Late-Onset Peripheral T-Cell Lymphoma Not Otherwise Specified in a Liver Transplant Recipient: A Rare Subtype of Posttransplant Lymphoproliferative Disorder

Abstract

Introduction

Posttransplant lymphoproliferative disorder (PTLD) is a rare complication seen in the period after liver transplant. The commonest subtype is B-cell PTLD which is usually associated with Epstein-Barr virus (EBV) infection. T-cell PTLD is rare and the association with EBV is again rarer.

Case

Our patient, a 21-year-old young adult, presented to us with generalized lymphadenopathy, 5 years after liver transplantation. The biopsy of the lymph node was suggestive of peripheral T-cell lymphoma not otherwise specified, which was associated with EBV infection. The Positron emission tomography and computerised tomography (PET-CT) scan showed stage 3 disease. He was treated with standard cyclophosphamide, doxorubicin, etoposide, vincristine, and prednisolone chemotherapy and is currently in remission.

Conclusion

Peripheral T-cell lymphoma not otherwise specified is a rare subtype of PTLD and its association with EBV is even more rare. A few patients can achieve complete remission with standard chemotherapy.

.

Posttransplant lymphoproliferative disorders (PTLDs) are a rare but a potentially life-threatening complication seen in liver transplant (LT) recipients with an overall incidence of 1–4%. It usually occurs within 2 years after transplantation (early-onset PTLD) or after two years (late-onset PTLDs). Most PTLDs are associated with reactivation of Epstein-Barr virus (EBV), which induces B-cell proliferation, and are of B-cell origin constituting around 90–95% of the whole spectrum. T-cell/natural killer (NK) cell PTLDs are relatively rare, constituting 2–15% of all cases.¹ T-cell PTLDs are usually aggressive, and outcomes are relatively poorer. Here, we describe an unusual case of T-cell PTLD associated with EBV infection, occurring 5 years after LT which responded very well to chemotherapy, and the patient is in complete remission currently.

Case

A 21-year-old man presented to us with a two-month history of nocturnal fever associated with sweating. He underwent a deceased donor LT five years ago for acute liver failure due to rat killer (yellow phosphorus) poisoning. Except for a moderate T-cell rejection in the immediate posttransplantation period, he was otherwise asymptomatic for 5 years on tacrolimus-based immunosuppression but was not compliant with the regular posttransplant clinic follow-ups.

On examination, there was lymphadenopathy involving the bilateral neck and left axilla. There was no hepatosplenomegaly. Initial clinical suspicion was of either tuberculosis or lymphoma. Complete blood count, peripheral blood film, and liver function tests were normal. His tacrolimus trough level at presentation was 7.8 ng/dL which was on the higher level than the desirable range for patients this late in the post-LT period, which is usually 2–4 ng/dL. The Epstein Barr virus - DNA polymerised chain reaction (EBV-DNA PCR) was 234,858 copies per mL. Positron emission tomography and computerised tomography (PET-CT) showed metabolically active bilateral cervical, suboccipital, axillary, retroperitoneal, bilateral external iliac, and inguinal nodes with Deauville score 5. An excision biopsy of the cervical lymph node showed effacement of the lymph node architecture with medium-sized malignant lymphoid cells, with scanty cytoplasm (Figure 1A). Admixed histiocytes were noted. There was brisk mitotic activity. Immunohistochemistry studies showed CD3 diffusely positive in the lymphoid cells (Figure 1B). CD8 was strongly positive in malignant T cells (Figure 1C). Scattered CD4-positive T cells were noted. CD30 was patchy positive (Figure 1D). CD5, CD10, and CD15 were negative. CD20 and PAX-5 were positive in reactive B cells. Bcl-6 and bcl-2 (B cell lymphoma) were patchy positive in malignant T cells (Figure 2A, 2B), and Ki-67 was 80% (Figure 2C). Epstein-Barr–encoding region in in situ hybridization studies showed positive expression (Figure 2D). Diagnosis of peripheral T-cell lymphoma not otherwise specified (NOS) in stage 3B was hence made.

Figure 1.

(A) Lymph node tissue displaying effacement of architecture by malignant lymphoid cells (H & E). (B) CD3 strong immunopositivity. (C) CD8-positive malignant lymphoid cells. (D) Patchy CD30 immunopositivity.

Figure 2.

(A) Patchy B cell lymphoma 2 (Bcl-2) immunopositivity. (B) B cell lymphoma-6 (Bcl-6) immunopositivity. (C) Ki67 immunopositivity. (D) Positive Epstein-Barr–encoding region (EBER) in situ hybridization.

His tacrolimus was withheld and he was started on cyclophosphamide, doxorubicin, etoposide, vincristine and prednisolone (CHOEP) chemotherapy, with intrathecal methotrexate and hydrocortisone given every three weekly. The PET-CT scan performed after the third cycle of chemotherapy showed complete metabolic resolution with Deauville score 1. The PET-CT scan performed at six weeks after completion of treatment, that is, after 6 cycles of chemotherapy, showed complete metabolic resolution. He was restarted on tacrolimus once complete remission was noted at a 6-month scan, targeting a low trough level of 2–3 ng/dL, and his graft function has remained normal. He is now 9 months post-chemotherapy and is being followed up three monthly for clinical evaluation and EBV titers.

Discussion

PTLDs are lymphoid or plasmacytic proliferations which usually range from EBV-driven polyclonal lymphoproliferations to EBV-positive or EBV-negative monoclonal lymphomas indistinguishable from a subset of B-cell or less often T/NK-cell lymphomas that occur in immunocompetent individuals. In the present World health organisation (WHO) classification, PTLD has been subclassified into plasmacytic hyperplasia PTLD, infectious mononucleosis PTLD, florid follicular hyperplasia PTLD, polymorphic PTLD, monomorphic PTLD (B- and T-/NK-cell types), and classical Hodgkin lymphoma PTLD.² Risk factors associated with PTLDs include EBV infection, type of solid organ transplanted, pediatric organ recipients, and choice of immunosuppression.³ It is known that EBV-positive PTLD usually presents within a year after transplant, whereas EBV-negative PTLD usually presents 5 years after transplantation.³

T cell/NK cell PTLDs (T/NK PTLDs) are one of the important types of monomorphic PTLD, and about one-third of them are associated with EBV infection. EBV-associated T/NK PTLD is more common in men and occurs relatively early in the posttransplant period.¹ Most patients have extranodal sites of involvement including the peripheral blood or bone marrow, spleen, skin, liver, gastrointestinal tract, and lung, although nodal involvement is also known and can have protean clinical presentations.¹ A recent case report highlights T-cell PTLD presenting as malabsorption which was the only clinical feature in the described patient.⁴

T/NK PTLDs show expression of pan-T cells and sometimes NK-associated antigens. Depending on the specific type, they may express CD4 or CD8, CD30, ALK-1, and either alpha beta or gamma delta T-cell receptors.

T/NK PTLD NOS (T/NK NOS) in the commonest among the T/NK PTLDs and usually presents in older adults.⁵ They have relatively higher lymph nodal involvement when compared with other T/NK PTLDs as seen in our patient, and most patients have B symptoms of fever, weight loss, and night sweats.⁵ Around 50% have associated EBV infection.⁶ Immunohistochemistry in T/NK PTLD shows strong positivity for CD3, negative for CD 7, and strong CD 4 positivity in case of lymph nodal involvement as seen in our patient.^5,7

The outcome in T/NK PTLD is poor and is even poorer in the T/NK NOS subtype. Previous experiences show a median survival of 3 months and the overall 5-year survival of 32%.^1,8 Treatment regimens are well established for B-cell variants but those for the T-cell variant are still in the evolving stage. T/NK NOS is traditionally treated with the CHOEP regimen, and the response rate is variable with rapid relapses also known at the end of therapy.⁹ Our patient is disease free for last 6 months since completion of chemotherapy. Adalimumab, romidepisn, belinostat, pralatrexate, bendamustine are some of the newer agents used in cases of treatment refractory or relapsed disease.⁹ Both autologous or allohematopoietic stem cell therapy have been recommended in the case of disease relapses, and outcomes described in either of these therapeutic options are variably reported.¹⁰

Over the last 10 years, we have performed 415 pediatric liver transplants, and seven children have had PTLDs (1.7%). All were EBV positive, and survival is 60% (3 died; 1, 3, and 24 months after PTLD diagnosis). Treatment of low-grade PTLD is by reducing immunosuppression and rituximab in the case of B-cell PTLDs. Treatment of refractory cases, monomorphic B-cell PTLDs (e.g., diffuse large B-cell lymphoma, Burkitt lymphoma), and T-cell PTLD is by chemotherapy along with withdrawal of immunosuppression.¹¹

We treated our patient by withholding the immunosuppression (tacrolimus) and commencing standard chemotherapy, as per the protocol. Chemotherapy was started on a compassionate basis for this patient, as parents were not able to afford for other therapy, and the EBV titer in the follow-up is not performed due to the same logistic/financial reasons. Sirolimus was not started in our patient as its role in T-cell PTLDs is yet uncertain.¹²

CRediT authorship contribution statement

Jagadeesh Menon: Prepared the manuscript. Mukul Vij: Reported the histopathology. Abdul R.Hakeem: Prepared the manuscript. Kakumudi Rajagopal Gopi: Did proof reading. Asma Bibi: reported the immunohistochemistry. Naresh Shanmugam: Did proof reading. Mettu S. Reddy: Did proof reading. Mohamed Rela: Did final proof reading and gave approval for publication.

Conflicts of interest

The authors have none to declare.

Funding

None.