| Abstract|| |
Iatrogenic immunodeficiency-associated lymphoproliferative disorders comprise a group of lymphoid neoplasms that are associated with an immunosuppressed state, either in the posttransplant period, or during the treatment of various autoimmune and rheumatologic disorders by immunomodulatory medications. Their morphologies vary widely but are generally classified according to the lymphomas that they most closely resemble. This group is strongly associated with infections by the Epstein-Barr virus as a result of impaired immune function in the immunosuppressed state. Although further classification may become necessary in the coming years, they are distinguished from lymphomas in immunocompetent hosts because reduction or cessation of immunosuppressive or immunomodulatory therapy can result in complete clinical remission.
Keywords: Iatrogenic, lymphoproliferative disorders, nontransplant, transplant
|How to cite this article:|
Kubica MG, Sangle NA. Iatrogenic immunodeficiency-associated lymphoproliferative disorders in transplant and nontransplant settings. Indian J Pathol Microbiol 2016;59:6-15
|How to cite this URL:|
Kubica MG, Sangle NA. Iatrogenic immunodeficiency-associated lymphoproliferative disorders in transplant and nontransplant settings. Indian J Pathol Microbiol [serial online] 2016 [cited 2019 Nov 21];59:6-15. Available from: http://www.ijpmonline.org/text.asp?2016/59/1/6/178215
| Introduction|| |
Iatrogenic immunodeficiency-associated lymphoproliferative disorders (LPDs), noted to occur in posttransplant and other clinical settings requiring immunosuppression, are recognized by the World Health Organization (WHO) classification as a heterogeneous group of lymphoid and plasmacytic proliferations with highly variable morphologies and clinical courses.  Posttransplant lymphoproliferative disorders (PTLDs) comprise the majority of cases and can be seen following transplantation of solid organs, bone marrow, or stem cells. Other iatrogenic immunodeficiency-associated LPDs constitute a smaller number of cases and have been described in patients receiving a variety of immunosuppressive and immunomodulatory medications. A large subset of these lymphoid proliferations is associated with the Epstein-Barr virus (EBV), particularly in the posttransplant setting. These lesions can be morphologically indistinguishable from lymphomas in immunocompetent hosts, but they are classified together by virtue of the fact that alteration or cessation of immunosuppression may lead to their complete regression.
| Posttransplant lymphoproliferative disorders|| |
PTLDs are generally considered to originate from benign polyclonal proliferations responding to EBV or other stimuli. Over time, there is a selection of an oligoclonal and eventually monoclonal subpopulation of follicular/postfollicular B-cells or, less commonly, postthymic T-cells. ,, As PTLDs progress, increasing clonal dominance and the acquisition of cytogenetic abnormalities renders them less susceptible to immune regulation. These clonal abnormalities are often the same as those associated with the morphologically similar lesions seen in immunocompetent individuals. ,,
Most cases of PTLD can be shown to contain EBV-infected lymphoid or plasmacytic cells that proliferate as a result of impaired cytotoxic T-cell function. Myeloablative chemotherapy regimens used in bone marrow and stem cell transplants also results in an immunological milieu that allows for the proliferation of these cells. ,, Specific immunologic changes documented include a decreased overall CD4 + T-cell count and perhaps unsurprisingly, a decreased EBV-specific CD8 + T-cell population. 
While the majority of cases are EBV-positive, up to 30% of PTLDs fail to show this typical EBV positivity, and the proportion of EBV-negative cases has been increasing in recent times. ,,,,, While some other infectious agents have been identified, such as human herpes virus 8 in posttransplant primary effusion lymphoma, ,, most cases of EBV-negative PTLD are of unknown etiology. It is possible that some of these cases developed in response to EBV, but that the expression of EBV-related proteins was lost in the course of transformation.  One genotypic study looking at a wide variety of PTLDs showed no significant difference between the expression of EBV-induced changes in EBV-positive and EBV-negative cases,  however conflicting results from smaller series do exist.  Nevertheless, these EBV-negative cases are classified as true PTLDs since altered immunosuppression regimens may lead to their regression. 
Nearly all cases of PTLD following solid organ transplant arise from host lymphoid cells,  although cases derived from donor cells seems to have a more favorable prognosis. , Those seen following bone marrow transplantation are almost always derived from donor cells, and this naturally follows from pretransplant ablation and subsequent establishment of a donor-based immune system.  Unfortunately, bone marrow transplant-associated lesions carry a much more guarded prognosis with mortality rates of up to 92%. ,
The rate of development of PTLDs varies depending on the type of transplant performed and the subsequent immunosuppressive regimen, however, they occur with an overall incidence of approximately 2%.  The lowest incidence of PTLD is seen among renal transplant recipients (<1%),  with only a modestly increased incidence after a bone marrow, stem cell, heart, and liver transplants (generally 1-2%).  A much higher incidence (33-47%) is estimated to occur in the setting of the lung, heart-lung, and multi-organ transplants. , Given that the majority of cases are associated with EBV, it is perhaps unsurprising that the most important risk factor for the subsequent development of a PTLD is negative EBV serology prior to transplantation.  This is also the likely explanation for the significantly higher incidence of PTLDs seen in children over adults. Of note, EBV mismatch, defined as transplantation of an organ or tissue from an EBV-seropositive donor to an EBV seronegative recipient, has been shown to increase the incidence of PTLD by up to 75 times. 
These different incidences in the development of PTLD may be explained in part by the length of treatment, relative intensity, and particular agents used in achieving posttransplant immunosuppression. Longer durations of immunosuppression are associated with the development of PTLD later in the clinical course,  whereas greater combined intensity of immunosuppression is associated with a higher incidence of PTLD within the 1 st year posttransplant. ,
The majority of cases of PTLD arise within the 1 st year after transplantation. Shorter durations of onset are usually associated with younger patients but have also been independently described following heart-lung, lung, and bone marrow transplants. , Although there is no definitive data from series performed to date, it seems that PTLDs presenting after a longer duration are more likely to be EBV-negative, less responsive to altered immunosuppressive regimens, and have a less favorable prognosis. , Hodgkin-type and T-cell PTLDs are seen more commonly in this late-presenting group as well. ,
The clinical presentation of patients with PTLD varies widely, and this is at least partly attributable to their diverse underlying morphologies and the various allografts with which they are associated. Documented cases include patients with nodal and extranodal tumors, widely disseminated disease, vague constitutional symptoms, or even asymptomatic processes discovered during routine follow-up.  Regardless of the type of allograft, the most common sites of involvement include lymph nodes, the gastrointestinal (GI) tract, liver, and lungs. Involvement of the central nervous system is rare and has become increasingly less common following the introduction of cyclosporin.  Localization of a PTLD to the allograft is associated with a favorable prognosis and is most commonly seen in the lung (20% of allograft-limited cases). ,,, It can be difficult to differentiate allograft-limited PTLD from transplant rejection since signs of allograft dysfunction can be present in either case. In contrast to localized processes, PTLDs that present as disseminated disease are associated with survival rates of <10%. 
Bone marrow involvement is relatively uncommon in PTLD patients, but it does occur. Whether the bone marrow is focally or extensively involved, the lesions are morphologically similar to those present in the allograft or other tissues. , Peripheral blood involvement occurs with even less frequency. 
While PTLDs can present even with low serum EBV levels, several studies have noted an increase in viral load preceding the development of a PTLD, and some have suggested its use in the surveillance of high-risk patients. ,,,, Unfortunately, universally accepted parameters for EBV viral load have yet to be established.  It is likely that the degree of increase in EBV load depends on the type and intensity of agents used in the immunosuppressive regimen.
EBV positivity is most reliably diagnosed via in situ hybridization of EBV-encoded small RNAs, however, it can also be confirmed with immunohistochemical markers for the EBV latent membrane protein 1. ,,,,,
Diagnosis and classification
The WHO classification stratifies PTLDs into four broad categories [Table 1]. There are three essential components that must be assessed to render an accurate diagnosis of PTLD. These are histological evaluation, determination of the immunophenotype, and evaluation of EBV status. Assessment of adequate tissue displaying the lesional architecture is essential. Given the often heterogeneous nature of these lesions, evaluation of morphology should be done on histologic sections whenever possible. This intra-lesional heterogeneity can make the classification of PTLDs difficult, and subjective interpretation on the part of the diagnosing pathologist is often required.
Plasmacytic hyperplasia (PH) most often presents as a mass lesion in lymph nodes or the tonsils. Despite the increased numbers of plasma cells and small lymphocytes with interspersed large cells, there is preservation of the underlying nodal or tonsilar architecture. , PH, when it lacks EBV positivity, is morphologically indistinguishable from nonspecific lymphoid hyperplasia [Figure 1].
|Figure 1: A 2-year-old boy who recently underwent a heart transplant presented with enlarging tonsils. An H and E section showed changes consistent with lymphoid hyperplasia (a), and higher magnification revealed an abundance of plasma cells (b). CD3 (c) and CD20 (d) staining were unremarkable, but there were more CD138 positive cells than expected (e). Given his history, a diagnosis of plasmacytic hyperplasia was made. As commonly seen in plasmacytic hyperplasia, Epstein-Barr virus-EBV-encoded small RNAs was negative (f)|
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Infectious mononucleosis (IM)-like PTLD usually presents in lymph nodes or the tonsils as well, and like PH, the underlying architecture of the involved tissue is preserved. , These specimens demonstrate the same changes associated with IM in immunocompetent individuals, with a florid proliferation of small lymphocytes, plasma cells, and often very prominent populations of transformed cells and immunoblasts. In cases with particularly high numbers of large cells, it can be impossible to distinguish IM-like PTLD from a polymorphic PTLD; however, if the morphology is within the range of morphologic changes seen in IM in immunocompetent patients, a diagnosis of IM-like PTLD is favored.
Early lesions tend to occur in younger patients, although they are seen with greater frequency in any transplant recipient without previous EBV exposure. , Patients with PH and IM-like lesions have a generally favorable prognosis, but the progression of IM-like lesions to aggressive polymorphic variants has been reported. ,,
In both PH and IM-like PTLD, immunohistochemical studies fail to demonstrate B- or plasma cell clonality. They also characteristically lack aberrant B- and T-cell phenotypes. More sensitive techniques, such as genotypic studies or EBV terminal repeat analysis, are usually required to demonstrate the small clonal populations in these lesions. 
Polymorphic posttransplant lymphoproliferative disorders
In contrast to the early lesions, polymorphic (P)-PTLDs tend to efface the architecture, with a destructive proliferation of small-to-intermediate sized lymphocytes, plasma cells, and immunoblasts [Figure 2].  The lymphocytes often have irregular nuclear contours with frequent clefting and angulation. Immunoblasts are scattered, but they may be focally increased surrounding the areas of geographic necrosis that are typical of P-PTLD. Atypical Reed-Sternberg-like forms may be present, and it is likely the presence of these atypical large cells that led to the diagnosis of Hodgkin-like PTLD in the past. However, the WHO no longer recognizes this diagnosis in posttransplant patients. Instead, immunohistochemical studies are used to differentiate between P-PTLD and classical Hodgkin lymphoma (CHL)-type PTLD. In cases where the large cells predominate, these lesions are instead classified as monomorphic PTLDs.
|Figure 2: A 56-year-old man, 1-year postliver transplant presented with enlarging axillary lymphadenopathy. An incisional biopsy showed partial effacement of the nodal architecture by a population of small-to-intermediate sized lymphocytes and immunoblasts (a and b). There was diffuse CD20 positivity in the interfollicular areas (c and d). CD3 staining was much less prominent (e). Epstein-Barr virus-EBV-encoded small RNAs was diffusely positive (f) consistent with a polymorphic posttransplant lymphoproliferative disorder|
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The polymorphic group is the most common type of PTLD in children, and it seems to occur most commonly following primary EBV infection. 
P-PTLDs contain variable, mixed populations of B- and T-cells. Occasional lesions will contain monoclonal B-cell proliferations. However clonality can be heterogeneous within individual lesions and between lesions in the same patient.  Some have a prominent background T-cell population, or contain only polyclonal plasma cells.
Monomorphic posttransplant lymphoproliferative disorders
The monomorphic (M)-PTLD group is composed of a variety of B-, T-, natural killer (NK)-, and plasma cell proliferations that fulfill the morphological and immunophenotypical criteria for an analogous lymphoid neoplasm seen in immunocompetent hosts. These lesions tend to have more dominant clones than do polymorphic PTLDs, , and although the majority of M-PTLDs are EBV-positive, EBV-negative lesions are most often monomorphic. , It is important to note that lesions that resemble indolent B- and T-cell lymphomas are not included in this classification.
M-PTLDs are less likely to respond to altered immunosuppressive regimens, ,, and they seem to have a less favorable prognosis than other PTLDs, but the data in this regard are variable. , Cytogenetic abnormalities are the most prevalent in M-PTLDs, and some of the more frequently encountered abnormalities include trisomy 9, trisomy 11, 8q24 and 14q32 rearrangements, and 1q11-21 breaks. 
Monomorphic B-cell posttransplant lymphoproliferative disorders
Monomorphic B-cell PTLDs often contain abundant transformed B-cells, and as such they tend to resemble diffuse large B-cell lymphoma (DLBCL) [Figure 3]. Also included in this group are lesions that resemble Burkitt lymphoma and plasma cell neoplasms, although these are less common. This group is termed monomorphic on the basis of their uniform populations of plasmacytic or transformed neoplastic cells. As per the WHO 2008 classification, small B-cell lymphomas such as follicular lymphoma or mucosa-associated lymphoid tissue lymphomas are not designated as PTLD. 
|Figure 3: A 60-year-old man presented with constitutional symptoms and cervical lymphadenopathy 4-year postkidney transplant. Tissue from an enlarged lymph node showed effacement of the underlying architecture by sheets of atypical large cells (a-c). There was background CD3 staining in the smaller lymphocytes (d) and the large lymphoid cells were positive for CD20 (e). Epstein-Barr virus-EBV-encoded small RNAs was diffusely positive, consistent with a monomorphic posttransplant lymphoproliferative disorders, diffuse large B-cell type|
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Plasma cell myeloma and plasmacytoma-like lesions should fulfill all the major criteria for plasma cell neoplasms in the immunocompetent host. Lesions with a plasma cell myeloma morphology carry a very poor prognosis.  Plasmacytoma-like lesions are seen predominantly in the GI tract, although they can arise in other nodal and extranodal sites,  and are associated with a more variable prognosis. 
The majority of monomorphic B-cell PTLDs express a late germinal center or postgerminal center phenotype (CD10 - , BCL6 +/- , MUM-1 + , CD138 +/- ). A subset of cases, particularly EBV-negative ones, express a germinal center phenotype (CD10 +/- , BCL6 + , MUM-1 - , CD138 - ). ,,, The DLBCL-type M-PTLD expresses pan-B-cell markers with clonal surface or cytoplasmic immunoglobulin. Burkitt lymphoma-like lesions express a characteristic CD10 + monoclonal B-cell phenotype. The plasma cell group should contain monoclonal plasma cell populations.
Monomorphic T- and natural killer-cell posttransplant lymphoproliferative disorders
Monomorphic T- and NK-cell PTLDs are the least common in this group, accounting for <15% of all PTLDs. , While they can contain transformed cells, they are not necessarily as prominent as in other monomorphic lesions. Similar to other PTLDs, most fulfill the criteria for another lymphoma and those that resemble a peripheral T-cell lymphoma are the most common.  Up to 15% of all hepatosplenic T-cell lymphomas arise in the posttransplant period,  and rare NK-cell neoplasms have been described as well. , These NK-cell lesions behave very aggressively and must be distinguished from the morphologically similar but indolent T-cell large granular lymphocytic leukemia. T- and NK-cell PTLDs generally, though not universally, carry a poor prognosis, but cases that respond to decreased immunosuppression have been reported. 
The morphology of T-cell PTLD can be identical to that of a P-PTLD, so it is extremely important to make use of genotypic and phenotypic studies when a T-cell PTLD is suspected. T/NK-cell PTLDs display phenotypes analogous to their counterpart lymphomas in immunocompetent hosts, with positive pan-T-cell and occasionally NK-cell markers. Fewer than one-third of T-cell PTLDs are EBV-positive, and NK-cell PTLDs probably express EBV-positivity even less frequently. ,
Classical Hodgkin lymphoma-type posttransplant lymphoproliferative disorders
The rarest PTLD, CHL-type most often resembles mixed cellularity CHL, ,,, and some may represent a transformation of another non-Hodgkin-type PTLD.  The presence of Reed-Sternberg-like cells alone is not enough to make a diagnosis of CHL-type PTLD since many contain Reed-Sternberg-like immunoblasts. As such, all morphological and immunophenotypical criteria for CHL must be demonstrated in these cases. Specifically, CHL-type PTLD contains a population of CD15 + , CD30 + , CD45 - Reed-Sternberg cells (occasionally CD15 - ) admixed in a T-cell-rich background. In contrast, the immunoblasts and transformed large cells in other PTLDs should be CD15 - , CD20 + , and CD45 + .
In accordance with their heterogeneous nature, there is no single effective treatment strategy for the various PTLD lesions. On diagnosis of a PTLD, patients tend to be treated with a decrease or cessation of immunosuppression if possible. Preservation of the graft is a critical consideration when formulating a treatment regimen for PTLD, but they represent a serious posttransplant complication with high-end mortality estimates ranging up to 50-80%.  As discussed in the preceding sections, the response rate to the alteration of immunosuppression is variable. , The cases least likely to respond to decreased immunosuppression include PTLDs causing organ dysfunction and those with central nervous system or multi-organ involvement. , In the case of localized lesions, lesions that do not respond to immunosuppression reduction can sometimes be successfully treated with surgical excision or targeted radiation therapy.
Recently, there has been increasing evidence supporting the use of rituximab, a chimeric monoclonal antibody against CD20, in CD20 + cases.  This strategy may be of particular interest in cases with highly dominant B-cell clones as these have historically tended to be less likely to respond to decreased immunosuppression. 
There is no clear consensus with regard to the timing at which combined chemotherapy should be instituted, and the decision is made more difficult given that patients with PTLDs tend to experience greater morbidity and higher rates of mortality related to chemotherapy than those with standard non-Hodgkin lymphomas. , Even still, chemotherapy is sometimes initiated prior to or in tandem with a trial of immunosuppression alteration, as is the case for patients with CHL-like and Burkitt lymphoma-like lesions.
Antiviral agents have generally been unsuccessful in the treatment of PTLD, and this is likely because most anti-EBV compounds target its lytic phase - a minor component of the EBV infections seen in PTLD. 
| Iatrogenic Immunodeficiency-Associated Lymphoproliferative Disorders in Nontransplant Settings|| |
Iatrogenic LPDs have been described in association with a number of immunosuppressive agents in nontransplant settings. , There is some overlap between the implicated agents and those used in the achievement of posttransplant immunosuppression, but others are specific to the treatment of autoimmune or LPDs. , As opposed to PTLDs, indolent lymphomas are included in this classification.
There is a well-recognized association between methotrexate use and the development of LPDs in patients undergoing treatment for rheumatoid arthritis, dermatomyositis, and less commonly, psoriasis. ,,,,,, The patients typically have histories of longstanding underlying disease, have been undergoing treatment with methotrexate for a median of 3 years, and are on methotrexate at the time of diagnosis. Half of these cases involve one or more of a variety of extranodal sites, including the GI tract, skin, liver, spleen, lung, kidney, thyroid, bone marrow, and soft tissues. ,,
Methotrexate-associated LPDs can present as a range of lesions similar to PTLDs, but the morphologic subtypes are seen at different rates. , DLBCL-like cases are the most common, and up to 25% of methotrexate-associated LPDs fulfill the criteria for CHL (mixed cellularity or other subtypes). Lesions resembling Burkitt lymphoma have also been frequently described. In contrast to PTLDs, polymorphic cases are uncommon, but they can occur and progression of these cases to monomorphic or CHL-type lesions has been documented as well. Because lesions resembling indolent lymphomas are included in this classification, there have been reported cases of the various small B-cell neoplasms or, less commonly, peripheral T-cell lymphomas including large granular lymphocytic lymphoma. 
Approximately, 40% of methotrexate-associated LPDs are EBV-positive, with CHL-like cases being the most likely to express EBV-positivity (up to 80%). ,,,
It is important to accurately diagnose methotrexate-associated LPDs since up to one-third of these lesions will regress following the withdrawal of methotrexate therapy, even in monoclonal lesions. , Regression can, however, be transient, and up to half of patients who experience it will eventually go on to require chemotherapy. Cases that are EBV-positive are the most likely to regress, but the response to treatment cessation has been documented in EBV-negative cases as well. , The response rate in CHL-like cases is less consistent.
Fludarabine, a purine analog and chemotherapeutic agent commonly used in the treatment of low-grade lymphomas, has been associated with the development of EBV-positive LPDs.  While this association can more difficult to demonstrate given the presence of an underlying lymphoma, these LPDs have been found to be morphologically and clonally distinct from the lymphoma being treated with this agent. EBV viral loads have also been demonstrated to rise following initiation of fludarabine therapy. , Fludarabine-associated LPDs have been reported as polymorphic-PTLD-like, monomorphic-PTLD-like, and CHL-like proliferations.  However in all cases it is important to first rule out a Richter-like transformation of the lymphoma being treated.
Infliximab, a chimeric monoclonal antibody against tumor necrosis factor-alpha (TNF-α), is used in the treatment of various autoimmune diseases and has been associated with the development of a variety of LPDs [Figure 4].  Like other TNF-α antagonists, it has a wide range of effects on the immune system, and the exact mechanisms that lead to the development of LPDs are not clearly understood. EBV appears to play a role, with evidence for EBV reactivation following administration of infliximab and subsequent regression following its cessation.  Of particular clinical importance, the use of infliximab in combination with azathioprine or mercaptopurine in the treatment of Crohn's disease has been linked with the development of lesions resembling hepatosplenic T-cell lymphoma.  This lesion behaves like its aggressive counterpart in immunocompetent patients, with a median survival of <2 years. 
|Figure 4: A 46-year-old man with a history of Crohn's disease, treated with Humira and azathioprine, complained of rapidly growing skin lesions on his face. An H and E section revealed a polymorphic lymphoid infiltrate in the dermis with large atypical cells showing convoluted nuclei (a-c). These large atypical cells were positive for CD20 (weak) (d), CD15 (e), CD30 (f) and Epstein-Barr virus-EBV-encoded small RNAs (g), and negative for CD3 (h). Based on our impression and second opinion consultation from an expert hematopathologist, the diagnosis was rendered as "Iatrogenic immunodeficiency-associated B-cell lymphoproliferative neoplasm, favor Hodgkin-like subtype." Following reduction of his immunomodulatory medications, the skin lesions disappeared in 4 weeks' time|
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Recently, a case of EBV-positive Hodgkin-lymphoma-like LPD in a patient on long-term mycophenolate mofetil for the treatment of autoimmune hepatitis was reported.  As the use of immunomodulatory medications becomes more widespread, it is likely that additional associations will be found.
| Summary|| |
Iatrogenic immunodeficiency-associated LPDs form a diverse group of lymphoid neoplasms, and further subclassification may be necessary in coming years. Although their morphologies can be quite varied, a clinical history including immunosuppression with or without transplantation is key and should point to this entity as a possible diagnosis. It remains an important diagnostic consideration in part because of the morbidity and mortality associated with these lesions, but also because its timely recognition aids in guiding clinical management with the potential for regression with altered immunotherapy.
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Nikhil A Sangle
UH A3 151, University Hospital, 339, Windermere Road, London, ON N6A5A5
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2], [Figure 3], [Figure 4]