DISCUSSION
18F-FDG-PET/CT has been formally incorporated into the
standard initial staging, interim response evaluation, and residual
disease evaluation at the end of treatment for both adult and pediatric
patients with HL23-25. PET/CT-based, response-adapted
treatment has been proven to improve survival and reduce the risk of
long-term toxicity in pediatric HL patients5. It is
critical that the response assessment is reliable and reproducible, but
the interpretation of interim and post-treatment PET/CT scans can be
difficult due to false-positive results8,26, 27. The IHPC and DC are the main
criteria for the clinical evaluation of both interim and post-treatment
PET/CT13-16. In the present study, we used the IHPC
and DC to analyze a homogeneous cohort of pediatric and adolescent HL
patients who underwent regular interim PET/CT after 2 cycles of
chemotherapy and underwent post-treatment PET/CT. Our study found that
post-treatment PET/CT showed a better diagnostic performance than
interim PET/CT in the prediction of the outcomes of pediatric and
adolescent HL patients. Moreover, the DC-4 cutoff could further improve
diagnostic accuracy when compared with the IHPC and DC-3 (Table2).
In our patient cohort, 89 patients underwent interim PET/CT after 2
cycles of chemotherapy, and their PET/CT scan results were analyzed.
Given that the index reflecting reduced metabolism is expected to be
more discriminating after 2 cycles of chemotherapy than after 4 or 6
cycles28, we excluded the results of irregular PET/CT
scans. Our study indicated that interim PET/CT had a relatively low PPV
(15%, 19%, and 15% when using the IHPC, DC-3, and DC-4,
respectively), but a high NPV (93%, 95%, and 88%, respectively). A
retrospective study of 34 children with HL indicated that interim PET/CT
had a good PPV of 75% and a high NPV of 96%29.
Similar results have been reported for adult patients with HL and NHL,
with PPVs of 57%–85% and NPVs of 80%–100%9,30, 31. However, some studies
concerning the interim PET/CT visual assessment in pediatric HL patients
have showed poor and variable PPVs (ranging between 11% and 30%) and
high NPVs (ranging between 80% and 100%)32. The poor
PPVs observed in the present study and in previous studies might be
explained by high false-positive rates. Like adult lymphomas, cervical
lymph node hyperplasia and inflammation show high FDG uptake on PET/CT
scans, but are benign processes and cause false-positive results in
pediatric and adolescent patients with lymphoma33. The
residual 18F-FDG uptake observed on interim PET/CT
scans might be related to inflammatory cells. Although the diagnostic
accuracy was improved by using DC-4 (75%) rather than IHPC (39%) or
DC-3 (55%) in the present study, the diagnostic performance of interim
PET/CT was still poor. Moreover, no significant differences in PFS were
observed between patients with positive and negative interim PET/CT
scans according to the IHPC, DC-3, and DC-4. It should be noted however
that both the present study and previous studies concerning interim
PET/CT in pediatric and adolescent HL were retrospective in nature and
limited by small sample sizes.
Given the results of interim PET/CT in our study, interim PET/CT could
not circumvent the need for post-treatment PET/CT evaluation. Thus, we
further analyzed the 147 post-treatment PET/CT scans. Improved PPVs were
observed using the post-treatment PET/CT scans as compared with the
interim PET/CT scans (IHPC: 23% vs. 15%, DC-3: 27% vs. 19%, and
DC-4: 33% vs. 15%), indicating that the use of post-treatment PET/CT
might reduce false-positive rates. Furthermore, the AUC and accuracy of
post-treatment PET/CT were both higher than those of interim PET/CT
(Tables 2). Consistent with our findings, a prospective study of 57
pediatric HL patients reported that the predictive value of interim
PET/CT was low, and that post-treatment PET/CT evaluated using the DC
had better specificity (96% vs. 76%) and PPV (33% vs. 8%) than
conventional imaging34. The above finding is probably
a consequence of response-adapted treatment in our study: Patients with
DC scores of 4 and 5 in the interim PET/CT evaluation received
chemotherapy-dose escalation and radiotherapy; hence, the post-treatment
PET/CT was more valuable in predicting progression.
In our study, among the three models of PET/CT evaluation, DC-4 showed
the highest specificity, AUC, and accuracy, indicating that DC-4 might
have a superior diagnostic performance than IHPC and DC-3. Furthermore,
Cox regression and Kaplan-Meier analyses revealed that a positive
post-treatment PET/CT according to DC-4 was strongly associated with a
high risk of progression (hazard ratio: 7.82). A similar conclusion was
drawn in a retrospective study of 101 adult patients with lymphoma: the
specificity, accuracy, and hazard ratio of positive post-treatment
PET/CT were all higher when using the DC-4 rather than the DC-3 and IHPC
(specificity: 87% vs.76% vs. 67%, accuracy: 86% vs. 84% vs. 76%,
and hazard ratio: 3.2 vs. 0.7 vs. 1.57,
respectively)9. However, another retrospective study
of 72 pediatric HL patients reported that the IHPC showed a higher
specificity (95% vs. 70%), accuracy (89% vs. 46%), and PPV (40% vs.
25%) than the DC in the evaluation of post-treatment
PET/CT11. The application of the IHPC depends on the
evaluator’s experience and is limited by the quality of image
reconstruction35, 36. In contrast,
concordance among observers when using the DC has been demonstrated, and
discordant interpretations among reviewers occur in only a few
challenging cases37. Furthermore, the threshold
selected for PET/CT positivity may vary depending on the histological
subtype and the treatment. Thus, on the basis of our results, we
tentatively regard that the DC-4 had a superior diagnostic performance
than the IHPC and DC-3 in the evaluation of post-treatment PET/CT among
pediatric and adolescent patients with HL.
Our study has several limitations. First, there was variability in image
and data acquisition due to the retrospective nature of our study.
Second, some patients received interim PET/CT-based, response-adapted
treatment, but the definition of the threshold of positivity varied
among doctors. Treatment bias might potentially influence survival.
Furthermore, we excluded patients with primary refractory HL, with a
consequent impact on overall survival. Further large prospective studies
are required to define the best strategy for the use of the DC in
specific clinical situations.