Autoimmune Phenomenon Associated With Posttransplant Lymphoproliferative Disorder

Introduction

Posttransplant lymphoproliferative disorders (PTLDs) encompass heterogeneous lymphoid or plasmacytic proliferations occurring in immunocompromised patients following both solid organ and hematopoietic stem cell transplantation.¹ Among them, T-cell and NK-cell monomorphic PTLDs are rare entities, representing 2% to 15% of all PTLDs that fulfil the criteria for any of the T-cell or NK-cell lymphomas.²

Angioimmunoblastic T-cell lymphoma (AITL) is a rare mature T-cell lymphoma accounting for 1% to 2% of all non-Hodgkin’s lymphomas and 15% to 20% of all mature T-cell lymphoma. However, AITL is the second most prevalent subtype of mature T-cell lymphoma in the Western world.^3,4 As suggested by gene expression profiling, AITL originates from the monoclonal proliferation of T-follicular helper (TFH) cells.⁵ Patients with AITL often present with exacerbated inflammatory response, immune dysregulation, and predisposition to autoimmunity phenomena, which is thought to be a consequence of TFH cell dysfunction.⁶ Although considerable progress has been made in the understanding of AITL, particularly on the molecular level, its prognosis remains very poor despite treatment.^3,4

In this article, we aim to report a unique condition where a TFH cell-derived PTLD was revealed by the recurrence of membranous glomerulonephritis (MN) on the renal graft in a context of new onset of autoimmune disorders, including leukocytoclastic vasculitis, polyclonal hypergammaglobulinemia, and serum markers of autoimmunity.

Case Presentation

A 66-year-old male received kidney transplantation for PLA2R-positive MN with no history of specific immunosuppressive treatment before kidney transplantation. Neither preexisting nor day 0 (D0) donor-specific HLA antibody was detected and crossmatch was negative at the time of transplantation. Anti-PLA2R antibody dosage at D0 of kidney transplantation was weakly positive and measured at 95.2 RU/ml. Small-vessel vasculitis serologies were negative for antineutrophilic cytoplasmic antibodies and antinuclear antibodies. Hepatitis B virus serology revealed an immune response to vaccination, and Hepatitis C virus serology was negative. Induction immunosuppressive therapy consisted of basiliximab associated with mycophenolate mofetil, tacrolimus, and corticosteroids regimen, which were continued as maintenance therapy. Subsequently, at 4 months, the transplantation was complicated by an antibody-mediated rejection with negative donor-specific HLA antibody. The Banff classification of allograft pathology was g1, cpt2, i0, t2, v0, cg0, C4d 1. The patient received i.v. immunoglobulin (120 g over 3 days) and high dose of methylprednisolone (500 mg daily over 3 days).

Ten months after the transplantation, the patient presented with asthenia, diffuse edema, ascites, and polyadenopathy. A skin examination revealed purpuric and necrotic lesions of the lower limbs. Laboratory investigations revealed a nephrotic syndrome with anuric acute kidney injury (serum creatinine 3.4 mg/dl, albuminemia 27 g/l, proteinuria 5g/24 h). Immunologic findings revealed a polyclonal hypergammaglobulinemia, antinuclear antibodies with a 1/800 titer without specificity and antismooth muscle antibodies. Kidney biopsy revealed a PLA2R-positive MN without antibody-mediated rejection (Figure 1a). Skin biopsy revealed leukocytoclastic vasculitis lesions (Figure 1b).

Figure 1.

Pathological analysis of the kidney, skin, and lymphadenopathy. (a) Microscopic analysis of the kidney biopsy with silver staining, anti-PLA2R immunohistochemistry and anti-IgG immunofluorescence revealing a PLA2R-positive membranous glomerulonephritis. (b) Skin biopsy of the purpuric lesions with hematoxylin and eosin (HE) staining revealing leukocytoclastic vasculitis lesions (black square). (c) Microscopic analysis of the lymphadenopathy using HE staining showing a completely effaced lymph node architecture by a diffuse proliferation of medium to large-sized cells. Immunohistochemical examination targeting CD3, CD7, BCL6, PD1, ICOS, CD21, KI67 and EBER in situ hybridization for Epstein-Barr virus allowing to establish the diagnosis of angioimmunoblastic T-cell posttransplant lymphoproliferative disorder.

Needle biopsy of a left axillary lymphadenopathy was performed and revealed a monomorphic T/NK-cell posttransplant lymphoproliferative disorder. The tumor cells showed the immunophenotype of TFH-cells, expressing CXCL13, ICOS, BCL6, and PD1. Follicular dendritic cell meshwork was expanded, and a subset of B-cells were positive for Epstein-Barr virus. Overall, a diagnosis of posttransplant AITL was established (Figure 1c). Next-generation sequencing analysis of a large panel of recurrently mutated genes in T-cell lymphomas found pathogenic variants of CD28, ARID1A, KMT2C, and SETD2. Flow cytometry analysis was performed and revealed dissemination of the T-cell lymphoma in peripheral blood, cerebrospinal fluid, and ascites. It should be noted that, before transplantation, no clinical, biological, or imaging signs suggestive of lymphoma were identified. Indeed, the Thorax Abdomen and Pelvis Computed Tomography scan performed as part of the pretransplant surgical work-up was normal and showed no adenopathy suggestive of lymphoma.

The patient received a polychemotherapy regimen, consisting of high-dose methotrexate, cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone, associated with intrathecal chemotherapy and ascites evacuation. A complete metabolic remission was obtained after 3 cycles, and the patient remained in complete remission at the end of the 6th cycle (Figure 2a). Regarding autoimmune features, the gamma globulin level, antinuclear and smooth muscle antibodies were normalized after treatment. More importantly, the patient recovered normal renal function with no proteinuria and anti-PLA2R antibodies became negative (Figure 2b and c).

Figure 2.

Evolution of biological, immunological, and metabolic markers. (a) Evolution of biological renal markers with serum creatinine and urine protein to creatinine ratio. (b) Evolution of the immunological markers with serum gamma globulin, antinuclear, antismooth muscle, and anti-PLA2R antibodies title. (c) Evolution of 18-FDG-TEP scan images (metabolic response) at diagnosis (M10) and at 8 months after lymphoma diagnosis (M18).

Of particular importance, our patient presented with a multisystemic relapse of the disease 1 year after the initial PTLD diagnosis. This relapse occurred again in the context of an increased proteinuria level of 2.3 g/g together with acute renal failure (serum creatinine at 215 μmol/l). In addition, a recurrence of the skin rash was observed. However, no histological documentation of MN recurrence or AITL could be confirmed, because the patient died of multisystemic failure with cardiac arrest shortly after the diagnosis of the relapse.

Discussion

Monomorphic T/NK-cell PTLDs represent a minority of total PTLDs, which mostly include peripheral T-cell lymphoma not otherwise specified and hepatosplenic T-cell lymphoma.^3,4 T-cell lymphomas in which the neoplastic cells have a TFH-cell origin, are frequently associated with autoimmune disorders, mainly cytopenias, as well as cutaneous and rheumatologic diseases.⁶ We report the case of a kidney transplant recipient with TFH derived monomorphic T/NK-cell PTLD presenting with several autoimmune manifestations and in particular the recurrence of an anti-PLA2R positive MN. In our case, autoimmune disorders included leukocytoclastic vasculitis (recurrently observed in AITL), polyclonal hypergammaglobulinemia, and serum markers of autoimmunity (antinuclear antibodies and smooth muscle antibodies). Of particular interest, polychemotherapy regimen allowed clinical, biological, and metabolic remission of both the lymphoma and all the autoimmune disorders, including the kidney disease further emphasizing the link between immune dysregulation and TFH-derived lymphoma.

CD28 is the major costimulatory receptor in T-cells and its activation is thought to drive autoimmune diseases such as rheumatoid arthritis and multiple sclerosis.⁷ In our patient, next-generation sequencing analysis identified an activating mutation in CD28, found in less than 10% of all AITLs⁸ and not reported with targeted sequencing in a study of 19 T/NK-cell PTLDs.⁹ Of interest, this CD28-activating mutation might have favored the autoimmune manifestations and more importantly, the recurrence of the kidney disease. In addition, recent data suggest that activated TFH can contribute to the pathogenesis of MN; therefore, the potential CD28-mediated activation of the patient's TFH most likely contributed to this recurrence.S1

Patients with AITL are traditionally treated with anthracycline-based polychemotherapy, followed by autologous stem cell transplantation. The overall 5-year survival is estimated at 30% to 40%, making AITL a tumor with a highly fatal course.^3,4 In the context of organ transplantation, AITLs are very rare and poorly described in the literature. For example, in a series of 19 patients with T-cell PTLD, only 2 AITL (10%) were reported, making them difficult to precisely understand and manage in this context.⁹ There is no clear consensus regarding the appropriateness of surveillance imaging for patients with AITL who achieved complete remission following initial therapy. In our case, the patient underwent monthly clinical and biological hematological monitoring for possible recurrence. Of particular importance, our patient presented with a multisystemic relapse of the disease, again in the context of increased proteinuria and acute renal failure, further strengthening the link between patient's renal disease and TFH lymphoma.

In conclusion, this report highlights a unique clinical and biological presentation of a rare T-cell mediated PTLD in a kidney transplant recipient who had a complete therapeutic response of his lymphoma and associated autoimmune manifestations, including the recurrence of his glomerulonephritis (Table 1).

Table 1.

Teaching points

Posttransplant lymphoproliferative disorders (PTLDs) encompass heterogeneous lymphoid or plasmacytic proliferations following both solid organ and hematopoietic stem cells transplantation.

T-cell and NK-cell monomorphic PTLDs are rare entities that fulfil the criteria for any of the T-cell or NK-cell lymphomas.

Angioimmunoblastic T-cell lymphoma (AITL) is a rare mature T-cell lymphoma that originates from the monoclonal proliferation of T-follicular helper cells.

Patients with AITL often present with exacerbated inflammatory response, immune dysregulation, and predisposition to autoimmunity phenomena.

We report a unique condition where a AITL PTLD was revealed by the recurrence of membranous glomerulonephritis in a context of new onset of autoimmune disorders, including leukocytoclastic vasculitis, polyclonal hypergammaglobulinemia, and serum markers of autoimmunity.

Disclosure

All the authors declared no competing interests.

Patient Consent

The authors declare that they have obtained consent from the patient discussed in the report.

Supplementary Material

Supplementary Reference.