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Post-immunosuppressive and immunomodulatory therapy lymphoproliferative disorders of the gastrointestinal tract
Post-immunosuppressive and immunomodulatory therapy lymphoproliferative disorders occur during immunosuppressive treatment following allogeneic solid organ or stem cell transplant (post-transplant lymphoproliferative disorder, PTLD) or for autoimmune disorders. These disorders commonly initially present in the gastrointestinal tract, and up to 30% of patients have been shown to have GI involvement. Post-immunosuppressive therapy lymphoproliferative disorders are frequently associated with Epstein–Barr virus (EBV) and encompass a wide spectrum of morphologic and clinical presentation. EBV-negative and T-cell lymphoproliferations occur to be increasing, and a high index of suspicion is required on the part of the pathologist for timely diagnosis and treatment.
Keywords: gastrointestinal tract, inflammatory bowel disorder, lymphoma, post-transplant lymphoproliferative disorder (PTLD).
Post-immunosuppressive and immunomodulatory therapy lymphoproliferative disorders encompass two main categories, the first being post-transplant lymphoproliferative disorder (PTLD). This term encompasses a heterogeneous (from both a clinical and histologic perspective) group of lymphoid proliferations that occur in the setting of solid organ or hematopoietic stem cell transplant. The other major category is lymphoid proliferations that arise in the setting of autoimmune disease and associated immunosuppressive or immunomodulatory treatment. This latter phenomenon was initially described in patients with rheumatoid arthritis treated with methotrexate, although as more patients are being treated with immunomodulatory agents (particularly in the context of inflammatory bowel disease); increased focus is being directed at the safety profile of these drugs.
Involvement of the gastrointestinal tract is common in these disorders. Studies have shown that the gastrointestinal tract is involved in up to 30% of patients diagnosed with PTLD, 1 and is the most frequent site of extranodal involvement. 2 As such, it is essential that surgical pathologists are aware of the histopathologic features of these challenging entities to ensure accurate and timely diagnosis.
Post-transplant lymphoproliferative disorder (PTLD)
PTLDs are a complex, heterogeneous group of atypical lymphoid and plasmacytic proliferations that arise in patients who have received solid organ transplant (SOT) or hematopoietic stem cell transplant (HSCT). The first cases were described in 1968 by Doak et al. in two patients who had received cadaveric renal transplants and immunosuppression with prednisone and azathioprine. 3 The term “post-transplant lymphoproliferative disorder” was coined by Starzl et al. in 1984, describing atypical lymphoid proliferations occurring in patients who had received kidney, liver, heart, and heart–lung cadaveric transplants. These were noted to be mostly Epstein–Barr virus related and responsive to reduction of immunosuppression. 4
The pathologic classification of these disorders is based on type of cell (B cell, plasma cell, T cell), morphology, and relation to EBV. The majority of cases are B-cell, with only a small minority being of T-cell derivation. The World Health Organization (WHO) classifies PLTD into four categories based on morphologic, immunophenotypic, and prognostic characteristics (see Table 1 ).
|Early lesions||Plasmacytic hyperplasia|
|Infectious mononucleosis-like lesion|
|Monomorphic PTLD||B, T or NK cell neoplasms which meet the definition for lymphoma or leukemia|
|Classical Hodgkin lymphoma-type PTLD|
Early lesions are characterized by an atypical lymphoid proliferation that shows preservation of the underlying architecture. Generally, these proliferations form mass lesions and are described as “plasmacytic hyperplasia” or “infectious mononucleosis-like” PTLD. These proliferations occur in patients who have not been previously exposed to EBV.
Histologically, early lesions consist of a polymorphous population of lymphocytes and plasma cells which do not exhibit phenotypic aberrancy. EBV (as demonstrated by EBER in situ hybridization or LMP1 immunohistochemistry) is usually positive. Most early lesions are polyclonal, although small monoclonal or oligoclonal populations may be identified. 5 Early lesions are rare in the gastrointestinal tract, occurring primarily within lymph nodes, tonsils and adenoids.
While spontaneous regression has been noted, and response to reduction of immunosuppression is typical, occasionally these lesions may be fatal, or may progress to polymorphic or monomorphic PTLD (see below).
In contrast to early lesions, polymorphic PTLD is characterized by a polymorphous lymphoid proliferation that effaces the underlying architecture of the involved tissue. Mature lymphocytes and plasma cells are generally present, along with immunoblasts and occasional atypical cells which may at times resemble Reed–Sternberg cells. Demonstration of clonality is much more frequent than in early lesions. Importantly, polymorphic lesions cannot fulfill criteria for another recognized type of lymphoma. 5
These cases can be difficult to pick up, especially in the lower gastrointestinal tract, where varying degrees of chronic inflammation exist in histologically normal biopsies. The effacement of architecture that occurs with polymorphic PTLD can often mimic the features of chronicity that are associated with inflammatory bowel disease, such as crypt architectural distortion and basal plasmacytosis ( Figure 1 ). Receiving appropriate clinical history of transplant is crucial in making an accurate diagnosis. Demonstration of EBV is also helpful, as most cases contain numerous EBV-positive cells.
Treatment and prognosis for polymorphic PTLD varies. Although some cases respond to reduction of immunosuppression, other cases progress and require additional treatment.
Monomorphic lesions fulfill criteria for a lymphoid neoplasm that occurs in immunocompetent individuals, with exception being given to small B-cell lymphomas (which are not designated as PTLD even though they may occur in the post-transplant setting). The histology of these lesions in the gastrointestinal tract varies, depending on the subtype of lymphoma present. Most frequently, monomorphic PTLD is of B-cell derivation, including diffuse large B-cell lymphoma (DLBCL), or less commonly Burkitt lymphoma or plasma cell neoplasm. The minority of monomorphic PTLD are of T/NK cell derivation.
Classical Hodgkin lymphoma-type PTLD
Classical Hodgkin lymphoma-type PTLD fulfills criteria for classical Hodgkin lymphoma in other settings, and is almost always EBV-positive. This is the least common type of PTLD. Care must be taken to distinguish this type of PTLD from early lesions or polymorphic PTLD with Reed–Sternberg like cells.
Role of EBV
EBV is a member of the gamma herpes virus family, and infection is ubiquitous; over 90% of the world's population acquire the infection in early childhood or adolescence. EBV infects B cells via the EBV receptor (CD21), and the ensuing acute infection is controlled by the host cytotoxic T lymphocyte (CTL) and natural killer (NK) cell response. Following acute infection, the virus establishes a latent infection in B cells in which viral protein expression is downregulated and the immune system is evaded.
EBV is thought to contribute to the development of lymphoproliferations mainly by expression of latent membrane protein (LMP)-1, which has been shown to behave as an oncogene in rodent fibroblast transformation assays. Transgenic mice with LMP1 have been shown to develop lymphoma at increased rates. LMP1 appears to mimic CD40 ligand, and through this receptor is able to upregulate anti-apoptotic proteins such as BCL-2 and A20. It also has been shown to cause B-cell activation, to stimulate cytokine production (such as IL-6, IL-8, and IL-10), and activate various signaling pathways such as NF-kappa B, and JAK/STAT.6, 7, and 8
The majority of PTLD is associated with EBV. These cases tend to occur early after transplant (often within the first year), and can be localized to the allograft itself or present within organs in the vicinity of the allograft, frequently including the GI tract ( Figure 2 ).
As might be expected, the risk of PTLD is highest in patients who are EBV-negative at the time of transplant and receive an allograft from an EBV-positive donor; these patients have a 6–7-fold increased risk. It is recommended that EBV viral load be monitored at least monthly by PCR for the first year following transplant in this cohort, although this is somewhat controversial as recent literature suggests that EBV viral load may not correlate well with the appearance of PTLD.
While it is well accepted that EBV plays a large role in the development of PTLD, it is interesting to note that the incidence of EBV-negative PTLD appears to be increasing over time. Nelson et al. reported a 2% incidence prior to 1991 vs. 23% in the following decade; currently these cases account for 35–40% of PTLD. The majority of cases are monomorphic, with an increased proportion accounting for T-cell PTLD. They tend to occur late following transplant, with a median time from solid organ transplant of 62 months and are often extranodal in presentation ( Figure 3 ). 9
T-cell PTLD accounts for approximately 7–15% of all PTLDs following solid organ transplantation. 5 Unlike its B-cell counterpart, there is no early or polymorphic precursor lesion and the lesion must meet criteria for a T-cell lymphoma or leukemia. T cells do not express CD21, which has been identified as the EBV receptor, and as expected, the majority of cases are not associated with EBV. However, this is clearly not as cut and dry as it may seem, as approximately 1/3 of T-cell PTLD may be EBV-positive.5 and 10
T-cell lymphoma makes up a minor proportion of PTLD. These cases tend to present later than B-cell cases, and may be related to other viral infection, such as HTLV-1. In fact, in some parts of the world, T-cell PTLD makes up a much higher proportion of cases due to increased incidence of this virus. In a recent study looking at data from the US Scientific Registry of Transplant Recipients, 6.2% of cases were diagnosed as a T-cell PTLD, with peripheral T-cell lymphoma and anaplastic large cell lymphomas as the most common subtypes. 11
A recent meta-analysis of 163 cases included a wide variety of T-cell lymphoma types, including peripheral T-cell lymphoma, not otherwise specified, adult T-cell leukemia/lymphoma (ATLL), cutaneous T-cell lymphoma, and others. Interestingly, 36.5% of cases were associated with EBV, and all cases of ATLL were associated with HTLV-1. The time following solid organ transplant was significantly longer than what is typically seen in B-cell PTLD, ranging from 48 to 84 months depending on the type of transplant; only hematopoietic stem cell transplant patients were observed to develop T-PTLD within the first year following transplant (median 5 months). 10
Risk factors for PTLD
The incidence of PTLD varies with type of transplant. The highest risk of PTLD has been described in recipients of small intestinal transplant. Multi-organ (such as heart–lung) transplants confer an elevated risk as well, presumably explainable due to the higher level of immunosuppression required. 12 Older patients (above age 60) have an increased risk of PTLD, perhaps due to lower baseline immune surveillance. The incidence is higher in pediatric patients for all transplant types, presumably due to the lower prevalence of EBV infection in that age group.
Besides the impact of EBV, other viral infections may play a role in the development of PTLD, such as HTLV-1, HHV-8, and HCV (as discussed above). Host genetic factors have been hypothesized to play a role, to that end polymorphisms in certain cytokine genes and specific HLA haplotypes have been associated with increased PTLD risk. 12
Post-immunosuppressive/immunomodulatory lymphoproliferative disorders
The topic of lymphoproliferative disorders associated with treatment for autoimmune disorders is a complex one, evidenced by the presence of an altered immune state within the patient, as well as iatrogenic immune suppression. It has been shown that some autoimmune disorders have an inherent increased risk for the development of lymphoma. For example, patients with rheumatoid arthritis have long been observed to have an increased risk of developing leukemia and lymphoma. 13 Increasing disease severity has also been associated with increased risk of lymphoma, regardless of type of therapy; however it remains somewhat unclear if this risk is solely related to the underlying disease process or to the increasingly aggressive treatment modalities used in advanced clinical disease.
In addition to B- and T-cell lymphoma, lymphoproliferations similar to those seen in PTLD have been described in patients treated with immunomodulatory agents. The WHO recognizes this spectrum of lymphoproliferation under the heading “other iatrogenic immunodeficiency-associated lymphoproliferative disorders”. Although the types of disorders seen are similar to that of PTLD, the distribution appears to be somewhat different, with perhaps an increased incidence of Hodgkin lymphoma and Hodgkin-like lesions. 5
Immunosuppressive drugs associated with lymphoproliferative disorders
Lymphoproliferative disorders in the iatrogenic immunodeficiency setting were first described in association with methotrexate (MTX) therapy in patients with rheumatoid arthritis. MTX irreversibly inhibits dihydrofolate reductase, which is necessary for purine and pyrimidine base synthesis, resulting in cytotoxic effects and immunosuppression.
An increased risk of lymphoma has been described in patients with RA, seemingly unrelated to therapy, ranging from 2× to 20×.13, 14, 15, and 16 The literature is divided on whether or not MTX confers an increased risk of lymphoma on top of the baseline increased risk inherent in the RA disease process. The problem typically arises from lack of an appropriate control group (patients with RA not treated with MTX, or perhaps any immunosuppressive agents). Many studies compare these patients to the general population, and given the seemingly increased risk of lymphoma associated with RA alone, this certainly does not provide definitive evidence of a correlation, and certainly not causation.16, 17, and 18
MTX-associated lymphoproliferations typically include diffuse large B-cell lymphoma (DLBCL) and classical Hodgkin lymphoma (cHL), often EBV-positive, although proliferations similar to early lesions and polymorphic PTLD can arise. Typically, patients who develop lymphoma while being treated with MTX have been on long term low dose maintenance therapy. 19 Complete remission has been described in patients upon cessation of MTX therapy. 20 Although it has been hypothesized that therapy results in inhibition of T-cell specific control of EBV infection, multiple studies have shown there is no increase in viral load in patients treated short term or long term with MTX.19 and 21
Development of lymphoma during MTX therapy has also been reported in patients with psoriasis, dermatomyositis, Sjogren's syndrome, and sarcoidosis, although the literature is scant.
This group of agents includes agents typically used in the treatment of inflammatory bowel disease, such as azathioprine and 6-mercaptopurine. These inhibit nucleotide synthesis and may directly inhibit cytotoxic T cell and NK cell function. Another drug in this class is mycophenolate mofetil (MMF), which functions by inhibiting inosine monophosphate dehydrogenase, which prevents the synthesis of guanosine nucleotides. MMF has been shown to inhibit both B- and T-cell function, and may have more T-cell inhibitory effect.
It has been shown that treatment with antimetabolites is associated with a 3–5-fold increased risk of lymphoma, particularly those which are EBV-associated. 22
Of particular concern is the increasingly reported association of immunomodulatory agents and lymphoproliferative disorders. While the term “immunomodulatory agent” is somewhat broad, the more recent application has applied mainly to monoclonal antibodies directed at various targets (mainly cytokines) of the immune system. Tumor necrosis factor (TNF)-alpha inhibitors are widely used to treat various autoimmune disorders, notably inflammatory bowel disease.
Hepatosplenic T-cell lymphoma
Hepatosplenic T-cell lymphoma (HSTCL) is a rare lymphoproliferative disorder of gamma/delta T cells that warrants special mention in the post-immunosuppressive therapy context. This lymphoma tends to affect young patients (median age 35), with a male predominance. Patients typically present with massive hepatosplenomegaly and systemic symptoms. The neoplastic cells are found within the sinusoids of the liver and splenic sinuses and red pulp. The prognosis is typically poor with an average survival of less than 2 years, even with aggressive therapy. 23 There are fewer than 200 cases reported in the literature, however 36 cases have been reported in association with patients taking thiopurines alone or in association with anti-TNF therapy. Many of these patients have been on treatment for inflammatory bowel disease, more often Crohn's disease than ulcerative colitis. Only one case of HSTCL has been reported in a patient treated with anti-TNF therapy without concurrent thiopurine therapy, in a patient with rheumatoid arthritis as the underlying autoimmune disorder. 23
Treatment for post-therapy lymphoproliferative disorders has historically centered on reduction of immunosuppression, which has been shown to be an effective first line treatment in at least a subset of patients. Clinical response is often not sustained in the majority of patients, so conventional chemotherapy is often added. 24 The introduction of rituximab (for B-cell lymphoproliferative disorders) with or without conventional chemotherapy, has significantly improved patient outcomes, especially when introduced early in the course of treatment. 25 Novel therapies include tyrosine kinase inhibitors and anti-CD30 monoclonal antibody (Brentuximab).
- Post-transplant and post-immunosuppressive therapy lymphoproliferations occur in the setting of transplant and autoimmune disease and frequently present in the GI tract.
- Early and polymorphic lesions are frequently associated with EBV, and require a high index of suspicion on the part of the surgical pathologist.
- EBV-negative and T-cell lymphomas appear to be increasing in incidence.
- Hepatosplenic T-cell lymphoma is a very rare, aggressive lymphoma that typically presents in young men, and has been associated with thiopurine and immunomodulatory therapy for inflammatory bowel disease.
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- 2 D. Jagadeesh, B.A. Woda, J. Draper, A.M. Evens. Post transplant lymphoproliferative disorders: risk, classification, and therapeutic recommendations. Curr Treat Options Oncol. 2012;13:122-136 Crossref.
- 3 P.B. Doak, J.Z. Montgomerie, J.D. North, F. Smith. Reticulum cell sarcoma after renal homotransplantation and azathioprine and prednisone therapy. Br Med J. 1968;4:746-748 Crossref.
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Rachel Ochs MD Fellow, Surgical Pathology, Department of Pathology, University of Pennsylvania, School of Medicine, Philadelphia, PA, USA. Conflicts of interest: none declared
Kristen M Stashek MD Assistant Professor, Department of Pathology, University of Pennsylvania, School of Medicine, Philadelphia, PA, USA. Conflicts of interest: none declared
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