In this study, we found that pretherapeutic ADC tumor measurements within contrast-enhancing regions were predictive of clinical outcome in patients with PCNSL. Specifically, we found that ADC25% (<692) and ADCmin (<384) values were predictive of shorter PFS and OS. Additionally, an inverse correlation was found between ADC measurements and tumor cellular density. Finally, we found that patients with prolonged PFS and OS had a significant reduction in post-therapeutic ADC values.
Currently, there are no established imaging biomarkers predictive of clinical outcome in patients with PCNSL, a potentially curable disease. In our study, stratification of patients with PCNSL by pretherapeutic ADC measurements retrospectively provided a robust measure of eventual clinical response to treatment and overall survival. This correlation was preserved even when other known prognostic variables were taken into account. To our knowledge, the use of pretherapeutic ADC values as a predictive factor of the clinical outcome in PCNSL has not been previously reported. The ability to identify patients at risk for primary refractory disease by using pretherapeutic ADC measurements has important clinical implications. A noninvasive pretherapeutic imaging biomarker able to accurately identify patients at high risk for tumor refractoriness to methotrexate-based chemotherapy could greatly facilitate clinical decision-making, allowing the initiation of individualized second-line salvage therapies, which may result in improved clinical outcome.9,10,19,20
Poor clinical outcome in patients with PCNSL treated with high-dose methotrexate chemotherapy has been positively correlated with increased intratumoral expression of activated STAT6
within high-density tumors based on histopathologic analysis of diagnostic tissue specimens.15,16,21
Quantification of STAT6
expression levels may eventually prove to be a sensitive and specific biomarker of clinical outcome; however, its analysis requires an invasive procedure and is not currently widely clinically available. The results of our study indicate that DWI-derived ADC measurements could potentially be used as a noninvasive imaging biomarker for identifying PCNSL tumors of high cellular density, which are at high risk for refractoriness to conventional high-dose methotrexate-based induction strategies.
In this study, we detected an inverse correlation between ADC measurements and tumor cellular density. Specifically, lower ADC values were correlated with increasing tumor cellular density. The results from our study are essentially in agreement with those of previous investigations. ADC values have been noted to be markedly reduced in PCNSL compared with other enhancing intra-axial tumors.11–14,22–26
Guo et al14
reported that ADC values were inversely related to tumor nuclear-to-cytoplasmatic ratios in their study of water diffusivity within PCNSL and high-grade astrocytomas.
Increased tumor cell density (as determined by counting lymphoma cell nuclei/high-power field from diagnostic brain biopsies) was found not to be a statistically significant predictor of clinical outcome. Additionally, a multivariable analysis of ADC measurements and tumor cell density found ADC to be the only predictor of clinical outcome. An important limitation of the quantification of tumor cell density by using microscopy in lymphoma is the inherent variability in the size and morphology of diffuse proliferations of large lymphoid cells. For this reason, we have also qualitatively defined tumor cell density on the basis of whether normal brain elements (neurons and glia) are detectable between the neoplastic cells within the pathologic specimen.16
Our results suggest that while ADC measurements correlate with tumor cell density, DWI is a more accurate predictor of clinical outcome, given the capacity of this technique to summate additional unidentified prognostic biologic features of tumor aggressiveness beyond cell density.
ADC measurements often facilitate the clinical differentiation of PCNSL from high-grade glioma and intra-axial meta-static disease.11–14,22–26
The ability to presumptively diagnose PCNSL on the basis of noninvasive molecular biomarkers as well as MR imaging may have a significant impact on clinical management. Unlike high-grade glioma, gross total surgical resection of enhancing regions offers no significant improvement in clinical outcome in patients with PCNSL.27–30
The need to establish a definitive diagnosis necessitates tissue acquisition via stereotactic biopsy. Often clinicians rely on conventional anatomic contrast-enhanced MR imaging without using physiologic MR images, such as ADC measurements, when targeting enhancing tumor for biopsy. The results of our study suggest that localization of tumor regions with the lowest ADC measurements may allow the collection of pathologic specimens of highest potential prognostic significance and may minimize the rate of false-negative biopsy collection. Our results indicate that tissue sampling by using ADC-guided stereotactic biopsy in patients suspected of having PCNSL is an application worthy of further investigation.
In this study, we found that patients stratified to the high ADC group who subsequently were found to have improved PFS and OS were noted to exhibit a significant decrease in ADC measurements following high-dose methotrexate chemotherapy. This decrease in ADC measurements could be suggestive of a net reduction of extracellular water molecular motion within treated lesions. We hypothesize that this decrease may, in part, be due to greater tumor cellular responsiveness to methotrexate-based chemotherapies within the high ADC group. This improved response may subsequently lead to treatment-induced cellular swelling, resulting from diminished cellular water homeostasis, which may lead to a decrease in extracellular space within contrast-enhancing regions.31
Several other studies have demonstrated change in post-therapeutic ADC values following radiation and chemotherapy in primary glial brain tumors.31–34
In a study of patients with unresectable glioma, Moffat et al31
used ADC-derived functional diffusion maps (fDMs) to monitor contrast-enhancing regions during the course of therapy. The fDMs were found to predict patient response at 3 weeks from the start of treatment, revealing that early changes in tumor diffusion values could be used as a prognostic indicator of subsequent volumetric tumor response.34
While fDMs have been suggested to be an early biomarker of eventual radiographic response in primary glial brain tumors, their utility as biomarkers in PCNSL has not previously been reported.
The use of serial ADC measurements in patients with PCNSL may have significant clinical implications. Currently, the response to methotrexate-based therapy is monitored by serial contrast-enhanced anatomic MR imaging. Increased enhancing volume has been correlated with worsened patient outcomes; however, clinical signs of disease refractoriness can occur before the manifestation of progressive contrast enhancement on serial follow-up MR imaging.4–7
The results of our study suggest that the use of serial ADC measurements in conjunction with contrast-enhanced anatomic MR imaging may be clinically useful in assessing early response to methotrexate-based treatment in patients with PCNSL.
Our study had several limitations. First, the results of our study may have been influenced by its relatively small sample size and retrospective nature. Second, because post-therapeutic biopsy samples are not normally obtained, we were unable to determine the pathophysiologic basis for the observed changes in ADC values on posttherapeutic MR imaging. We suggest that future studies may use image-guided stereotactic biopsy techniques to directly correlate tissue specimen characteristics with ADC measurements.
The technique for measuring ADC values described in this study was chosen to investigate PCNSL because it is robust and timely and clinically feasible. The image processing software and MR scanners used in this study are commercially available and frequently used in the clinical interpretation of MR images because DWI has become a standard imaging sequence in the evaluation of many diseases.