The study, published in BMC Medical Imaging, addresses a long-standing tension in lymphoma staging. Diffuse large B-cell lymphoma, the most common aggressive non-Hodgkin lymphoma in adults, is staged in part by determining whether the disease has spread to the bone marrow. For decades, the only way to answer that question definitively was the iliac crest biopsy, a procedure that samples just a tiny fraction of the total marrow volume. Meanwhile, positron emission tomography using the radioactive glucose analog fluorodeoxyglucose offers a whole-body view of metabolic activity, because rapidly dividing lymphoma cells consume glucose voraciously and light up on the scan. The problem has always been knowing when a bright signal in the marrow truly means cancer rather than something benign.

The Korean team, led by Sang Jun Byun and Yunhwi Hwang, who contributed equally to the work, with corresponding author Byungwook Choi, proposed an elegantly simple solution: use the liver as an internal brightness yardstick. Two nuclear medicine physicians independently classified the uptake of the radioactive tracer in both the bone marrow and the spleen as either High or Low relative to the liver’s own signal. If either organ appeared brighter than the liver — or if either showed focal, localized hot spots — the case was labeled “Any High.” If both organs stayed dimmer than the liver, the case was “Both Low.” The logic is rooted in lymphoma biology: the spleen, like the marrow, is a lymphoid organ where disseminated disease tends to lodge, so simultaneous metabolic activation in both sites is far more suspicious than activation in either alone.

To test the rule, the researchers assembled a primary diagnostic cohort of 107 patients with newly diagnosed diffuse large B-cell lymphoma who had undergone both pretreatment PET/CT and adequate bone marrow biopsy. The biopsy came back positive in 18 of those patients. When the Any High classification was applied, it correctly identified 83.3 percent of the true positive cases — a sensitivity with a 95 percent confidence interval running from 58.6 to 96.4 percent. More importantly for patients hoping to avoid the needle, the rule correctly cleared 80.9 percent of the true negatives, yielding a specificity of 71.2 to 88.5 percent. The negative predictive value — the probability that a Both Low result truly means the marrow is clean — reached an extraordinary 96.0 percent, with a confidence interval of 88.8 to 99.2 percent. Overall accuracy was 81.3 percent.

That negative predictive value is the number that matters most clinically. In this cohort, only 3 of the 75 patients classified as Both Low actually harbored marrow involvement. In other words, if a patient’s PET scan showed subdued marrow and splenic activity relative to the liver, there was a 96 percent chance the biopsy would find nothing. For the remaining small fraction, the biopsy would still catch the disease, but for the overwhelming majority, the painful procedure could potentially be skipped — pending the prospective validation the authors themselves insist is required before any change to clinical practice.

The researchers did not stop at the combined rule. They compared it against the simpler alternative of looking at the bone marrow alone. The combined Any High approach traded some specificity for sensitivity: it caught more true positives but flagged more false alarms. Yet the overall accuracy was statistically indistinguishable — 81.3 percent for the combined rule versus 82.2 percent for marrow alone, with an exact McNemar p value greater than 0.999. The team also ran a sensitivity analysis excluding patients whose marrow showed focal uptake, reducing the cohort to 94 patients with 12 biopsy-positive cases, and confirmed the estimates held. They even stress-tested the results by reclassifying or excluding two indeterminate biopsies, and the numbers remained robust.

Reproducibility is where many visual classification schemes in nuclear medicine collapse, but this one held up well. Inter-reader agreement between the two independent physicians was substantial to almost perfect for the principal criteria, with Cohen’s kappa values ranging from 0.750 to 0.843. The one soft spot was background splenic uptake, which showed lower agreement at kappa 0.648, compared with 0.773 for background marrow uptake. The spleen, it turns out, is a trickier organ to grade because its normal tracer uptake sits closer to the liver’s baseline, making the visual distinction more subtle. Still, the authors note that the combined classification itself — the decision that ultimately drives the clinical call — was highly reproducible.

Beyond diagnosis, the team explored whether the PET-based classification carried prognostic weight. In a separate cohort of 141 patients, they tracked progression-free survival and overall survival using Cox regression models. Over the follow-up period, 66 progression events and 49 deaths occurred. When adjusted for the International Prognostic Index — the standard clinical risk score incorporating factors such as age, stage, lactate dehydrogenase, and performance status — patients classified as Any High had roughly twice the hazard of progression or death compared with Both Low patients, with a hazard ratio of 2.04 and a confidence interval of 1.08 to 3.84. Adjustment for the more granular National Comprehensive Cancer Network version of the index yielded a nearly identical result: hazard ratio 1.96, confidence interval 1.05 to 3.69. However, the classification was not independently associated with overall survival, and the authors are careful to frame these survival findings as exploratory rather than practice-changing.

The implications, if validated prospectively, could reshape the staging pathway for thousands of patients each year. Diffuse large B-cell lymphoma is typically treated with the R-CHOP regimen — rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone — and accurate staging determines both the intensity of treatment and the radiation fields in some approaches. A reliable noninvasive alternative to marrow biopsy would spare patients a painful procedure, reduce healthcare costs, and accelerate the time from diagnosis to treatment. The liver-referenced approach requires no additional scanning, no new tracers, and no specialized software — just a disciplined visual comparison that any trained nuclear medicine physician can perform on images already acquired as standard of care.

The authors are appropriately measured in their conclusions. They acknowledge that BMB positivity did occur in some Both Low patients, that the study was retrospective and single-centre, and that the survival associations were secondary and exploratory. They explicitly call for prospective external validation before the classification is used clinically. But the core finding stands on its own weight: by reading two organs against one internal reference, a century-old diagnostic dilemma gets a modern, image-based answer that is 96 percent reliable when it says the marrow is clear. For a disease that afflicts tens of thousands of people annually, that is not a small refinement — it is a potential reordering of the very first steps of cancer care.

Subject of Research: Diagnostic performance of integrated bone marrow and splenic FDG PET/CT uptake for predicting bone marrow biopsy positivity in diffuse large B-cell lymphoma

Article Title: Integrated bone marrow and splenic [18F]FDG PET/CT uptake for predicting bone marrow biopsy positivity in diffuse large B-cell lymphoma — a retrospective single-centre study

Article References: Byun, S. J., Hwang, Y., Kim, H. W., & Choi, B. (2026). Integrated bone marrow and splenic [18F]FDG PET/CT uptake for predicting bone marrow biopsy positivity in diffuse large B-cell lymphoma — a retrospective single-centre study. BMC Medical Imaging. https://doi.org/10.1186/s12880-026-02761-x

Image Credits: AI Generated

DOI: 10.1186/s12880-026-02761-x

Keywords: diffuse large B-cell lymphoma, FDG PET/CT, bone marrow biopsy, splenic uptake, liver-referenced classification, negative predictive value, inter-reader agreement, lymphoma staging, nuclear medicine, progression-free survival, International Prognostic Index, diagnostic imaging