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 ^[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 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. ^[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 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, ^[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 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. ^{[5, 6]}  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. ^[7]

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%. ^[8]

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). ^[9] 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. In PTLD isolated to renal transplantation, which may arise from immunosuppression with muromonab-CD3 (OKT3), monomorphic PTLD has been associated with a PTLD-related mortality rate of 78%, compared with a 0% PTLD-related mortality rate for polymorphic PTLD. ^[10]

A single-institution study by King et al found median overall survival in PTLD to be 82 months, with median event-free survival being 21 months. Those PTLD patients suffering from classic Hodgkin lymphoma had the best 2-year overall survival rate, at 100%, while the rate in those with monomorphic PTLD, T-cell subtype, was just 20%. ^[11]

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. ^[12] 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. ^[13] 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. ^[14] 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.

Signs and symptoms of posttransplantation lymphoproliferative disorder

Findings can include the following:

• Cranial nerve neuropathies
• Focal neurologic deficits
• Altered mental status
• Febrile illnesses
• Dysphagia
• Odynophagia
• Pharyngitis
• Acute stridor with supraglottic involvement
• Acute tonsillitis

Workup in posttransplantation lymphoproliferative disorder

PTLDs are diagnosed based on histopathologic examination; these disorders have been classified according to the World Health Organization (WHO) 2017 criteria, which places them into six subclasses, as follows ^{[15, 11]} :

• Nondestructive PTLD - Plasmacytic hyperplasia, infectious mononucleosis–like PTLD
• Destructive PTLD - Florid follicular hyperplasia destructive PTLD, polymorphic PTLD, monomorphic PTLD (B-cell, T-cell, natural killer-cell types), and Hodgkin lymphoma–like PTLD

Cross-sectional imaging can reveal pertinent clinical findings after transplantation. The imaging features of non-Hodgkin lymphoma in immunocompetent persons differ from those of PTLDs in transplant recipients.

Management of posttransplantation lymphoproliferative disorder

Treatment may include the following:

• Excision of obstructing lymphoid tissue
• Reduction or cessation of immunosuppression (successful with the polymorphic type of PTLD but less likely to be successful in the monomorphic form of the disease) ^{[16, 17, 18]}
• Antiviral treatment with ganciclovir to control 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 pathologically)

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). ^[7] 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 PTLD in renal transplant recipients at a referral center in Iran revealed that the prevalence of PTLD was 0.66%, which was less than previous reports from Western countries. ^[19]

In a series concerning 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. ^[20]

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. ^[21]  (However, a study by Luskin et al indicated that in adults with PTLD, EBV status does not affect survival rate or treatment response. The report included 176 adult solid organ transplantation recipients, 58 of whom were EBV negative and 118 of whom were EBV positive. ^[22] 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 groups.)

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 chemoradiation/radiotherapy with a reduction of immunosuppression. Alternatively, a subtype of hepatosplenic T-cell lymphoma and patients with pathology of the graft, central nervous system, and bone marrow had worse outcomes. ^[23]

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 immunosurveillance, late childhood PTLD usually mimics tumors that have distinctive alterations in pathology and distinctive appearance in affected the nodes. ^[24]

The occurrence of EBV-associated PTLD involving the central nervous system, after autologous hematopoietic stem cell transplantation for neuroblastoma, was reported in 2014. ^[25]

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 prior to transplantation. ^[26]

Etiologic factors include the following:

• Epstein-Barr virus (EBV) (Ninety percent of patients with PTLD are EBV positive.)

• Rearrangements of the c-myc protooncogene are present in some patients with PTLD.

• Molecular analysis of PTLD has demonstrated that 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 lymphoma. ^{[27, 28]}

• At least 90% of PTLDs that develop following solid-organ transplantations arise from recipient cells.

• Immunosuppressive medications

• BCL6 mutations are found in 40% of patients with polymorphic PTLD.

Advances continue to be made defining the landscape of molecular changes in PTLD. ^[29]

The risk of PTLD has been shown to be influenced by the type of organ transplanted. For example, in adult patients, kidney transplant recipients have the lowest reported incidence (0.8-2.5%), followed by pancreatic (0.5-5.0%), liver (1.0-5.5%), heart (2.0-8.0%), lung (3.0-10.0%), and multi-organ and intestinal (< 20%) transplant recipients. ^{[30, 31]}

In patients undergoing allogeneic hematopoietic stem cell transplantation, the incidence of PTLD is related to the degree of human leukocyte antigen (HLA) matching, which correlates directly with the degree of needed T-cell depletion prior to transplantation. The greatest incidence of PTLD is observed in haploidentical allogeneic stem cell transplantation (>20% in individuals with selective T-cell depletion protocols). However, this incidence has been shown to approach 0% with the use of posttransplantation cyclophosphamide. Patient age over 50 years has also been implicated as a risk factor in hematopoietic stem cell transplantation. ^{[32, 33]}

The clinical presentation of patients with posttransplantation lymphoproliferative disorder (PTLD) is heterogeneous. Findings, which may range from incidental, asymptomatic signs/symptoms to fulminant organ failure and/or tumor lysis syndrome, include the following:

• Cranial nerve neuropathies

• Focal neurologic deficits

• Altered mental status

• Febrile illnesses

• Dysphagia

• Odynophagia

• Pharyngitis

• Acute stridor with supraglottic involvement

• Acute tonsillitis

Clinical findings may include the following:

• Upper airway obstruction

• Sinusitis

• Serous otitis media

• Cervical adenopathy

• Tonsillar hypertrophy

• Supraglottic mass

• Prolapsing epiglottic mass

• Pituitary involvement ^[34]

• Skin manifestations ^[35]

• Multiple cystic nodules (in renal transplant recipients) ^[36]

Rombaux et al state that in the head and neck region, tonsillar and adenoidal hypertrophy are the most encountered clinical features of PTLD in orthotopic liver transplantations. ^[37]

Invasive fungal disease

Sinusitis

Leiomyosarcoma

Lymphoma

Leukemia

Metastatic carcinoma

Tonsillitis

Allograft rejection

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. ^[38]

Nalesnik (2001) stated that PTLD is best diagnosed with tissue biopsy. ^[7] Cytological preparations are useful, particularly in the analysis of effusions, where it 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. ^[7] 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, which 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 diagnosed based on histopathologic examination; these disorders have been classified according to the World Health Organization (WHO) 2017 criteria, which places them into six subclasses. ^{[15, 11]}

Nondestructive PTLD

This includes the following:

• Plasmacytic hyperplasia
• Infectious mononucleosis–like PTLD

Destructive PTLD

This includes the following:

• Florid follicular hyperplasia destructive PTLD
• Polymorphic PTLD
• Monomorphic PTLD (B-cell, T-cell, natural killer-cell types)
• Hodgkin lymphoma–like PTLD

Analysis

All nondestructive subtypes have been shown to have an association with EBV. In addition, over 90% of polymorphic and Hodgkin lymphoma–like PTLDs as well as approximately 50% of monomorphic subtypes have been associated with EBV. ^[39]  Gene expression profiling and immunohistochemistry are also useful in categorizing PTLD type. ^[40]

Immunohistochemical marker analysis in PTLD can show positive results for CD45, CD138, CD20, and CD79a markers and for BCL6. An association with EBV is not required for the diagnosis of PTLD; however, EBV-encoded RNA in-situ hybridization assay may be useful in the diagnosis of PTLD in solid-organ transplant recipients. ^[41]  Despite this association, peripheral blood monitoring for EBV viral load has not shown diagnostic utility.

The 2017 WHO classification has facilitated a more uniform approach to diagnosis and classification of PTLD. However, it should be noted that this is a purely pathologic classification system and that therefore certain factors are negated, including transplant type (solid organ vs hematopoietic stem cells), EBV status (positive vs negative), and molecular-genetic features. ^[42]  Following pathologic confirmation of the diagnosis, disease staging should be performed to guide management.

Cross-sectional imaging can reveal pertinent clinical findings 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: ^[43]

• 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 abscess formation; this necrosis tends to extend submucosally into the parapharyngeal space.

Cervical lymphadenopathy is relatively common and is typically 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 disease predilection, particularly in children. The disease may be asymmetrical and necrotic, mimicking abscess formation. PTLD occasionally involves the orbit, especially the lacrimal fossa, and can also involve the paranasal sinuses, where it may mimic nasal polyposis. ^[43]

Loevner (2000) noted that all patients in his study had imaging abnormalities that involved the Waldeyer ring; specifically, focal 2- to 4.5-cm masses were present in 6 patients (unilateral palatine tonsil in 2, bilateral palatine tonsils in 1, nasopharyngeal adenoids in 3, unilateral pharyngeal tonsil and ipsilateral nasopharynx in 1). ^[9] The mass was centrally low in 3 patients, with attenuation on a computed tomography (CT) scan or isointensity to fluid on MRI, and with enhancement of solid peripheral lymphoid tissue. ^[9]

Technological advances continue to be made in CT imaging and functional positron emission tomography (PET) scanning for assessment of PTLD. ^[44]  Benefits are being derived from new advances in imaging to parse nodal and extranodal PTLD. ^[45]  Although 18F-fluorodeoxyglucose PET scanning in conjunction with CT imaging (PET-CT scanning) has been shown to be highly sensitive for PTLD, its use in staging is currently undetermined and requires prospective validation. ^[46]  (See the images below.)

A positron emission tomography-computed tomography (PET-CT) scan was obtained on day 61 after a matched unrelated donor (MUD) bone marrow transplant in a 7-year-old female with left orbital myeloid sarcoma and low-level bone marrow involvement, to evaluate for PTLD. This 3-D maximum intensity projection (MIP) readily reveals significant extensive supraclavicular and axillary lymphadenopathy bilaterally, as well as extensive bilateral pelvic, inguinal, and femoral lymphadenopathy, all with intense fluorodeoxyglucose (FDG) avidity. The largest left axillary node measures 2.2 x 1.4 cm, and the largest right axillary node measures 2.1 x 1.5 cm. The largest pelvic node is on the left and measures 2.2 x 1.1 cm. The largest left inguinal node measures 1.4 x 0.8 cm, and the largest right inguinal lymph node measures 1.6 x 1.0 cm.

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Axial PET-CT imaging in the same patient reveals extensive bilateral hilar, subcarinal, and paratracheal lymphadenopathy, with the largest right hilar mass measuring 1.7 x 1.1 cm and the largest left hilar mass measuring 1.2 x 1.4 cm. There is also a new intense focus of FDG avidity adjacent to the inferior vena cava, likely representing periaortic lymph nodes.

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Axial PET-CT imaging in the same patient reveals a new 2.0 x 1.1 cm soft tissue mass within the mesentery and concomitant intense FDG avidity.

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Treatment may include the following:

• Excision of obstructing lymphoid tissue
• Reduction or cessation of immunosuppression (successful with the polymorphic type of PTLD but less likely to be successful in the monomorphic form of the disease) ^{[16, 17, 18]}
• Antiviral treatment with ganciclovir to control 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 pathologically)

Reduction or cessation of immunosuppression

This is successful with the polymorphic type of PTLD but is less likely to be successful in the monomorphic form of the disease ^{[16, 17]}

Reduction of immunosuppression is the foundation of initially managing the restoration of EBV-directed cellular immunity while balancing the risk of graft rejection

Reduction of immunosuppression has shown to result in PTLD regression in 20-80% of polyclonal or monoclonal cases ^{[47, 48]}

A proposed initial management strategy includes dose reduction of calcineurin inhibitors by at least 50% and discontinuation of antimetabolic agents ^[49]

EBV-negative disease has been shown to be less responsive than EBV-positive PTLD to immunosuppression reduction. In addition, tumor burden greater than 7 cm in diameter, Ann Arbor stage III/IV (advanced disease), and age over 50 years have all independently been associated with lack of response to reduced immunosuppression. ^{[31, 50]}

Rituximab administration

Rituximab is a monoclonal anti-CD20 antibody. It is standard treatment in nondestructive subtypes of PTLD, polymorphic PTLD, or monomorphic diffuse large B-cell lymphoma–like PTLD when a response to reduced immunosuppression is not observed.

Overall response rates after implementation of both reduced immunosuppression and rituximab therapy range from 40-80%, with reported complete remission rates of 20-55%. ^{[51, 52, 53]}

Chemotherapy

Immunochemotherapy is indicated in the following cases:

• Patients with B-cell PTLD who have failed to respond to reduced immunosuppression and rituximab ^[54]
• Specific histologic features of peripheral T-cell lymphoma, Hodgkin lymphoma, Burkitt lymphoma, or primary CNS lymphoma ^{[55, 56, 57, 58]}

Experimental therapeutic options

Prospective clinical trials are still needed for the following:

• Ibrutinib ^[59]
• Idelalisib ^[60]
• Bortezomib ^[61]
• Pembrolizumab, nivolumab ^[62]
• Brentuximab ^[63]

Further information

Hirokawa (2007) noted prolonged reactivation of cytomegalovirus infection following successful rituximab therapy for EBV-associated PTLD. ^[64]

More aggressive forms of PTLD, particularly monomorphic types, may not respond to any type of treatment. As a result, early diagnosis is the key to optimizing potential response.

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. ^[65]

The introduction of treatment protocols including rituximab, lymphoma-specific regimens, and advances in diagnosis and subtype classification have resulted in notably improved outcomes in patients with PTLD. ^{[66, 67]} However, although prognostication criteria and scoring systems have been published, limitations in sample size, heterogeneous patient populations, differing treatment protocols, and lack of validation have as yet prevented these tools from becoming uniformly applicable for clinical use. The classic International Prognostic Index (IPI) provides the criteria that continue to be most commonly cited in studies. The IPI consists of five variables (age, performance status, lactate dehydrogenase level, stage, and number of extranodal sites) and is used widely by hematologists and oncologists for categorization of patients into prognostic subgroups. The utility of the IPI in formal prognostic evaluation has been illustrated in clinical trials, with receipt of thoracic implants and suboptimal response to rituximab induction protocols being identified as additional poor prognostic indicators. ^[68]

It should be noted that retransplantation following the diagnosis and successful treatment of PTLD is possible. However, most studies describe wait times of at least 1 year following PTLD treatment. A French study of 52 kidney transplant recipients who underwent 55 retransplantations following PTLD treatment showed a median time from diagnosis to retransplantation of 90 months (range, 28-224 months). Of these patients, only one developed PTLD following retransplantation.