Body imaging for newly diagnosed CNS lymphoma: Evaluating the utility of the evaluation

Primary CNS lymphoma (PCNSL) is a rare form of non-Hodgkin lymphoma that is restricted to the brain, spinal cord, cerebral spinal fluid, and vitreoretinal space, with most cases classified as diffuse large B-cell type.¹ The CNS can also be involved secondarily in systemic lymphoma. The most effective first-line treatment regimens for CNS lymphoma include high-dose methotrexate, rituximab, and an alkylating chemotherapy, resulting in 2-year progression-free survival rates of 50%-60%.² Methotrexate-based regimens, however, are generally ineffective for the management of extracranial disease, highlighting the importance of a full assessment of sites of lymphoma involvement. Therefore, the International PCNSL Collaborative Group (IPCG), the European Association for Neuro-Oncology, and the National Comprehensive Cancer Network all recommend a full extent of disease evaluation after the diagnosis of lymphomatous lesions affecting the CNS, in order to rule out the presence of systemic disease,^3,4 involving a contrast-enhanced CT scan of the chest, abdomen, and pelvis or a whole-body PET/CT scan.

The incidence of finding extracranial disease at the same time as newly discovered intracranial lymphoma varies widely in the literature, ranging between 4% and 16% of cases in a variety of small, single-institution series.⁵ A recent meta-analysis of 9 articles reported the diagnostic yield of 2.5% and 4.9% for systemic lymphoma by body CT and PET/CT, respectively.⁶ Based on the limited evidence to support the current imaging guidelines and reported false-positive rates up to 5%, Suh et al set out to evaluate the efficacy of the extent of disease imaging guidelines, published in this issue of Neuro-Oncology.⁵ In light of the high false-positive to true-positive ratio that has been previously reported, the authors additionally set out to investigate for patient criteria that are associated with an increased likelihood of extracranial disease.

To begin, the authors assembled an international, multicenter cohort of patients with newly diagnosed CNS involvement of lymphoma diagnosed by biopsy, to systemically study detection rates for extracranial disease. The 1043 patients included in the study, from five hospitals across two countries, had all undergone a contrast-enhanced chest/abdomen/pelvis CT (CT body) or whole-body PET/CT between 1998 and 2019. The mean age at diagnosis and gender was consistent across study sites, reflecting the demographics associated with the disease. Rate of Epstein-Barr virus (EBV) positivity varied between 1.1% and 5.9% but was not tested at all sites nor on all specimens. The choice of imaging modality for extracranial disease screening was nearly evenly divided between CT body and whole-body PET/CT, and 71% underwent both.⁵

While abnormal findings raising concern for extracranial lymphoma were detected in 8.3% of patients, systemic lymphoma was ultimately confirmed in 2.6% of patients and led to change in therapy in 1.9% of cases (20 of 1043 patients). Notably, the false referral rate was 5.8%, more than twice the true-positive rate. However, in a predefined analysis, the authors found that the yield of full-body imaging was higher in patients over the age of 61 and in cases that were associated with EBV, with true-positive rates of 4.0% and 8.3%, respectively. These two factors remain independently associated with an increased risk of extracranial lymphoma involvement on multivariate analysis. PET/CT is preferred for staging of FDG-avid lymphomas such as DLBCL,⁷ however, the authors found that CT body and whole-body PET/CT performed equally well in detection of abnormal findings, with no significant difference in true-positive or false-positive rates. Additionally, despite the high incidence of CNS involvement in testicular lymphoma and the IPCG recommendation to consider testicular ultrasound in older men, no cases of testicular involvement were detected by PET/CT or testicular ultrasound, although only 12.8% of patients underwent testicular ultrasound.

This study is the first large, multi-institutional investigation to assess the current imaging recommendations for extent of disease evaluation in newly discovered CNS lymphoma. Although these rates are largely concordant with smaller reports in the literature, it is surprising that the incidence of extracranial disease is low while the false-positive rate, nearly 6%, is substantial. This seeming imbalance is driven by the high stakes associated with not detecting extracranial disease, highlighted by the fact that the chemotherapy regimen was altered in the vast majority of these cases. It is also clear from this report that performing both contrast-enhanced body CT and whole-body PET/CT perform equally well in detecting systemic disease, and in patients less than 61 where detection rate was only 1.2% with false-positive rate of 6.4%, one study is sufficient. In older patients or those with EBV-positive disease, both imaging modalities may be indicated. The authors appropriately assert that consensus guidelines for contrast-enhanced body CT or PET/CT in patients with newly diagnosed CNS DLBCL are supported by these data. Still, the findings serve as a reminder that a complete imaging evaluation will lead some proportion of patients to undergo potentially extraneous and costly procedures. Genomic characterization of CNS lymphomas has revealed frequent alterations in components of the B-cell receptor pathway, including mutations in MYD88 and CD79B,² which have also been documented in extracranial sites of disease. In future studies, it will be of interest to ascertain whether the presence of these recurrent alterations in CNS samples is predictive for non-CNS involvement.

Conflict of interest statement. J.J.M. and N.W. have no conflict of interest.

Authorship statement. J.J.M. and N.W. conceived, wrote, and revised the manuscript.

Funding

There was no funding related to the preparation of this manuscript.