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.