Permeability Estimates in Histopathology-Proved Treatment-Induced Necrosis Using Perfusion CT: Can These Add to Other Perfusion Parameters in Differentiating from Recurrent/Progressive Tumors?

Radiation-Induced Permeability Changes

Late radiation effects in normal tissues are classically attributed to damage to various critical target-cell populations; in the brain, these 2 cell populations are glial cells and endothelial cells.¹⁶ More recently, the contribution of chronic oxidative stress to late radiation brain injury has been implicated.¹⁷ One school of thought is that endothelial damage is the primary essential event in the pathophysiology of delayed radiation necrosis because the endothelium is relatively vulnerable to reproductive death. The endothelium is sensitive to radiation, but the effect has a longer latency in contrast to the glial cells, which are less sensitive but have a shorter latency. In the first weeks after irradiation, there is a modest but definite breakdown of the BBB; this effect is transitory and is followed by a period of functional recovery and a latent period of normal BBB function.^18,19 However, the endothelial cells have significant irreparable chromosomal damage and reproductive death, leading to a relatively declining number of surviving cells. This latent period, the period of apparent recovery, ends when the number of surviving cells drops below the level required to maintain function, leading to an eventual increase in vascular permeability.²⁰

Another study showed that after irradiation, the neuropil seemed morphologically intact at 3.5 months, though necrosis was seen at 4 months after radiosurgery with 75 Gy in the rat cortex.²¹ In another rat-model study, it was shown that the BBB breakdown increased up to the 6-month time point and thereafter appeared to stabilize or decrease.²² Another rat-model study showed detectable disruption of the BBB at 2 weeks postirradiation shown as discrete leakage, whereas late injury seen at 24 weeks indicated more diffuse vascular leakage.²³

Postradiation therapy permeability changes in the NAWM have also been studied in the past by using dynamic contrast-enhanced MR perfusion techniques.^24,25 Lee et al²⁵ showed a dose-dependent increase in vascular permeability 2 months after radiation therapy, which decreased at 4 months; however, this study did not have absolute quantification of permeability, and changes obtained in recirculation phase were presumed to represent vascular permeability. Cao et al²⁴ also showed an increase in vascular permeability during radiation therapy, which decreased after RT and also was correlated with neurocongnitive dysfunction.

In Vivo Permeability Estimates in Radiation-Induced Injury

Quantitative permeability estimates by using any of the available perfusion imaging techniques have not been performed in the past to differentiate TIN or radiation effects from RPT.^13,14 Part of the reason involves many complexities and assumptions associated with accurate permeability estimates using dynamic contrast-enhanced MR perfusion modalities. Previous authors have used relative PSR or signal-intensity enhancement-time curves as an indirect measure of vascular leakiness successfully; however, absolute quantitative estimates of permeability have not been used yet, to our knowledge, for this very important clinical scenario. Absolute quantitative estimates of PS have been performed by using PCT in brain tumors and have been used for preoperative glioma grading as well as to differentiate high-grade gliomas from non-neoplastic lesions, such as tumefactive demyelinating lesions.^15,26 PS estimates using PCT have shown much more robust results due to a linear relationship of contrast agent with the tissue attenuation curve as well as the availability of a stable arterial input signal intensity compared with MR perfusion techniques. In addition to PS estimates, other hemodynamic perfusion parameters can also be obtained in 1 single experiment by using PCT and, hence, can add to the diagnostic value of the test.

In the present study, we obtained absolute quantification of vascular permeability (ie, PS by using PCT) and have shown increased PS in patients with TIN, but this increased PS is still significantly (P = .001) less compared with much more increased PS seen in RPTs. RPTs are usually higher grade tumors with increased vascularity and also increased neoangiogenesis with higher VEGF expression, which leads to increased CBV as well as increased PS, as seen in our observed results. Barajas et al¹³ showed lower relative PSR in recurrent glioblastoma multiforme compared with radiation necrosis by using dynamic susceptibility contrast MR perfusion imaging, suggesting a disrupted BBB that was more permeable to macromolecular contrast agents; however, their measurements were not a direct estimate of lesion leakiness. They also noted a large degree of overlap between the 2 groups, making rPSR a less robust predictor of recurrent tumor.¹³ The same group also published the same methodology with stronger results by using rPSR to differentiate metastatic tumors from radiation necrosis, suggesting that PSR may be a better prognostic indicator of tumor recurrence than rCBV,²⁷ hence probably, to some degree, exposing the limitations of nonquantitative and indirect methods of permeability assessment.

Practical Problems Using Permeability Estimates to Differentiate TIN From RPT

Apart from the limited resolution of clinically available imaging tools for permeability estimates in RPTs, most of these lesions have viable tumor mixed with variable amounts of tumor or treatment-induced necrosis. This combination not only leads to a very heterogeneous morphologic imaging appearance but also restricts the utility of most of the functional imaging modalities. Most of these modalities, whether using metabolic or physiologic imaging, are banking on the differences in metabolic or physiologic demands of the tissue. Another factor that can particularly complicate permeability estimates is the fact that upregulation of VEGF, which is known to be 1 of the major factors responsible for increased leakiness of blood vessels in tumors,²⁸ and is also upregulated in radiation injury.²⁹ Recent reports suggesting that anti-VEGF therapy can be used in patients with radiation necrosis supports the role played by VEGF signaling cascade in radiation injury.^30,31

Vascular Perfusion Parameters in Differentiating TIN from RPT

Blood volume estimates obtained by using MR^8,11,27 or PCT⁷ techniques have been previously used with significant success in differentiating the 2 entities. Blood volume estimates are based on the differences in vascularity of the 2 entities, with recurrent tumors showing high blood volume due to tumor angiogenesis and increased vascular density; whereas radiation necrosis shows low blood volume because it consists primarily of hyalinized vasculopathy and coagulative necrosis, leading to hypoperfusion. However, tumor vasculature and perfusion also depend on a number of other variables and are usually very heterogeneous. In a rapidly growing high-grade tumor, vasculature can be severely compromised due to the rapid growth of the tumor cells, necrosis, and increased permeability of the vessels causing interstitial edema, which can result in compression of the smaller vessels, also leading to areas of hypoperfusion. Similarly, within irradiated brain tissue, in addition to occlusive vasculopathy, a variety of other vascular phenomena are noted, such as aneurysmal formation, telangiectasia, vascular elongation, and a remarkable proliferation of endothelial cells, especially in the capillary bed,³² which can even increase CBV in radiation necrosis, thus inducing some overlap of the vascular perfusion parameters. Hence, the addition of permeability measurements, as in the present study, can provide another aspect of the vasculature that may help differentiate the 2 entities better.

CBV and PS, even though they are probably correlated, have been shown to represent different aspects of tumor angiogenesis in a recent publication.²⁸ CBV has been shown to correlate with microvascular density, whereas PS has shown a stronger correlation with microvascular cellular proliferation.²⁸ In the present study, we showed a similar association of rCBV and PS (Fig 4), with some patients showing lower rCBV but high PS and vice versa, suggesting that the perfusion imaging modalities that will provide estimates of both CBV and PS may help better differentiate non-neoplastic lesions such as TIN from RPT. However, most of the commercially available perfusion software is vendor-specific and uses different postprocessing methodology; hence, absolute or even relative values of perfusion parameters obtained by using one software may not match those in another center using a different vendor and software. However, understanding the histologic and angiogenic bases of these perfusion parameters will help in better use of these imaging tools, especially in clinical practice, where most of these recurrent enhancing lesions consist of variable degrees of viable tumor and necrosis.

Limitations of the Study

One of the major limitations of our study is the small sample size, particularly of histopathology-proved radiation necrosis, apart from being a retrospective study. Another important factor is that 9 (33%) patients with RPT were on stable doses of steroids at the time of PCT examination compared with only 1 (9%) of the patients with TIN, which could potentially lead to erroneous estimates of permeability because steroids are known to repair the damaged BBB. However, if that is the case, in fact, this will enhance our statistically significant results by increasing PS estimates further in the RPT group. Another limitation of our study is that 3 (27%) of the patients with TIN were diagnosed with biopsies, which may not be a true representative of the whole lesion; however, 2 of these 3 patients had stable or improving enhancing lesion on follow-up MR imaging studies.