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Saudi Journal of Kidney Diseases and Transplantation
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ORIGINAL ARTICLE  
Year : 2021  |  Volume : 32  |  Issue : 2  |  Page : 418-427
Posttransplant lymphoproliferative disorder in renal transplant recipients: Experience from a Tertiary Care Center


1 Department of Laboratory Science and Molecular Medicine, Army Hospital (Research and Referral), New Delhi, India
2 Department of Nephrology, Army Hospital (Research and Referral), New Delhi, India

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Date of Web Publication11-Jan-2022
 

   Abstract 


Posttransplant lymphoproliferative disorders (PTLDs) are potentially fatal complications arising after solid organ or hematopoietic stem cell transplant. The most crucial factor in pathogenesis of PTLDs is either a primary infection with Epstein–Barr virus or reactivation of its latent state due to immune dysregulation. This complex pathobiology leads to a myriad of clinical manifestations due to uncontrolled lymphoproliferation that may be reactive, polymorphous or monomorphous. We report our experience at a tertiary center of six cases detected over a span of six years. All our patients were proven as high grade B-cell lymphoma on histopathology, which remains the gold standard for diagnosis. Two cases were of primary central nervous system lymphoma, two had disseminated disease, fifth showed allograft involvement, and last case presented with gastrointestinal obstruction. All the patients were managed with reduction of immunosuppression, chemotherapeutic agents, and rituximab. Five patients responded well with a follow-up period of 3–28 months since the time of treatment initiation and had preserved renal function with no episodes of disease recurrence or allograft rejection.

How to cite this article:
Gupta D, Mendonca S, Tewari R, Ahuja A, Singh L, Joshi A, Chatterjee T. Posttransplant lymphoproliferative disorder in renal transplant recipients: Experience from a Tertiary Care Center. Saudi J Kidney Dis Transpl 2021;32:418-27

How to cite this URL:
Gupta D, Mendonca S, Tewari R, Ahuja A, Singh L, Joshi A, Chatterjee T. Posttransplant lymphoproliferative disorder in renal transplant recipients: Experience from a Tertiary Care Center. Saudi J Kidney Dis Transpl [serial online] 2021 [cited 2022 Jan 28];32:418-27. Available from: https://www.sjkdt.org/text.asp?2021/32/2/418/335454



   Introduction Top


Posttransplant lymphoproliferative disorders (PTLDs) encompass a spectrum of lymphoid proliferations ranging from indolent, benign, to malignant population of polyclonal to monoclonal cells. PTLDs are defined as lymphomas arising in transplant recipients on immunosuppression. Recipients of both solid organ transplant (SOT) and hematopoietic stem cell transplant (HSCT) have increased risk of developing lymphoproliferative disorders, mostly Epstein–Barr virus (EBV) related.[1],[2] The oncogenic EBV causes abnormal lymphoid proliferation in 50%–80% of PTLDs, especially in early-onset disease (<2 years after transplantation).[3],[4],[5] About 20%–40% of PTLDs are EBV negative, and the pathogenesis in these remains unclear. The first case series of five patients was reported in the late 1960s by Penn et al;[6] however, the term PTLD was coined in the 1980s and was applied to lymphoid proliferations seen in posttransplant patients, ranging from uncomplicated infectious mono-nucleosis to indolent polyclonal population and to aggressive malignant clones. It is one of the most common malignancies after both transplant settings, i.e., SOT and HSCT, with an incidence ranging from 1% to 20%. PTLDs are usually associated with poor prognosis, with a 5-year overall survival rate of 20%.[7],[8]

The latest classification of PTLDs was incur-porated in World Health Organization (WHO) 2017 and includes four histologic types as follows: a) early lesions, b) polymorphic PTLDs, c) monomorphic PTLD, and d) classic Hodgkin’s lymphoma-like PTLD. PTLDs are of two types – nondestructive PTLD (plasma-cytic hyperplasia, infectious mononucleosis-like PTLD, and florid follicular hyperplasia) and destructive PTLDs, which include polymorphic PTLD, monomorphic PTLD (B-cell, T-cell, or natural killer–cell types) and classic Hodgkin’s lymphoma-like PTLD.

As per the classification, PTLDs can be polymorphic or monomorphic. The majority (>90%) are of B-cell origin, but they can also be of T-cell origin/null cell origin, more so in late-onset diseases. PTLDs can have varied clinical presentations, and hence, a high index of suspicion is critical for making a diagnosis. We report, here, the pattern of various categories of PTLDs in renal transplant recipients, their diagnosis, treatment, and outcome, as observed at our center.


   Materials and Methods Top


At our tertiary center, we are performing both live and deceased donor kidney transplants over last two decades. This was a retrospective observational analysis of 350 patients of Asian ethnicity who underwent renal transplant in our hospital over a period of last six years (2014–2019). Pretransplant immunological workup included human leukocyte antigen (HLA) typing, complement-dependent cytotoxicity crossmatch, flow cytometry cross match, panel reactive antibody (PRA) level, and EBV serum immunoglobulin G status. Patients who were at high risk in terms of 5–6/6 HLA mismatch and unrelated donors received induction therapy with injection basiliximab 20 mg on D+0 and D+4. Patients having high pretransplant PRA levels, second transplants, deceased donor transplants were given induction with antithymocyte globulin (ATG) in a cumulative dose of 4.5 mg/kg. Other immunosuppressants added were steroids, tacrolimus 0.1 mg/kg in divided doses, and mycophenolate mofetil (MMF) 30 mg/kg in divided doses. We identified six cases out of a total of 350 transplant recipients who developed lymphoproliferative disease after kidney transplant during this period. All our six cases on clinical suspicion were subjected to organ-specific biopsy. The tumors were classified based on the latest WHO 2017 classification of PTLDs, taking into consideration the morphology, supported by immunohistochemistry (IHC).


   Results Top


Patient demographics

Six cases were diagnosed with PTLDs out of total of 350 renal transplant cases (1.7%). The median interval from transplant to diagnosis was 48 months. As per histological classification, all our six cases were of monomorphic B-cell non-Hodgkin’s lymphoma, of which five presented with diffuse large B-cell lymphoma (DLBCL) and one patient developed plasmablastic lymphoma. Two of our cases presented within two years of renal transplant (early onset), whereas other four had a late onset.

Clinical presentation

The clinical presentation was varied, depending on the organ involved by the tumor. One case was a second transplant and he was detected with multiple organ involvement. [Table 1] summarizes the demographic profile of patients including the time interval from renal transplant to development of lympho-proliferative disease. Organ involvement was primarily extranodal (5 cases). Case 3 presented with enlarged bilateral cervical and inguinal lymph nodes. Only one showed involvement of the allograft by lymphoma cells [Figure 1]. Localized involvement of single organ was seen in three cases. Two patients presented with central nervous system (CNS) manifestations and on imaging followed by stereo tactic biopsy, were confirmed to be primary CNS lymphoma [Figure 2]. Sixth patient presented with complaints of pain in abdomen with melena, followed by small bowel intussusception. He underwent an emergency laparotomy for intussusception and loop of jejunum was resected. A large submucosal tumor mass was identified and histomorphology along with an extensive IHC panel confirmed it as plasmablastic lymphoma.
Figure 1: (A) Renal biopsy showing infiltration of interstitium by sheets of atypical lymphoid cells (H&E, ×100), (B and C) On higher magnification, the atypical cells have coarse chromatin, prominent nucleoli, and scant cytoplasm. (H&E ×200, ×400), (D) Immunohistochemical expression showing strong positivity of lymphoid cells for cytoplasmic CD20.

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Figure 2: A) Stereotactic Brain Biopsy showing prominent perivascular cuffing by atypical lymphoid cells, B) These lymphoid cells have vesicular nuclei with prominent nucleoli, C and D) The tumor cells show strong membranous and nuclear positivity for CD20 and Ki67, respectively.

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Table 1: Demographics of renal transplant recipients.

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Microscopic findings

Histological subgroups seen in our cohort were primarily DLBCL involving different organs, including allograft. The tumor cells were large with immunoblastic morphology, had vesicular nuclei with prominent nucleoli. Mitosis was brisk. These lymphoid cells were positive for leukocyte common antigen, CD20 and Ki67 was 80%–85%. The tumor cells were negative for ALK, CD30, Pan CK, Melan-A, and CD68. The negative panel ruled out a poorly differentiated carcinoma and malignant melanoma. They were further typed using CD10, MUM1, and BCL6 immunostains and classified into germinal and nongerminal center type of DLBCL.

The sixth case was of jejunal mass showing diffuse infiltration of submucosa by sheets of monomorphic large atypical cells having immunoblastic morphology. The tumor cells had large vesicular nuclei with prominent nucleoli. Interspersed were seen numerous plasma cells. The overlying mucosal epithelium was intact and uninvolved. On IHC, the atypical lymphoid cells were positive for CD38, CD138, and Ki67 – 90%. The cells were negative for CD20, CD3, CD56, and anti-MPO [Figure 3].
Figure 3: (a) Growth from jejunal resection specimen showing infiltration of submucosa by sheets of atypical lymphoid cells (H and E, ×100), (b) On higher magnification the atypical cells have immunoblastic morphology, coarse chromatin, prominent nucleoli and scant cytoplasm. (H and E, ×200, ×400), (c and d) Immunohistochemical expression showing strong positivity of lymphoid cells for cytoplasmic CD138 and Ki67-90%.

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Treatment and outcome

The standard protocol for the treatment of PTLD was followed at our center with variation based on the tumor histology, stage of the disease, and clinical condition of the patient.

All cases were of B-cell non-Hodgkin’s lymphoma (DLBCL and plasmablastic lymphoma) and were treated by our oncology team with R-CHOP regime (cyclophosphamide, doxorubicin, vincristine, and prednisone plus the monoclonal antibody rituximab). The case of plasmablastic lymphoma was treated with CHOP regime only.

While on treatment, the patients were subjected to frequent 18-fluorodeoxyglucose positron emission tomography–computed tomography (18FDG PET-CT) that has clinical significance in the evaluation of PTLD. 18FDG PET-CT scan allows precise anatomic localization of FDG-avid lesions, hence is helpful in staging of disease and evaluation of response to therapy. It can characterize the persistent disease and help to differentiate residual tumor from fibrosis.

The routine immunosuppression was reduced in all patients. MMF was tapered and stopped. Mammalian target of rapamycin (mTOR) agents in the form of everolimus was added as the third immunosuppressant, and the dose of calcineurin inhibitors was reduced after explaining the risk of graft rejection. Patients of primary CNS lymphoma were also subjected to whole-brain radiotherapy before commencing chemotherapy. Interim 18FDG PET-CT done (after four cycles) showed a complete response to treatment in four of our patients. One case of primary CNS lymphoma succumbed to the disease while on treatment. The patient of plasmablastic lymphoma (PBL-PTLD) has completed his second cycle of chemotherapy and has responded well. The clinical presentation, organ involvement, treatment given, and outcome, i.e., median survival of these patients since the time of diagnosis, are depicted in [Table 2].
Table 2: Clinical presentation, histological features, treatment, and outcome of patients with posttransplant lymphoproliferative disorder.

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   Discussion Top


We hereby summarize six years of our experience with PTLD in renal allograft recipients at our transplant center. PTLD occurred in 1.7% of the recipients with monomorphic B-cell NHL as the primary histological type. Sakhuja et al reported an incidence of 1.45% of PTLD in their study of 2000 Indian transplant cases.[9] The major histological type as seen in their cohort was monomorphic B-cell NHL (DLBCL), as also seen in our study. The diagnosis was confirmed in all our patients by histopathology with immunostaining suggesting B-cell origin.

The primary clinical complaints seen in our patients were either constitutional or localized to organ involved. PTLDs can have myriad ways; hence, familiarity and high index of suspicion are critical for making a diagnosis.[10] The symptoms are nonspecific such as fever, weight loss, anorexia, night sweats, and allograft dysfunction, or it may be related to lymphoid proliferation in organs or specific sites, i.e., symptoms of gastrointestinal tract (GIT), liver, lungs, brain, or kidneys. Extra-nodal involvement of various organs, i.e., GIT (30%), followed by CNS (10%–15%), lungs (4%), and liver (5%–12%), is more common.[11] Involvement of allograft is seen in up to 15% of kidney recipients, and this may be higher in cardiothoracic organs. One of the patients had allograft involvement, two presented with primary CNS lymphoma, two had a disseminated disease, and one presented with GIT symptoms of small bowel obstruction due to a large jejunal mass. PTLD after SOT follows a bimodal peak, i.e., before two years (early onset) of transplant and second peak after 5–10 years (late onset). We had two cases with early onset of disease. Among monomorphic B-cell lymphomas, DLBCL is the most common PTLD, PBL-PTLD being comparatively rarer entity. It had initially been described as EBV-associated B-cell neoplasm arising in human immunodeficiency virus patients; however, it is now also known to occur in transplant recipients. Plasmablastic lymphomas display immunoblastic morphology and have aggressive clinical course and poorer survival rates.[12] There are various risk factors associated with the disease, of which EBV sero- negativity in the recipient at time of transplant carries the highest chances of lymphoma development. Other factors implicated are organ transplanted, type and duration of immunosuppression used, etc.[13],[14],[15],[16],[17],[18] Two of our high immunologic risk recipient cases received induction with basiliximab (IL-2 receptor antagonist), whereas the deceased donor–recipient and second transplant case received ATG (T-cell depleting agent). Use of T-cell depleting monoclonal antibodies and Thymoglobulin significantly increases the risk of PTLD as against the use of IL-2 receptor antagonists. Moreover, it is the intensity of combination drugs used in maintenance that predisposes to lymphomagenesis, rather than the specific agents used.[19],[20],[21],[22] Three of the cases had episodes of rejection during the follow-up period that was treated with intravenous methylprednisolone. Intravenous immunoglobulin and plasmapheresis was added in cases of mixed rejection or antibody-mediated rejection. However, none received ATG. Although the gold standard for establishing the diagnosis was site-specific biopsy, we found PET-CT scan to be very useful in diagnosing as well as assessing response to treatment. In their report, Panagiotidis et al have found PET-CT to have a sensitivity of 88.2% and specificity of 91.3% in the diagnosis of PTLD.[23],[24],[25]

Treatment of PTLDs is challenging and involves a step-wise strategy starting with decrease in immunosuppression. Based on histomorphological subtype and patient response to reduction in immunosuppression, the patient is subjected to chemotherapy. Reducing the dosage of immunosuppressive agents is the most useful therapy in PTLDs. The rationale is that the recovery of cytotoxic T-lymphocytes against EBV prevents expansion of EBV-driven B-lymphocytes and thus regresses the B-cell proliferation. All our patients had monomorphic high-grade B type NHL, and hence, all were treated with reduced immunosuppression along with chemotherapy, to which they responded well. Finally, five patients received rituximab as part of the treatment protocol along with CHOP. MMF was replaced by mTOR inhibitor, everolimus, whereas the rest of the immune chemotherapy was continued. mTOR inhibitors have been found to maintain a state of immune senescence, hence curbing the expansion of EBV-positive B-cells.[26],[27],[28],[29],[30],[31] Primary CNS lymphoma cases in addition to the protocol chemotherapy also underwent whole-brain irradiation. One of the primary CNS lymphoma cases was diagnosed late with and in spite of initiating treatment, succumbed to the disease. All the other five patients responded well to treatment, achieved remission, and are presently rejection free and on regular follow-up in nephrology outpatient department.


   Conclusion Top


PTLD is a life-threatening complication that presents after both SOT and HSCT with varied clinical manifestations and is a major cause of increased mortality and morbidity. Our patients responded well to the standard treatment regimens of reduction in immunosuppression, use of chemotherapeutic agents, and rituximab. However, more insight and research into the pathogenesis of post-transplant lymphomas can definitely improve the diagnosis, management, and outcome of these disorders. Furthermore, PTLDs are rare diseases, and hence, a high index of suspicion on the part of clinicians can help clinch the diagnosis in early stages and prevent fatal complications. In our experience, the overall survival of patients has improved while maintaining a stable graft function, in this rituximab era. The role of adoptive immuno-therapy and immunomodulatory agents in PTLD management is also being explored.

Conflicts of interest: None declared.



 
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Correspondence Address:
Tathagata Chatterjee
Department of Laboratory Science and Molecular Medicine, Army Hospital (Research and Referral), New Delhi
India
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DOI: 10.4103/1319-2442.335454

PMID: 35017336

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