International Benchmark for Total Metabolic Tumor Volume Measurement in Baseline 18F-FDG PET/CT of Lymphoma Patients: A Milestone Toward Clinical Implementation

Abstract

Total metabolic tumor volume (TMTV) is prognostic in lymphoma. However, cutoff values for risk stratification vary markedly, according to the tumor delineation method used. We aimed to create a standardized TMTV benchmark dataset allowing TMTV to be tested and applied as a reproducible biomarker. Methods: Sixty baseline ¹⁸F-FDG PET/CT scans were identified with a range of disease distributions (20 follicular, 20 Hodgkin, and 20 diffuse large B-cell lymphoma). TMTV was measured by 12 nuclear medicine experts, each analyzing 20 cases split across subtypes, with each case processed by 3-4 readers. LIFEx or ACCURATE software was chosen according to reader preference. Analysis was performed stepwise: TMTV1 with automated preselection of lesions using an SUV of at least 4 and a volume of at least 3 cm³ with single-click removal of physiologic uptake; TMTV2 with additional removal of reactive bone marrow and spleen with single clicks; TMTV3 with manual editing to remove other physiologic uptake, if required; and TMTV4 with optional addition of lesions using mouse clicks with an SUV of at least 4 (no volume threshold). Results: The final TMTV (TMTV4) ranged from 8 to 2,288 cm³, showing excellent agreement among all readers in 87% of cases (52/60) with a difference of less than 10% or less than 10 cm³ In 70% of the cases, TMTV4 equaled TMTV1, requiring no additional reader interaction. Differences in the TMTV4 were exclusively related to reader interpretation of lesion inclusion or physiologic high-uptake region removal, not to the choice of software. For 5 cases, large TMTV differences (>25%) were due to disagreement about inclusion of diffuse splenic uptake. Conclusion: The proposed segmentation method enabled highly reproducible TMTV measurements, with minimal reader interaction in 70% of the patients. The inclusion or exclusion of diffuse splenic uptake requires definition of specific criteria according to lymphoma subtype. The publicly available proposed benchmark allows comparison of study results and could serve as a reference to test improvements using other segmentation approaches.

Keywords: 18F-FDG PET/CT; benchmark; lymphoma; total metabolic tumor volume.

Graphical abstract

FIGURE 1.

TMTVs for follicular lymphoma patient. TMTV3 shows removal of right renal uptake after manual editing, and TMTV4 included small lesions in pelvis and groin with SUV ≥ 4.0 (volume < 3 cm³) added using single mouse clicks.

FIGURE 2.

Individual reader TMTV measurements plotted against respective reference values. Different colors for symbols represent different readers.

FIGURE 3.

TMTV values for reference or median TMTV2, TMTV3, and TMTV4 against median initial preselection-based TMTV1. LOI = line of identity.

FIGURE 4.

Correlation between TMTV4 assessed by 12 readers (in different colors) and median TMTV4 among readers per scan (reference). Close alignment with line of identity suggests excellent reader agreement. Outliers, indicated by red circles, were all related to interpretation of diffuse splenic uptake. Two outliers enclosed by dashed ellipse are from same scan of B-cell lymphoma patient 16 (B16) with 1 score above and 2 scores below median, in which readers disagreed whether to include spleen or not). For large outliers, patient IDs are indicated. B = diffuse large B-cell lymphoma patient; F = follicular lymphoma patient; H = Hodgkin lymphoma patient.

FIGURE 5.

Maximum-intensity projections of Hodgkin lymphoma patient 15 (H15, left 2 panels) and follicular lymphoma patient 5 (F05, right 2 panels) with discrepant TMTV assessment between readers who chose to include or exclude spleen uptake. For other visible lesions, TMTVs were identical.