyngeal tonsils in 1, nasopharyngeal adenoids in 3, unilateral pharyngeal tonsil and ipsilateral nasopharynx in 1). [7] In 3 patients, the mass was centrally low and attenuating on a CT scan or isointense to fluid on MRI, with enhancing solid peripheral lymphoid tissue. [7]

Advances continue to be made in the use of computed tomography (CT) and functional positron emission tomography (PET) scanning to assess PTLD. [30]   Benefits are being derived from new advances in imaging to parse nodal and extranodal PTLD. [31]

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Treatment and Other Considerations

Treatment may include the following:

  • Excision of obstructing lymphoid tissue
  • Reduction or cessation of immunosuppression (successful with polymorphic type of posttransplantation lymphoproliferative disorders [PTLDs] but is less likely to be successful in the monomorphic form of the disease); ie, this condition is an immune issue and lowering the dose of immunosupressive drugs can cause this disease to abate [32, 33]
  • Antiviral treatment with ganciclovir to control Epstein-Barr virus (EBV) replication
  • Rituximab administration
  • Chemotherapy
  • Radiotherapy
  • Immunotherapy with monoclonal antibodies
  • Surgery to remove the transplanted organ
  • Bexarotene
  • Tonsillectomy combined with tapering of immunosuppression (if tonsils are involved)

Hirokawa (2007) noted prolonged reactivation of cytomegalovirus infection following successful rituximab therapy for EBV-associated posttransplantation lymphoproliferative disorder. [34]

More aggressive forms of PTLD, monomorphic types in particular, may not respond to any treatment. Early diagnosis optimizes response to treatment.

Note that erythromycin increases cyclosporine levels; thus, erythromycin and other medications that affect the A3P4 isoenzyme should be used with care and foreknowledge in patients who receive cyclosporine.

A prospective study by Choquet et al of 299 heart transplant patients indicated that the incidence of PTLD can be reduced by tapering immunosuppression on reactivation of or primary infection with EBV (and administering rituximab when the virus is unresponsive to tapering or the viral load is particularly high), without increasing graft rejection. [35]

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Liver Transplant

Koch (2007) analyzed 621 liver transplant recipients in which 22 cases of PTLD were discovered in 21 patients. [36] Five patients were children and 16 were adults. Extranodal disease was present in 77% of cases involving a wide variety of organ systems. Lymphadenopathy was present in 23% of cases. The spectrum of PTLD histopathology varied. In situ hybridization for EBV showed negativity in 62% of cases and was positive in 38% of cases. EBV status did not influence the time interval from transplantation to presentation (median 33 months) or the mortality (average 32%).

Mucha (2007) noted 2 patients with tonsil enlargement after liver transplantation in adults due to tonsillar posttransplantation lymphoproliferative disease. [37]

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