Radiation necrosis differential diagnosis

Radiation necrosis differential diagnosis

Radiation necrosis (RN) may mimic recurrent (or denovo) tumor both clinically and radiographically. Differences in prognosis and treatment make it important to distinguish between tumor and RN.

Over the years many methods have been championed to differentiate radiation necrosis from recurrent high-grade glioma. None have proven adequately reliable, and this may not even be a useful exercise. Tumor cells are frequently found on biopsy. The decision whether to reoperate is usually based on whether there is progressive mass effect (regardless of whether it is necrosis or tumor), taking into consideration the patient’s neurologic condition, projected longevity, patient desires…

It is widely accepted that the capture, enumeration and identification of circulating tumor cells (CTCs) hold significant promise for early cancer screening, diagnosis and prognosis. These cells originate from primary tumors and disseminate to distant sites via the blood 1) 2) 3)

Differentiating treatment necrosis from tumor recurrence poses a diagnostic conundrum for many clinicians in neuro-oncology. To investigate the potential role of circulating tumor cells (CTCs) detection in differentiating tumor recurrence and treatment necrosis in brain gliomas, Gao et al. retrospectively analyzed the data of 22 consecutive patients with tumor totally removed and new enhancing mass lesion(s) showed on MRI after initial radiotherapy. The 22 patients were finally classified into tumor recurrence group (n = 10) and treatment necrosis group (n = 12), according to evidence from the clinical course (n = 11) and histological confirmation (n = 11). All 22 patients received CTCs detection, and DSC-MRP and 11C-MET-PET were performed on 20 patients (90.9%) and 17 patients (77.3%) respectively. The data of the diagnosis efficacy to differentiate the two lesions by CTC detection, MPR and PET were analyzed by ROC analysis. The mean CTCs counts were significantly higher in the tumor recurrence group (6.10 ± 3.28) compared to the treatment necrosis group (1.08 ± 2.54, p < 0.001). The ROC curve showed that an optimized cell count threshold of 2 had 100% sensitivity and 91.2% specificity with AUC = 0.933 to declare tumor recurrence. The diagnostic efficacy of CTC detection was superior to rCBV of DSC-MRP and rSUVmax in MET-PET. Furthermore, they observed that CTCs detection could have a potential role in predicting tumor recurrence in one patient. The research results preliminarily showed the potential value of CTC detection in differentiating treatment necrosis from tumor recurrence in brain gliomas, and is worthy of further confirmation with large samples involved 4).

Cannot reliably differentiate some cases of RN from tumor (especially astrocytoma; RN occasionally resembles glioblastoma).

Proton magnetic resonance spectroscopic imaging was reliable in distinguishing pure tumor (elevated choline) from pure RN (low choline), but was less definitive with mixed tumor/necrosis 5).

Magnetic resonance perfusion imaging, particularly Dynamic Contrast-Enhanced (DCE), help in the differential diagnosis by tumor recurrence and radiation necrosis during the follow-up after radiosurgery.

Mean ADCs were lower with recurrence (1.18 ± 0.13 X 10–3 mm/s) vs. necrosis (1.4 ± 0.17 X 10–3 mm/s) 6) (not all cases biopsy proven).

Some reports of success with thallium 201 and technetium-99 m brain scans.

PET (positron emission tomography) scan: because positron emitting isotopes have short half–lives, PET scanning requires a nearby cyclotron to generate the radiopharmaceuticals at great expense. Utilizing [18F]-fluorodeoxyglucose (FDG), regional glucose metabolism is imaged and is generally increased with recurrent tumor, and is decreased with RN. Specificity for distinguishing RN from tumor recurrence is >90 %, but sensitivity may be too low to make it reliable 7) Amino acid tracers such as [11C]methionine and [18F]tyrosine are taken up by most brain tumors 8), especially gliomas, and may also be used to help differentiate tumor from necrosis. Accuracy may be increased by fusing PET scan with MRI 9).

SPECT (single positron emission computed tomography): “poor man’s PET scan.” Uses radio- labeled amphetamine. Uptake depends on presence of intact neurons and the condition of cerebral blood vessels (including blood brain barrier). Decreased radionuclide uptake indicates necrosis, whereas tumor recurrence has no decreased uptake.

For delayed radiation injury, image analysis has considerably advanced, but neuropathological findings are still required to establish diagnosis. A patient who had received radiation therapy for pineal germinoma at age 14 developed neurological and psychiatric abnormalities after 15 years as a late delayed radiation injury. Autopsy at age 59 revealed diffuse changes in the white matter consisting in order of severity of myelin pallor, demyelination, and necrosis which were characterized by a lack of glial reaction. The cerebral cortex was relatively well preserved. As delayed radiation injuries, hyalinous changes in the vascular wall, angiomatous lesions and, fresh and old petechial hemorrhages were found. Moreover, vascular changes associated with arteriosclerosis were also present. Furthermore, a focal glial nodule was detected which was considered to be a new radiation-induced neoplasia. These findings suggest that late delayed radiation injury may slowly develop over 30 years and may involve damage to neuroglial stem cell compensation. It is also evident that arteriosclerotic changes and newly induced neoplasia may develop in delayed radiation injury cases 10).

A purely radiological diagnosis of recurrence or progression can be hampered by flaws induced by pseudoprogressionpseudoresponse, or radionecrosis.

Radiation necrosis (RN), or its imaging equivalent, treatment-related imaging changes (TRIC), is an inflammatory reaction to high-dose radiation in the brain.

Patients who receive immunotherapy (IT) alone may have an increased rate of RN/treatment-related imaging changes (TRIC) compared with those who receive chemotherapy (CT) or targeted therapy (TT) alone after stereotactic radiosurgery, whereas receiving any CT may in fact be protective against RN/TRIC. As the use of immunotherapies increases, the rate of RN/TRIC may be expected to increase compared with rates in the chemotherapy era 11).


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Woo D., Yu M. Circulating tumor cells as “liquid biopsies” to understand cancer metastasis. Transl. Res. 2018;201:128–135. doi: 10.1016/j.trsl.2018.07.003

Gao F, Zhao W, Li M, Ren X, Jiang H, Cui Y, Lin S. Role of circulating tumor cell detection in differentiating tumor recurrence from treatment necrosis of brain gliomas. Biosci Trends. 2021 Apr 29. doi: 10.5582/bst.2021.01017. Epub ahead of print. PMID: 33952802.

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Thiel A, Pietrzyk U, Sturm V, et al. Enhanced Accuracy in Differential Diagnosis of Radiation Necrosis by Positron Emission Tomography-Magnetic Resonance Imaging Coregistration: Technical Case Report. Neurosurgery. 2000; 46:232–234

Tanikawa S, Kato Y, Tanino M, Terasaka S, Kurokawa Y, Arai N, Nagashima K, Tanaka S. Autopsy report of a late delayed radiation injury after a period of 45 years. Neuropathology. 2019 Jan 4. doi: 10.1111/neup.12528. [Epub ahead of print] PubMed PMID: 30609132.

Colaco RJ, Martin P, Kluger HM, Yu JB, Chiang VL. Does immunotherapy increase the rate of radiation necrosis after radiosurgical treatment of brain metastases? J Neurosurg. 2015 Nov 6:1-7. [Epub ahead of print] PubMed PMID: 26544782.

Radiation necrosis treatment

Radiation necrosis treatment

Radiation necrosis (RN) will be increasingly encountered due to the widespread use of SRS. Symptomatic RN can cause significant morbidity and should be managed pro-actively. There is no single modality which can reliably distinguish RN from recurrent tumor, and a multi-modal approach is often required. For patients with symptomatic RN, oral corticosteroid therapy and bevacizumab are both effective. A minority of patients, with an unclear diagnosis, or refractory symptoms, will require surgical resection. As RN proves to be a challenging condition to diagnose and manage, risk factor mitigation becomes important in clinical decision making 1).

Using the internal database for pharmaceutical products, all patients who received BEV in the University of Munich were identified. Only patients who received BEV as symptomatic treatment for radiation necrosis were included. Patient characteristics, symptoms before, during, and after treatment, and the use of dexamethasone were evaluated using medical reports and systematic internal documentation. The symptoms were graded using CTCAE version 5.0 for general neurological symptoms. Symptoms were graded directly before each cycle and after the treatment (approximately 6 weeks). Additionally, the daily steroid dose was collected at these timepoints. Patients who either improved in symptoms, received less dexamethasone after treatment, or both were considered to have a benefit from the treatment.

Twenty-one patients who received BEV due to radiation necrosis were identified. For 10 patients (47.6%) symptoms improved and 11 patients (52.4%) remained clinically stable during the treatment. In 14 patients (66.7%) the dexamethasone dose could be reduced during therapy, 5 patients (23.8%) received the same dose of dexamethasone before and after the treatment, and 2 patients (9.5%) received a higher dose at the end of the treatment. According to this analysis, overall, 19 patients (90.5%) benefited from the treatment with BEV. No severe adverse effects were reported.

BEV might be an effective and safe therapeutic option for patients with radiation necrosis as a complication after cranial radiation therapy. Patients seem to benefit from this treatment by improving symptomatically or through reduction of dexamethasone 2).

Perez-Torres et al. validated the VEGF specificity by comparing the therapeutic efficacy of anti-VEGF with non-specific isotype control antibody. Additionally, they found that VEGF over-expression and radionecrosis developed simultaneously, which precludes preventative anti-VEGF treatment 3).



Vellayappan B, Tan CL, Yong C, Khor LK, Koh WY, Yeo TT, Detsky J, Lo S, Sahgal A. Diagnosis and Management of Radiation Necrosis in Patients With Brain Metastases. Front Oncol. 2018 Sep 28;8:395. doi: 10.3389/fonc.2018.00395. eCollection 2018. Review. PubMed PMID: 30324090; PubMed Central PMCID: PMC6172328.

Bodensohn R, Hadi I, Fleischmann DF, Corradini S, Thon N, Rauch J, Belka C, Niyazi M. Bevacizumab as a treatment option for radiation necrosis after cranial radiation therapy: a retrospective monocentric analysis. Strahlenther Onkol. 2019 Oct 4. doi: 10.1007/s00066-019-01521-x. [Epub ahead of print] PubMed PMID: 31586230.

Perez-Torres CJ, Yuan L, Schmidt RE, Rich KM, Drzymala RE, Hallahan DE, Ackerman JJ, Garbow JR. Specificity of vascular endothelial growth factor treatment for radiation necrosis. Radiother Oncol. 2015 Sep 12. pii: S0167-8140(15)00462-4. doi: 10.1016/j.radonc.2015.09.004. [Epub ahead of print] PubMed PMID: 26376163.

Ionizing radiation

Ionizing radiation is typically used during spine surgery for localization and guidance in instrumentation placement.

Minimally invasive (MI) surgical procedures are increasingly popular often require significantly more fluoroscopy, placing surgeons at risk for increased radiation exposure and radiation-induced complications.
PubMed database was queried for relevant articles pertaining to radiation exposure in spine surgery.
Discectomy, Percutaneous Pedicle screw fixation, MI transforaminal lumbar inter body fusion (TLIF), MI lateral lumbar inter body fusion, andvertebroplasty/kyphoplasty procedures were assessed. The highest radiation doses were seen with MI pedicle screw placement, MI TLIF, vertebroplasty/kyphoplasty, and percutaneous endoscopic lumbar discectomy. Use of lead aprons and thyroid shields reduces effective dose by several orders of magnitude. Proper operator positioning also minimizes radiation exposure. Lead gloves decrease dose to the surgeon’s hand from scatter if the hand is out of the x-ray beam the majority of the time. If prolonged exposure of the hand cannot be avoided, the technician should collimate the surgeon’s hand out of the beam or use instruments to position the hand farther from the beam. In addition to using less fluoroscopy, pulsed fluoroscopy can also decrease overall dose in a procedure.
Spine surgeons should reduce radiation exposure to minimize risk of potential long-term complications. Strategies include minimizing fluoroscopy use and dose, proper use of protective gear, and appropriate manipulation of fluoroscopic equipment 1).
1) Srinivasan D, Than KD, Wang AC, La Marca F, Wang PI, Schermerhorn TC, Park P. Radiation Safety and Spine Surgery: Systematic Review of Exposure Limits and Methods to Minimize Radiation Exposure. World Neurosurg. 2014 Jul 31. pii: S1878-8750(14)00701-3. doi: 10.1016/j.wneu.2014.07.041. [Epub ahead of print] Review. PubMed PMID: 25088230.
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