Pulmonary lesions in early response assessment in pediatric Hodgkin lymphoma: prevalence and possible implications for initial staging.

BACKGROUND: Disseminated pulmonary involvement in pediatric Hodgkin lymphoma (pHL) is indicative of Ann Arbor stage IV disease. During staging, it is necessary to assess for coexistence of non-malignant lung lesions due to infection representing background noise to avoid erroneously upstaging with therapy intensification. OBJECTIVE: This study attempts to describe new lung lesions detected on interim staging computed tomography (CT) scans after two cycles of vincristine, etoposide, prednisolone, doxorubicin in a prospective clinical trial. Based on the hypothesis that these new lung lesions are not part of the underlying malignancy but are epiphenomena, the aim is to analyze their size, number, and pattern to help distinguish true lung metastases from benign lung lesions on initial staging. MATERIALS AND METHODS: A retrospective analysis of the EuroNet-PHL-C1 trial re-evaluated the staging and interim lung CT scans of 1,300 pediatric patients with HL. Newly developed lung lesions during chemotherapy were classified according to the current Fleischner glossary of terms for thoracic imaging. Patients with new lung lesions found at early response assessment (ERA) were additionally assessed and compared to response seen in hilar and mediastinal lymph nodes. RESULTS: Of 1,300 patients at ERA, 119 (9.2%) had new pulmonary lesions not originally detectable at diagnosis. The phenomenon occurred regardless of initial lung involvement or whether a patient relapsed. In the latter group, new lung lesions on ERA regressed by the time of relapse staging. New lung lesions on ERA in patients without relapse were detected in 102 (7.8%) patients. Pulmonary nodules were recorded in 72 (5.5%) patients, the majority (97%) being<10 mm. Consolidations, ground-glass opacities, and parenchymal bands were less common. CONCLUSION: New nodules on interim staging are common, mostly measure less than 10 mm in diameter and usually require no further action because they are most likely non-malignant. Since it must be assumed that benign and malignant lung lesions coexist on initial staging, this benign background noise needs to be distinguished from lung metastases to avoid upstaging to stage IV disease. Raising the cut-off size for lung nodules to ≥ 10 mm might achieve the reduction of overtreatment but needs to be further evaluated with survival data. In contrast to the staging criteria of EuroNet-PHL-C1 and C2, our data suggest that the number of lesions present at initial staging may be less important.

Interobserver variability in interim PET assessment in Hodgkin lymphoma-reasons and solutions.

INTRODUCTION: Interim PET (iPET) assessment is important for response adaptation in Hodgkin lymphoma (HL). The current standard for iPET assessment is the Deauville score (DS). The aim of our study was to evaluate the causes of interobserver variability in assigning the DS for iPET in HL patients and to make suggestions for improvement. METHODS: All evaluable iPET scans from the RAPID study were re-read by two nuclear physicians, blinded to the results and patient outcomes in the RAPID trial. The iPET scans were assessed visually according to the DS and, thereafter, quantified using the qPET method. All discrepancies of more than one DS level were re-evaluated by both readers to find the reason for the discordant result. RESULTS: In 249/441 iPET scans (56%) a concordant visual DS result was achieved. A "minor discrepancy" of one DS level occurred in 144 scans (33%) and a "major discrepancy" of more than one DS level in 48 scans (11%). The main causes for major discrepancies were 1) different interpretation of PET-positive lymph nodes-malignant vs. inflammatory; 2) lesions missed by one reader and 3) different assessment of lesions in activated brown fat tissue. In 51% of the minor discrepancy scans with residual lymphoma uptake, additional quantification resulted in a concordant quantitative DS result. CONCLUSION: Discordant visual DS assessment occurred in 44% of all iPET scans. The main reason for major discrepancies was the different interpretation of PET positive lymph nodes as malignant or inflammatory. Disagreements in evaluation of the hottest residual lymphoma lesion can be solved by the use of semi-quantitative assessment.

Assessment of Waldeyer's ring in pediatric and adolescent Hodgkin lymphoma patients-Importance of multimodality imaging: Results from the EuroNet-PHL-C1 trial.

BACKGROUND: In the EuroNet Pediatric Hodgkin Lymphoma (EuroNet-PHL) trials, decision on Waldeyer's ring (WR) involvement is usually based on clinical assessment, that is, physical examination and/or nasopharyngoscopy. However, clinical assessment only evaluates mucosal surface and is prone to interobserver variability. Modern cross-sectional imaging technology may provide valuable information beyond mucosal surface, which may lead to a more accurate WR staging. PATIENTS, MATERIALS, AND METHODS: The EuroNet-PHL-C1 trial recruited 2102 patients, of which 1752 underwent central review including reference reading of their cross-sectional imaging data. In 14 of 1752 patients, WR was considered involved according to clinical assessment. In these 14 patients, the WR was re-assessed by applying an imaging-based algorithm considering information from 18 F-fluorodeoxyglucose positron emission tomography, contrast-enhanced computed tomography, and/or magnetic resonance imaging. For verification purposes, the imaging-based algorithm was applied to 100 consecutive patients whose WR was inconspicuous on clinical assessment. RESULTS: The imaging-based algorithm confirmed WR involvement only in four of the 14 patients. Of the remaining 10 patients, four had retropharyngeal lymph node involvement and six an inconspicuous WR. Applying the imaging-based algorithm to 100 consecutive patients with physiological appearance of their WR on clinical assessment, absence of WR involvement could be confirmed in 99. However, suspicion of WR involvement was raised in one patient. CONCLUSIONS: The imaging-based algorithm was feasible and easily applicable at initial staging of young patients with Hodgkin lymphoma. It increased the accuracy of WR staging, which may contribute to a more individualized treatment in the future.

Quantitative assessment of interim PET in Hodgkin lymphoma: An evaluation of the qPET method in adult patients in the RAPID trial.

AIM: qPET is a quantitative method used to assess FDG-PET response in lymphoma. qPET was developed using 898 scans from children with Hodgkin Lymphoma (HL) in the EuroNet-PHL-C1 (C1) trial. The aim of this study was to determine if qPET could be applied as an alternative response method in adults in the RAPID trial. METHODS: PET-CT scans performed after 3 cycles of ABVD in RAPID were re-evaluated by an independent reader, blinded to PET results and outcome in RAPID. All initially involved regions were assessed visually and by qPET. The distribution of qPET measurements was compared for RAPID and C1 patients. Previously published qPET thresholds corresponding to visual DS (vDS) of 1-5 in C1 were used to derive quantitative DS (qDS) for RAPID patients. RESULTS: PET-CT scans were available for 450 patients from RAPID. vDS were 1 (171 scans), 2 (153 scans), 3 (72 scans), 4 (31 scans) and 5 (23 scans) respectively. The distribution of qPET values was similar to C1 patients, with a unimodal 'normal' distribution and a long tail to the right, suggestive of favorable response in the majority and less favorable response in the minority with outlying values. qPET thresholds from C1 applied in RAPID patients gave 86% concordance for vDS and qDS. There was 97% concordance for complete metabolic response (CMR; DS 1-3) vs. no-CMR using the Lugano classification. CONCLUSION: qPET which was developed in pediatric patients receiving more intensive OEPA chemotherapy, was a suitable quantitative method for assessing response in adult patients treated with ABVD in a response-adapted setting in the RAPID trial.

Inter-Reader Reliability of Early FDG-PET/CT Response Assessment Using the Deauville Scale after 2 Cycles of Intensive Chemotherapy (OEPA) in Hodgkin's Lymphoma.

PURPOSE: The five point Deauville (D) scale is widely used to assess interim PET metabolic response to chemotherapy in Hodgkin lymphoma (HL) patients. An International Validation Study reported good concordance among reviewers in ABVD treated advanced stage HL patients for the binary discrimination between score D1,2,3 and score D4,5. Inter-reader reliability of the whole scale is not well characterised. METHODS: Five international expert readers scored 100 interim PET/CT scans from paediatric HL patients. Scans were acquired in 51 European hospitals after two courses of OEPA chemotherapy (according to the EuroNet-PHL-C1 study). Images were interpreted in direct comparison with staging PET/CTs. RESULTS: The probability that two random readers concord on the five point D score of a random case is only 42% (global kappa = 0.24). Aggregating to a three point scale D1,2 vs. D3 vs. D4,5 improves concordance to 60% (kappa = 0.34). Concordance if one of two readers assigns a given score is 70% for score D1,2 only 36% for score D3 and 64% for D4,5. Concordance for the binary decisions D1,2 vs. D3,4,5 is 67% and 86% for D1,2,3 vs D4,5 (kappa = 0.36 resp. 0.56). If one reader assigns D1,2,3 concordance probability is 92%, but only 64% if D4,5 is called. Discrepancies occur mainly in mediastinum, neck and skeleton. CONCLUSION: Inter-reader reliability of the five point D-scale is poor in this interobserver analysis of paediatric patients who underwent OEPA. Inter-reader variability is maximal in cases assigned to D2 or D3. The binary distinction D1,2,3 versus D4,5 is the most reliable criterion for clinical decision making.