The aim of this study was to analyze the prevalence and characters of non-enhancing T2-FLAIR hyperintensity lesions of neoplasia nature in PCNSL patients. Better understanding of the pattern and mechanism of non-enhancing T2-FLAIR hyperintensity lesions is vital for early detection and accurate evaluation of the true burden of disease, potentially guiding the management.
Of 89 PCNSL patients, we observed that 10 (11.2%) patients had non-enhancing T2-FLAIR hyperintensity lesions at a distance from the enhancing lesions that markedly decrease or disappear. This dynamic change indicated that these white matter non-enhancing T2-FLAIR hyperintensity lesions had neoplastic nature. It has been reported that the prevalence of this phenomenon was about 23% . In our research, the most frequently involved locations of non-enhancing T2-FLAIR hyperintensity lesions were deep and juxtacortical white matter. We found that patients with non-enhancing T2-FLAIR hyperintensity lesions exhibited significantly more multiple enhancing tumor lesions (p =0.027) and bilateral enhancing lesions (p =0.001) compared to the patients without non-enhancing T2-FLAIR hyperintensity lesions. The underlying mechanism of this phenomenon is still unknown. The consideration of PCNSL as a whole brain disease might contribute to this .
Pathology reveals that PCNSL is highly proliferative tumor cells in an angiocentric growth pattern, in which lymphoma cells accumulate around small and medium-sized blood vessels . During the angiotropic invasive growth of tumor, tumor cells arrange themselves centripetally around the Virchow–Robin space and show a sleeve-like infiltration pattern. When those lesions grow larger, this will lead to disruption of the blood-brain barrier and enable their detection by virtue of pathological contrast enhancement. We thought the non-enhancing lesions might be the early phase of lymphoma, while they have not yet disrupted the blood-brain barrier. Routine contrast enhanced MRI only reflects the damage of the blood brain barrier, but not the degree of tumor angiogenesis. It is important to keep in mind that contrast enhancement is a surrogate for disruption of blood-brain barrier, which does not exhibit the true extent of tumor in the central nerve system. Very few PCNSL cases have been reported that do not have contrast enhancement [9,11]. Most of those cases exhibited a diffuse brain inﬁltration with lymphoma cells. Those diseases include lymphomatosis cerebri and intravascular lymphoma (IVL), a rare variant of aggressive (usually B cell) non-Hodgkin’s lymphoma with selective growth of neoplastic cells within blood vessel lumina.
Recognizing the features of non-enhancing T2-FLAIR hyperintensity lesions that of neoplastic nature is key for early detection. However, it is challenging to distinguish the non-enhancing lymphomatous infiltration from non-specific white matter hyperintensities lesion, which can be caused by diverse etiologies, including migraine, stroke, dementia, and healthy aging [17-19]. We observed that most of non-enhancing T2-FLAIR hyperintensity lesions of tumor nature mostly located in deep and juxtacortical white matter, with relatively large volume and irregular shape. Those characters might be helpful to differentiate non-enhancing white matter high signal lesions of tumor nature from other diseases. MRI spectroscopy and PET scan should be investigated as complementary tools. However, there is no specific diagnostic method, and the most important is the follow up.
More importantly, knowing the features of non-enhancing T2-FLAIR hyperintensity lesions that of neoplastic nature is key for accurate evaluation of tumor burden. This might provide potential insight into the mechanisms of PCNSL pathogenesis, as well as help develop appropriate strategies of treatment. It is generally appreciated that the radiographic appearance of the tumor underestimates the disease extent . Our result was consistent with this. However, non-enhancing lesions have not been taken into consideration in the current IPCG response criteria . According to IPCG criteria, lack of contrast-enhancing lesions in the absence of other lymphoma manifestations is regarded as complete response in PCNSL. Non-enhancing T2-FLAIR hyperintensity lesions that of neoplastic nature should be incorporated in refined criteria defining response and progression in PCNSL. Previous research has reported that the non-enhancing high signal could become the relapsing site of tumor during the follow up , though we did not find this. Perhaps it is because of the small sample size in our study.
Our study has several limitations. First, it is an observational, retrospective cohort study, which may generate some biases due to confounding factors. Second, the sample size is relatively small in our study. Third, MRI scans were obtained in different type of scanner and imaging parameters, but all 3 T scanner. There was no systematic difference in diagnostic imaging qualities which influence the assessment.