Discussion
PTLD is a proliferative disease that results in abnormal cloning of
lymphocytes or plasma cells after solid organ transplantation or stem
cell transplantation due to immunosuppression of the recipient, and it
can eventually progress to malignant invasive lymphoma. At present, it
is believed that the occurrence of PTLD is closely related to
postoperative EBV infection(14). The incidence of PTLD after pLT can
reach 2%–20%(15-17). In pLT, EBV serological negativity before
transplantation is considered to be a major risk factor for PTLD. In
adult liver transplantation, there are fewer EBV-seronegative
recipients(18), which is one of the reasons why the incidence of PTLD
after pLT is higher in children than in adults(19). In addition, another
major cause of EBV-related PTLD after pLT is the use of
immunosuppressive regimens of high intensity and long duration.
There is limited research on the clinical application of18F-FDG PET/CT in children with PTLD, who are usually
combined with adult PTLD cohorts(19-23). The results of an adult cohort
showed that 18F-FDG PET/CT is a feasible imaging
method for the diagnosis of PTLD. However, the sensitivity values and
NPVs of 18F-FDG PET/CT in the detection of PTLD were
not high in children(21, 24). At present, there are three problems in
the study of 18F-FDG PET/CT in children with PTLD.
First, most existing studies were descriptive studies, meta-analyses, or
reviews(22, 25, 26) or involved comparisons of other non-pathological
examination methods using 18F-FDG PET/CT(27). Second,
the numbers of cases in studies on 18F-FDG PET/CT and
PTLD in children have been small(28), and there are few studies on PTLD
after pLT.
The third problem involves the use of 18F-FDG PET/CT
in the diagnosis of PTLD in children. At present,18F-FDG PET/CT has no definite quantitative index in
the diagnosis of PTLD in children, and it relies more on the experience
of nuclear medicine doctors without a formal guideline(29). When reading
the report, the nuclear medicine physician will more or less refer to
the patient’s reasons for seeing a doctor and cannot complete the18F-FDG PET/CT diagnosis of PTLD in a completely
independent manner. In this study, 18F-FDG PET/CT
reports from nuclear medicine doctors for the diagnosis of
non-destructive PTLD had high sensitivity values and NPVs, but the
specificity values and PPVs were not high. Considering that low uptake
of non-destructive or low-grade PTLD may lead to false-negative results,
while high uptake related to infection or inflammatory process may lead
to false-positive results, the application of SUV in differentiating
benign and malignant lesions is still controversial(22, 30). Therefore,
finding a quantifiable 18F-FDG PET/CT index to judge
PTLD after pLT was the focus of this study.
Unlike traditional tumor-induced lymphadenopathy, our experience found
that there was no significant difference in the longest diameter of
lymph nodes between PTLD-negative cases and non-destructive PTLD cases.
Moreover, the longest diameter of lymph nodes in different parts of the
body also varies. Clinically, we are not concerned about the longest
diameter of lymph nodes in PTLD patients in the early stage but instead
with the morphology of lymph nodes. We found that the lymph nodes of
patients with non-destructive PTLD were rounder than those of
PTLD-negative cases. This was reflected in the ratio of the shortest
diameter of the lymph node to the longest diameter of the lymph node; if
the ratio was closer to 1, it meant that the shape of the lymph node was
more spherical, while, if it was closer to 0, it meant that the shape of
the lymph node was closer to an ellipse. Another problem we found in
clinical practice pertains to the SUVmax value. The SUVmax value in our
data can effectively distinguish between monomorphic PTLD and
polymorphic or non-destructive PTLD. However, although there was a
statistical difference in SUVmax between PTLD-negative and
non-destructive PTLD cases, the sensitivity, specificity, PPV, NPV, and
accuracy obtained using this index were poor. In clinical practice, we
have found that there are many reasons that can lead to increased uptake
of 18F-FDG in tonsils, posterior pharyngeal wall, or
adenoids, such as a high EBV DNA load or tonsil hypertrophy(31, 32).
Moreover, 18F-FDG uptake also increases in patients
with other conditions after transplantation, such as postoperative
inflammation, infection, bone marrow activation, or transplant
rejection(19). Therefore, we used the ratio of SUVmaxBio to SUVmaxTon to
numerically validate our reasoning in the above clinical practice.
Through our calculation, we found that (SDL/LDL)*(SUVmaxBio/SUVmaxTon)
had the largest AUC in each combination, and the cut-off value
calculated by this index can effectively judge the non-destructive PTLD
in children. Using this cut-off value, the sensitivity, specificity,
PPV, and accuracy can reach >90%, and the NPV can also
reach 85.7%. However, according to this index, there will still be
errors. In the data of our center, there were three false-negative cases
and one false-positive case. We found that SUVmaxBio was high in the
false-positive case, but the high uptake sites of18F-FDG were concentrated in the neck or
supraclavicular lymph nodes, and there was no abnormal uptake of18F-FDG in other parts of the body. In the three
false-negative cases, the SUVmaxBio or SDL/LDL was too low, resulting in
an incorrect prediction. However, in these three cases, abnormally high
uptake of 18F-FDG could be seen in many parts of the
patient’s body, including the neck, supraclavicular fossa, armpit,
retroperitoneal para-aortic, and inguinal lymph nodes. Therefore, the
use of (SDL/LDL)*(SUVmaxBio/SUVmaxTon) and the subjective judgment of
nuclear medicine physicians can further improve the accuracy of
diagnosing PTLD-negative and non-destructive PTLD cases. It is worth
noting that one false-negative case underwent inguinal lymph node
biopsy. The inguinal lymph node SUVmax was 1.25, while the cervical
lymph node SUVmax was 6.81. If the cervical lymph node SUVmax value was
used, the result of this quantitative index would have been PTLD
positivity, which was consistent with the pathological results.
It is undeniable that this study has some limitations. First, this study
was a retrospective study, necessitating prospective and multicenter
studies for internal and external validation in the future. Second,
since the gold standard for the diagnosis of PTLD in this study is lymph
node biopsy, the selection of lymph node biopsy site became key. The
longest and shortest diameters and SUVmax values of lymph nodes involved
in this study were those at the biopsy site. Due to clinical
limitations, we selected superficial and easily accessible lymph nodes
as much as possible. Therefore, some selected lymph nodes were not the
most typical lymph nodes used in 18F-FDG PET/CT
reports.