Discussion:
We report two unique pediatric cases of monomorphic PTLD. They both occurred after solid organ transplant, with the first patient presenting with isolated pleural and pericardial effusions and the second with intestinal obstruction. Both cases showed aberrant cytoplasmic CD3 expression (negative TCR-gene clonal rearrangement by PCR), variable B cell antigen loss, kappa or lambda light chain restriction, EBV positive or negative, high Ki67 proliferation rate and plasmablastic morphology, consistent with PBL.11,12,14,16 AlthoughMYC -rearrangement has been identified in up to 50-70% of PBL,9,11,16-19 both of our cases were negative forMYC rearrangement by FISH.
An in depth literature search revealed three additional reported pediatric cases of PT-PBL.11 Similar to our second patient, these three reported PT-PBLs (cases 4-6, Table-1) were EBV negative, occurring at least 9 years after original solid organ transplant and involving intestine.11 Prior studies have shown that gastrointestinal tract (including oropharynx) is one of the most common sites of PBL,11,16,20 while bone marrow involvement appears uncommon.
Our first case is a unique PT-PBL case with isolated pleural/pericardial effusion. We searched the literature and identified three adult patients with effusion-based PT-PBL (cases 1-3, Table-1).21 The morphology and immunophenotype of effusion-based monomorphic PTLD are varied. The tumor cells often show large size, prominent nucleoli, and variable cytoplasm, resembling immunoblasts or plasmablasts. Depending on the expression of HHV8, effusion based monomorphic PTLD is divided into two categories. Absent expression of CD20 is common in effusion based monomorphic PTLD,22,23 which has been reported with poor prognosis. Our first case was negative for HHV8 and CD20. Given the EBV positivity, our first case also resembles the new entity of “fluid overload-associated large B-cell lymphoma (FO-LBCL)” in World Health Organization (WHO) 5th edition24.
There are scarce genetic studies of PT-PBL. MYC deregulation, due to copy number alteration, translocation or somatic mutations of certain signaling pathway genes is the well-recognized pathobiological mechanism for the development of PBL.11,25-27 A recent study of 11 childhood and adult patients with PT-PBL reveals some unique genetic features of PT-PBLs.11 For instance, mutations in epigenetic modifiers were identified in up to 70% of PT-PBL, followed by DNA damage response and repair pathway genes (64%), mitogen-activated protein kinase (MAPK) pathway genes (55%), NOTCH signaling pathway genes (45%), JAK-STAT signaling pathway genes (36%).11 However, genomic research focusing on childhood PT-PBL is absent thus far.
The treatment of PT-PBL is a challenge.28 The use of treatment regimens developed for immunocompetent individuals is often complicated by the reduced chemotherapy tolerance of transplant recipients.4 The outcomes of PT-PBL patients appear variable. Leeman-Neill et al 11 reported two patients with EBV negative PT-PBL with MYC -rearrangement achieving a durable remission, while many other patients appear to have poor outcome. Moreover, the effusion-based monomorphic PTLD patients have poor response to chemotherapy.8,29-31 Our first patient did not respond to rituximab, the accepted first line therapy for pediatric EBV+ CD20+ PTLD. However, this patient’s lymphoma initially responded to chemotherapy with addition of daratumumab, a CD38 monoclonal antibody but relapsed a few months later. He successfully achieved remission with EPOCH-based chemotherapy. Our second patient was treated up front with EPOCH-based chemotherapy with addition of bortezomib but after initial partial response progressed and the parents withdrew further care.
In summary, we report two pediatric PT-PBL, who showed unusual pathology and variable treatment response to aggressive chemotherapy. It is well known that EBV positive PTLD has a more favorable outcome which may have contributed to the difference in outcome in our patients. It is important to recognize this rare subtype of monomorphic PTLD. Future collaborative studies are required to understand the biology and best treatment of this devastating disease in children.