Differentiation between rebound thymic hyperplasia and thymic relapse after chemotherapy in pediatric Hodgkin lymphoma.

BACKGROUND: Rebound thymic hyperplasia (RTH) is a common phenomenon caused by stress factors such as chemotherapy (CTX) or radiotherapy, with an incidence between 44% and 67.7% in pediatric lymphoma. Misinterpretation of RTH and thymic lymphoma relapse (LR) may lead to unnecessary diagnostic procedures including invasive biopsies or treatment intensification. The aim of this study was to identify parameters that differentiate between RTH and thymic LR in the anterior mediastinum. METHODS: After completion of CTX, we analyzed computed tomographies (CTs) and magnetic resonance images (MRIs) of 291 patients with classical Hodgkin lymphoma (CHL) and adequate imaging available from the European Network for Pediatric Hodgkin lymphoma C1 trial. In all patients with biopsy-proven LR, an additional fluorodeoxyglucose (FDG)-positron emission tomography (PET)-CT was assessed. Structure and morphologic configuration in addition to calcifications and presence of multiple masses in the thymic region and signs of extrathymic LR were evaluated. RESULTS: After CTX, a significant volume increase of new or growing masses in the thymic space occurred in 133 of 291 patients. Without biopsy, only 98 patients could be identified as RTH or LR. No single finding related to thymic regrowth allowed differentiation between RTH and LR. However, the vast majority of cases with thymic LR presented with additional increasing tumor masses (33/34). All RTH patients (64/64) presented with isolated thymic growth. CONCLUSION: Isolated thymic LR is very uncommon. CHL relapse should be suspected when increasing tumor masses are present in distant sites outside of the thymic area. Conversely, if regrowth of lymphoma in other sites can be excluded, isolated thymic mass after CTX likely represents RTH.

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.

Optimized Whole-Body PET MRI Sequence Workflow in Pediatric Hodgkin Lymphoma Patients.

18F-FDG PET/MRI might be the diagnostic method of choice for Hodgkin lymphoma patients, as it combines significant metabolic information from PET with excellent soft-tissue contrast from MRI and avoids radiation exposure from CT. However, a major issue is longer examination times than for PET/CT, especially for younger children needing anesthesia. Thus, a targeted selection of suitable whole-body MRI sequences is important to optimize the PET/MRI workflow. Methods: The initial PET/MRI scans of 84 EuroNet-PHL-C2 study patients from 13 international PET centers were evaluated. In each available MRI sequence, 5 PET-positive lymph nodes were assessed. If extranodal involvement occurred, 2 splenic lesions, 2 skeletal lesions, and 2 lung lesions were also assessed. A detection rate was calculated dividing the number of visible, anatomically assignable, and measurable lesions in the respective MRI sequence by the total number of lesions. Results: Relaxation time-weighted (T2w) transverse sequences with fat saturation (fs) yielded the best result, with detection rates of 95% for nodal lesions, 62% for splenic lesions, 94% for skeletal lesions, and 83% for lung lesions, followed by T2w transverse sequences without fs (86%, 49%, 16%, and 59%, respectively) and longitudinal relaxation time-weighted contrast-enhanced transverse sequences with fs (74%, 35%, 57%, and 55%, respectively). Conclusion: T2w transverse sequences with fs yielded the highest detection rates and are well suited for accurate whole-body PET/MRI in lymphoma patients. There is no evidence to recommend the use of contrast agents.

Automatic classification of lymphoma lesions in FDG-PET-Differentiation between tumor and non-tumor uptake.

INTRODUCTION: The automatic classification of lymphoma lesions in PET is a main topic of ongoing research. An automatic algorithm would enable the swift evaluation of PET parameters, like texture and heterogeneity markers, concerning their prognostic value for patients outcome in large datasets. Moreover, the determination of the metabolic tumor volume would be facilitated. The aim of our study was the development and evaluation of an automatic algorithm for segmentation and classification of lymphoma lesions in PET. METHODS: Pre-treatment PET scans from 60 Hodgkin lymphoma patients from the EuroNet-PHL-C1 trial were evaluated. A watershed algorithm was used for segmentation. For standardization of the scan length, an automatic cropping algorithm was developed. All segmented volumes were manually classified into one of 14 categories. The random forest method and a nested cross-validation was used for automatic classification and evaluation. RESULTS: Overall, 853 volumes were segmented and classified. 203/246 tumor lesions and 554/607 non-tumor volumes were classified correctly by the automatic algorithm, corresponding to a sensitivity, a specificity, a positive and a negative predictive value of 83%, 91%, 79% and 93%. In 44/60 (73%) patients, all tumor lesions were correctly classified. In ten out of the 16 patients with misclassified tumor lesions, only one false-negative tumor lesion occurred. The automatic classification of focal gastrointestinal uptake, brown fat tissue and composed volumes consisting of more than one tissue was challenging. CONCLUSION: Our algorithm, trained on a small number of patients and on PET information only, showed a good performance and is suitable for automatic lymphoma classification.

Quantitative evaluation of interim positron emission tomography in peripheral T-cell lymphoma.

BACKGROUND: Interim [18F]fluoro-deoxyglucose-positron emission tomography predicts outcome in peripheral T-cell lymphoma (PTCL). We compared two quantitative evaluation methods. METHODS: Interim scans from 43 patients with anaplastic lymphoma kinase-negative PTCL from the 'Positron Emission Tomography-Guided Therapy of Aggressive Non-Hodgkin Lymphomas' trial were re-analyzed by qPET (relating residual lymphoma-related uptake to liver uptake) and ∆SUVmax (relating interim scan to baseline scan). The endpoint was progression-free survival. RESULTS: qPET and ∆SUVmax were closely correlated (Pearson's r = 0.627). Up to the 60th percentile of values ranked by increasing residual activity, the positive predictive value for progression or death increased from 60 to 95%, with stable negative predictive values (NPV) of 60%. Beyond the 60th percentile, the NPV decreased to 40%. qPET ≥ 2 and ∆SUVmax < 50% identified high-risk populations comprising 41.9% and 39.5% of patients, with 3-year progression-free survival rates of 5.6% (95% confidence interval, 0.8-37.3) and 0%, respectively, as compared to 63.7% (47.4-85.8) and 61.3% (45.1-83.3) in low-risk patients. CONCLUSIONS: qPET and ∆SUVmax identify large fractions of PTCL patients destined to experience treatment failure. qPET may be preferred because it requires a single PET scan, halving the diagnostic effort.

Vital Hepatic Lymphoma Residuum or Excessive Immune Response? Challenging Treatment Decisions in a Patient With Systemic Lupus Erythematosus and Liver-Dominant Diffuse Large B-Cell Lymphoma: Case Report.

A 28-year-old female patient with active and difficult-to-treat systemic lupus erythematosus (SLE) was diagnosed with liver-dominant diffused large B-cell lymphoma. Repeated response 18F-FDG-PET studies showed persistently high, and, despite intensified immunochemotherapy, further increasing metabolic activity of one of the hepatic lymphoma residuals, whereas all other initial lymphoma manifestations had achieved complete metabolic remission. As biopsy of the 18F-FDG-PET-positive liver residual turned out to be inconclusive, complete resection was performed. Subsequent histopathological examination, however, revealed only necrotic tissue. Thus, no further lymphoma treatment was scheduled. The patient undergoes regular surveillance and is disease-free 13 months after resection. Similarly, treatment of SLE is no longer required due to lack of activity already after the first two cycles of lymphoma treatment. The case shows how closely SLE and diffused large B-cell lymphoma can be connected and stresses the importance of interdisciplinary treatment approaches. In the future, artificial intelligence may help to further classify 18F-FDG-PET-positive lymphoma residuals. This could lead to an increase of the positive predictive value of interim- and end-of-treatment 18F-FDG-PET. The patient's point of view enables another instructive perspective on the course of treatment, which often remains hidden to treating physicians due to lack of time in clinical routine.

Interim PET in Diffuse Large B-Cell Lymphoma.

In diffuse large B-cell lymphoma, early assessment of treatment response by 18F-FDG PET may trigger treatment modification. Reliable identification of good and poor responders is important. We compared 3 competing methods of interim PET evaluation. Methods: Images from 449 patients participating in the "PET-Guided Therapy of Aggressive Non-Hodgkin Lymphomas" trial were reanalyzed by applying the visual Deauville score and the SUV-based qPET (q = quantitative) and ΔSUVmax scales to interim PET scans performed after 2 cycles of chemotherapy. qPET relates residual lymphoma 18F-FDG uptake to physiologic liver uptake, converting the ordinal Deauville scale into a continuous scale and permitting a direct comparison with the continuous ΔSUVmax scale, which is based on SUVmax changes between baseline and interim scans. Positive and negative predictive values were calculated for progression-free survival. Results: When established thresholds were used to distinguish between good and poor responders (visual Deauville score 1-3 vs. 4-5; ΔSUVmax > 66% vs. ≤ 66%), the positive predictive value was significantly lower with Deauville than ΔSUVmax (38.4% vs. 56.6%; P = 0.03). qPET and ΔSUVmax were strongly correlated on the log scale (Pearson r = 0.75). When plotted along corresponding percentiles, the positive predictive value curves for qPET and ΔSUVmax were superimposable, with low values up to the 85th percentile and a steep rise thereafter. The recommended threshold of 66% SUVmax reduction for the identification of poor responders was equivalent to qPET = 2.26, corresponding to score 5 on the visual Deauville scale. The negative predictive value curves were also superimposable but remained flat between 80% and 70%. Conclusion: Continuous scales are better suited for interim PET-based outcome prediction than the ordinal Deauville scale. qPET and ΔSUVmax essentially carry the same information. The proportion of poor-risk patients identified is less than 15%.

Comparison of Interim PET Response to Second-Line Versus First-Line Treatment in Classic Hodgkin Lymphoma: Contribution to the Development of Response Criteria for Relapsed or Progressive Disease.

In first-line treatment of Hodgkin lymphoma (HL), Deauville scores 1-3 define complete metabolic remission. Interim 18F-FDG PET is also used for relapse-treatment adaptation; however, PET response criteria are not validated for relapse treatment. Methods: We performed a pairwise comparative analysis of early response to first- and second-line treatments in 127 patients with classic HL who experienced relapse. The patients participated in the prospective, multicenter EuroNet-PHL-C1 study. Residual uptake was measured retrospectively using the qPET method, a validated semiautomatic quantitative extension of the Deauville score. Empiric cumulative distribution functions of the qPET values were used to systematically analyze the response to first- and second-line treatments. Results: Individual patients responded variably to first- and second-line treatments. However, the empiric cumulative distribution functions of the qPET values from all patients were nearly superimposable. Conclusion: The findings support that first- and second-line treatments in HL do not require different response criteria.

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.

18F-FDG PET Response of Skeletal (Bone Marrow and Bone) Involvement After Induction Chemotherapy in Pediatric Hodgkin Lymphoma: Are Specific Response Criteria Required?

To determine whether the current 18F-FDG PET response criterion for skeletal involvement in Hodgkin lymphoma (HL) is suitable, we performed a systematic evaluation of the different types of skeletal involvement and their response on PET after 2 cycles of chemotherapy (PET-2). A secondary objective was to observe the influence of the initial uptake intensity (measured as qPET) and initial metabolic tumor volume (MTV) of skeletal lesions on the PET-2 response. Methods: The initial PET scans of 1,068 pediatric HL patients from the EuroNet-PHL-C1 trial were evaluated for skeletal involvement by central review. Three types of skeletal lesions were distinguished: PET-only lesions (those detected on PET only), bone marrow (BM) lesions (as confirmed by MRI or BM biopsy), and bone lesions. qPET and MTV were calculated for each skeletal lesion. All PET-2 scans were assessed for residual tumor activity. The rates of complete metabolic response for skeletal and nodal involvement on PET-2 were compared. Results: Of the 1,068 patients, 139 (13%) showed skeletal involvement (44 PET-only, 32 BM, and 63 bone). Of the 139 patients with skeletal involvement, 101 (73%) became PET-2-negative in the skeleton and 94 (68%) became PET-2-negative in the lymph nodes. The highest number of PET-2-negative scans in the skeleton was 42 (95%) in the 44 PET-only patients, followed by 22 skeletal lesions (69%) in the 32 BM patients and 37 (59%) in the 63 bone patients. Lesions that became PET-2-negative showed a lower initial median qPET (2.74) and MTV (2 cm3) than lesions that remained PET-2-positive (3.84 and 7 cm3, respectively). Conclusion: In this study with pediatric HL patients, the complete response rate for skeletal involvement on PET-2 was similar to that for nodal involvement. Bone flare seemed to be irrelevant. Overall, the current skeletal PET response criterion-comparison with the local skeletal background-is well suited. The initial qPET and MTV of skeletal lesions were predictive of the PET-2 result. Higher values for both parameters were associated with a worse PET-2 response.