Histopathologically confirmed radiation necrosis: Risk factors and clinical outcomes in patients with primary brain tumors

Abstract

Background

Radiation necrosis is a recognized complication following radiotherapy for primary brain tumors, presenting diagnostic and therapeutic challenges, and potentially masquerading as tumor recurrence. This study aims to delineate the clinical trajectory, management strategies, and outcomes of histologically confirmed radiation necrosis in patients treated for primary brain tumors.

Methods

We conducted a retrospective review of patients who underwent surgical intervention for suspected tumor recurrence at our institution between 2010 and 2022, following adjuvant radiotherapy. Cases with histopathologically confirmed radiation necrosis were identified and analyzed for onset, clinical symptoms, radiological features, correlation with radio- and chemotherapy, management approaches, and disease progression.

Results

Out of 276 patients operated for suspected recurrent brain tumors, 14 (5%) were histopathologically diagnosed with radiation necrosis. The latency period from radiotherapy to diagnosis ranged from 3 to 40 months. Notably, patients with oligodendrogliomas exhibited a significantly higher incidence of radiation necrosis (26%), underscoring a substantial risk association (P < 0.001). Conversely, the rates of radiation necrosis in patients with glioblastoma and astrocytoma (WHO grade II and III) were lower, at 2% and 0%, respectively, suggesting a lower risk association (P < 0.001 and P = 0.036, respectively). The majority (79%) of these patients were asymptomatic and exhibited a favorable clinical course, with most cases showing no progression of necrosis. During the follow-up period, tumor recurrence was verified in 2 patients.

Conclusion

Radiation necrosis post-radiotherapy for primary brain tumors occurs infrequently but predominantly in patients with oligodendrogliomas, often following a benign course. The study underscores the importance of close monitoring for this condition, given the potential for sampling errors and the critical need for histopathological confirmation to guide appropriate management.

Key Points.

• - Oligodendrogliomas may carry a higher risk of radiation necrosis than glioblastomas and astrocytomas.

• - Most radiation necrosis cases are asymptomatic with no progression.

• - Histopathology is crucial to confirm radiation necrosis and guide treatment.

Importance of the Study.

This study investigates the clinical course, risk factors, and outcomes of histopathologically confirmed radiation necrosis in patients with primary brain tumors. Unlike prior research, which often lacked histological confirmation, this study retrospectively analyzed 276 cases of suspected tumor recurrence after radiotherapy, identifying 14 cases (5%) of radiation necrosis. Patients with oligodendrogliomas demonstrated a significantly higher incidence (26%) compared to glioblastomas (2%) and astrocytomas (0%), underscoring distinct tumor-specific risks. Radiation necrosis typically develops within 3–40 months post-radiotherapy, with most cases being asymptomatic and exhibiting a benign course. Management strategies included gross total resection or conservative treatment, with no observed progression in necrosis. This study highlights the importance of histopathological confirmation to differentiate necrosis from tumor recurrence and optimize treatment decisions. Future implications include improving diagnostic accuracy through advanced imaging and exploring tailored follow-up protocols to enhance outcomes for high-risk patient groups.

Brain radiation necrosis is a well-known phenomenon following radiotherapy for primary brain tumors and brain metastases. Radiotherapy has become a cornerstone for the treatment of many brain tumors. Radiation necrosis was first identified in 1930 and the primary pathogenesis is thought to be the direct damage to endothelial and glial cells, particularly oligodendrocytes, which causes vascular hyalinization and demyelination.¹ The reported incidence of radiation necrosis varies from 3% to 24 %, which can probably be attributed to multiple aspects of the administered radiotherapy including methods and dose of radiation as well as the underlying pathology.^1,2 Diagnosis of radiation necrosis is generally established depending on radiological features along with the clinical presentation of the patients. Following radiotherapy, the usual procedure is to perform regular T1-weighted post-gadolinium MR imaging to identify new contrast-enhancing tumor and/or enlargement of tumor remnants. A necrosis is considered if serial MR imaging showed reduction or stability in the size of the enhancing lesion over time, while recurrence is considered if repeated follow-up MRI scans showed sustained growth of the enhancing lesion.³ Watch and scan might be suitable in asymptomatic patients with small enhancing lesions. Nevertheless, this strategy might delay a surgical resection or a systemic therapy that probably would have been easier or more effective at an earlier stage. Therefore, the use of perfusion and diffusion MRI, MR spectroscopy, and positron emission tomography imaging was suggested to distinguish between tumor recurrence and radiation necrosis, with the best sensitivity and specificity achieved by applying a combination of these imaging measures to diagnose brain radiation necrosis.^4–6 Stereotactic biopsy represents a serious option to investigate whether a growing enhancing lesion is a radiation necrosis or a tumor recurrence.⁷ According to the literature, neither option allows for 100% sensitivity or specificity.⁸ Regardless of the diagnostic approach, treatment of radiation necrosis once the diagnosis is established is still a matter of controversy. The available evidence on the treatment options is low. In addition, few studies involved patients in whom, radiation necrosis was established based on histopathological examination. In this retrospective, single-institutional study, we aimed to investigate the clinical course of patients who underwent surgery for a suspected recurrence of primary or metastatic brain tumor and had a histopathological diagnosis of radiation necrosis.

Methods

Patients

We identified all adult patients who were operated on for a suspected recurrent primary brain tumor after receiving adjuvant therapy at our institution between 2010 and 2022 through the neurosurgical database.

In addition, cases of radiation necrosis were identified by a comprehensive search of the database of the local department of neuropathology. The database includes histopathological findings of all samples that were obtained during surgical resection of intracranial tumors. Histopathological diagnosis was established according to the 2007 World Health Organization Classification of Tumors of the Central Nervous System or its later version (2016).^9,10 The search process in the histopathological databank covered the same period (2010 and 2022). Search terms included: Radiation necrosis, necrosis, and no tumor cells. Histopathological findings of search matches were investigated for fibrinoid necrosis or hyalinization / fibrosis of blood vessels, proliferation of the adventitia, dystrophic calcifications, and inflammatory infiltrates consisting predominantly of macrophages, radiation-induced cytologic atypia.

The study was performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. The study was approved by the local ethics committee of the University Medical Center Göttingen with the registration number 18/8/22.

Treatment Protocols

Treatment protocols for primary brain tumors were in line with the international recommendations including adjuvant concomitant radio- and chemotherapy or radiotherapy alone.^11,12 In accordance with current guidelines, GTV-CTV margins were discussed on an individual basis in the clinical routine. If possible, margins were reduced to minimize toxicities.¹³

All patients with primary brain tumors received routine MRI scans. Evaluation of MRI scans was routinely performed through a dedicated neuroradiologist and was based on the features of the enhancing lesion and its enlargement in the repeated MRI scans based on RANO criteria,¹⁴ as well as on diffusion-weighted sequences and perfusion sequences if available. Every case was discussed at a multidisciplinary tumor board including neurosurgeons, radiation oncologists, neuropathologists, and neurooncologists. Patients with suspected recurrent tumors underwent gross total resection whenever possible. Subtotal resection or biopsy was performed in case the lesion was of eloquent localization and therefore not amenable for total resection.

Clinical and Radiological Features

Clinical features were retrieved from the patient’s charts and included the primary diagnosis, adjuvant therapy including method and dose of radiotherapy, chemotherapy, time interval between radiotherapy and onset of necrosis, radiological features of the necrosis, symptoms associated with radiation necrosis, surgical approach, treatment strategies as well as clinical and radiological course of the necrosis. Localization of radiation necrosis on MRI scans was considered local if the lesion had contact with the resection cavity or the surgical corridor, otherwise, it was considered distant. If further surgery was performed upon progression within 6 months, resulting histology was also taken into consideration to detect possible sampling errors.

Statistical Analysis

For all tests, a P-value less than 0.05 was considered significant. Statistical analysis was performed using IBM SPSS Statistics (v20, IBM Corp, Armonk, New York, USA), Microsoft Excel (2013, Microsoft Inc, Seattle, Washington, USA), and SigmaPlot (v12.5, Systat Software Inc, Erkrath, Germany). Chi-square statistic was used to test the correlation between tumor pathology and occurrence of necrosis.

Results

Patients

Two hundred and seventy-six patients were operated on for a suspected recurrent primary brain tumor at our institute between 2010 and 2022. Median age was 51 years, range 19–83 years. Among these patients, 172 patients (62%) had a primary diagnosis of glioblastoma, 45 had astrocytoma (16%), WHO grade II in 8 patients (3%) and grade III in 37 patients (13%), 39 had oligodendroglioma, 14 had ependymoma, 5 had PNET, and 1 patient had medulloblastoma. Details of progression-free survival, interval between radiotherapy and surgery for a suspected recurrent tumor as well as total dose of radiotherapy can be found in Supplementary Table 1.

During the same period, a total of 543 radiations were performed on patients with primary brain tumors. Figure 1 includes a flow chart of the study cohort.

Figure 1.

A flow chart demonstrates the total number of performed radiotherapies for a primary brain tumor between 2010 and 2022, number of surgeries for suspected recurrent tumors, and rate of resulting radiation necrosis, with the thickness of the arrows correlating with rate of radiation necrosis. N = number of patients. *14 had ependymoma, 5 had PNET, and 1 patient had medulloblastoma.

Fourteen of the 276 patients (5%) had a histopathological diagnosis of radiation necrosis. Median age was 61 years, range 28–82 years. There were 10 males (71%). Detailed histopathology of the included tumors is presented in Figure 1 as well as in Table 1. All patients had received fractionated radiotherapy. Median dose of radiation was 60 Gy, range 54–60 Gy. Patients with high-grade glioma received 59.4–60 Gy in 30–33 fractions, while those with low-grade glioma received 54 Gy in 27–30 fractions. Technical details of radiotherapy in patients who developed radiation necrosis can be found in Supplementary Table 2.

Table 1.

Characteristics and Clinical Course of Patients With Radiation Necrosis

Patient’s number	Age in years	Diagnosis*	Total dose [Gy]	Administration of chemotherapy during radiotherapy	Interval between radiotherapy and occurrence of radiation necrosis in months	Location of radiation necrosis in relation to the primary tumor	Symptoms	Type of surgery	Treatment with steroids	Treatment with Avastin	Recurrent tumor at further follow-up
1	58	Oligodendroglioma WHO II°	60	No	31	Local	No	GTR	No	No	No
2	32	Oligodendroglioma WHO II°	54	Yes	4	Local	No	GTR	Yes	No	No
3	54	Oligodendroglioma WHO II°	54	No	22	Local	Yes	GTR	Yes	No	Yes
4	65	Oligodendroglioma WHO II°	54	No	6	Local	No	GTR	No	No	No
5	34	Oligodendroglioma WHOII°	60	No	22.5	Distal	no	Partial resection	Yes	No	No
6	67	Oligodendroglioma WHO II°	60	Yes	4	Distal	Yes	GTR	No	No	No
7	67	Oligodendroglioma WHO III°	60	Yes	37	Distal	No	Biopsy	Yes	Yes	Yes
8	60	Oligodendroglioma WHO III°	54	Yes	9	Local	Yes	GTR	No	No	No
9	65	Oligodendroglioma WHO III°	60	No	18	Local	No	GTR	No	No	No
10	28	Oligodendroglioma WHO III°	60	Yes	21	Local	No	GTR	No	No	No
11	80	Glioblastoma WHO IV°	60	Yes	4	Local	No	GTR	No	No	No
12	82	Glioblastoma WHO IV°	60	Yes	40	Distal	No	GTR	No	No	No
13	62	Glioblastoma WHO IV°	60	Yes	4	Local	No	GTR	No	No	No
14	35	Glioblastoma WHO IV	59.4	Yes	3	Distal	No	Partial resection	Yes	Yes	No

^*According to the 2007 World Health Organization Classification of Tumors of the Central Nervous System or its later version (2016) [9, 10]. GTR = gross total resection, Gy = gray, GTV = gross tumor volume, CTV = clinical target volume, PTV = planning target volume, Dmax = maximum dose, D0.1cm3 = dose in 0.1 cm³, VMAT = volumetric intensity-modulated arc therapy, IMRT = intensity-modulated radiation therapy, N/A = not available.

Nine patients (64%) received chemotherapy concomitantly during radiotherapy. Three patients (21%) presented with symptoms; 2 with seizures and one with general clinical deterioration. The remaining patients were asymptomatic and were diagnosed on routine imaging follow-ups. The median duration between the end of radiotherapy and diagnosis of radiation necrosis was 16 months, range 3–40 months, for the whole cohort. In patients with glioblastoma, radiation necrosis occurred after a median interval of 4 months after radiotherapy, range 3–40 months. In patients with oligodendroglioma, radiation necrosis occurred after a median interval of 20 months after radiotherapy, range 4–37 months (detailed median intervals for grade II and III oligodendroglioma are presented in Table 2).

Table 2.

Histopathology of Tumors in Patients Who Developed a Radiation Necrosis

Histopathology*	Oligodendroglioma WHO II°	Oligodendroglioma WHO III°	Glioblastoma WHO IV°
Number of patients	6	4	4
Median time of diagnosis in months, with range in brackets.	14 (4–31)	20 (9–37)	4 (3–40)

^*According to the 2007 World Health Organization Classification of Tumors of the Central Nervous System or its later version (2016).^9,10

Imaging

MRI of patients with radiation necrosis demonstrated enhancing mass lesions with central necrosis and reactive edema. Diffusion-weighted sequences were available in all preoperative MRIs and perfusion sequences were performed only in 6 of the14 patients with radiation necrosis. None of the patients demonstrated typical radiological features of radiation necrosis including restricted diffusion and hypo-perfusion. Furthermore, there was increased edema in 5 of 14 cases (36%). The lesion was located within or close to the previous resection cavity in 9 of 14 patients (64%) and distant to it in 5 of 14 patients (36%). All lesions were located within the field of radiotherapy.

Surgical Aspects

Complete removal of the lesion (gross total resection) was successfully achieved in 11 patients, accounting for 79% of the cases. A partial resection or biopsy was performed in the remaining 3 patients, making up 21% of the cases.

5-ALA Fluorescence Application: The 5-ALA fluorescence technique was employed in 7 instances. Of these, 71% (5 cases) demonstrated noticeable intraoperative fluorescence enhancement, aiding in the surgical procedure. This group included 3 patients with glioblastoma and 2 patients with oligodendroglioma WHO grade II.

In 2 patients, 1 with oligodendroglioma WHO grade III and 1 with oligodendroglioma WHO grade II, the 5-ALA fluorescence did not provide the expected enhancement, highlighting variability in fluorescence response.

Surgical complications were encountered in 2 cases, which represents 14% of the total. These complications were specifically related to bone flap infections.

Clinical Course

Following the histopathological confirmation of radiation necrosis, out of 11 patients who underwent gross total resection, 2 were treated with corticosteroids postoperatively. The other 9, exhibiting no significant symptoms, were placed under observation without additional treatment. Patients who were biopsied or partially resected were treated with corticosteroids and 2 of them received additional Bevacizumab.

None of the patients showed signs of radiological or clinical progression of radiation necrosis. Tumor progression was suspected during the follow-up in 2 patients: one with oligodendroglioma WHO grade III showed signs of progression after 5 months and another with oligodendroglioma WHO grade II demonstrated potential progression after 2 months. Subsequent surgical interventions for these patients confirmed the recurrence of the tumor. The main characteristics of patients with radiation necrosis and their clinical course are presented in Table 2.

Analysis

Among patients with oligodendrogliomas, the rate of radiation necrosis was found to be 26% (10 out of 39 cases). There was a statistically significant association between the occurrence of oligodendroglioma and the development of radiation necrosis, with a P-value of less than 0.001.

For patients with glioblastoma, the incidence of radiation necrosis was markedly lower, at 2% (4 out of 172 cases).

No cases of radiation necrosis were observed among the 45 patients with astrocytoma, resulting in a 0% incidence rate. Based on these findings, patients with glioblastoma or astrocytoma were unlikely to develop radiation necrosis in the event of suspected tumor recurrence, P ≤ 0.001 and P = 0.036, respectively.

There was no observed correlation between the histopathological characteristics of the tumors, or the treatment protocols followed and the specific features of radiation necrosis, such as the lesion’s location or the clinical progression.

Discussion

MRI has become instrumental in differentiating between tumor recurrence and radiation necrosis, although their radiological characteristics can sometimes converge in conventional imaging.¹⁵ Despite advancements in MR spectroscopy, diffusion, and perfusion imaging, the diagnostic accuracy can still fall short in effectively guiding clinical decisions. For instance, a meta-analysis reported that distinguishing recurrent high-grade glioma from radiation necrosis achieved a sensitivity of 87% and a specificity of 86%.^15,16 In situations of suspected radiation necrosis, a cautious approach of observation over time may be employed. However, this strategy bears significant risks, especially for symptomatic patients or those with progressing tumors. Consequently, histopathological examination continues to be the definitive diagnostic measure, providing essential insights for therapeutic planning.

Our investigation encompassed a substantial cohort undergoing surgery for suspected tumor recurrence, all of whom had undergone prior radiotherapy. Histopathological analysis disclosed radiation necrosis in 5% of the 276 evaluated patients, with onset times post-radiotherapy ranging from 3 to 40 months. Notably, only patients with oligodendrogliomas exhibited a significant predisposition to developing radiation necrosis, a finding that has been sparsely addressed in existing literature. This study pioneers in validating this association through comprehensive histopathological scrutiny.

In terms of clinical outcomes, the progression of radiation necrosis observed in our patient group was generally benign. While the majority underwent gross total surgery, a subset of patients who had either a biopsy or a partial resection did not necessitate interventions beyond the administration of corticosteroids or Bevacizumab. However, it’s important to note that the relatively limited size of our patient sample precludes a statistically robust comparison of the efficacy among the different therapeutic strategies for managing radiation necrosis.

Our data indicated a low rate of radiation necrosis in patients with glioblastoma (2%). Similarly, a low rate of radiation necrosis (4.7%) has been reported elsewhere.¹ This suggests that radiation necrosis may have less clinical significance than pseudoprogression, which can occur at a rate of 10%–30%.² The issue of radiation necrosis has been frequently raised along with pseudoprogression in the context of the treatment of high-grade gliomas. Pseudoprogression and radiation necrosis are 2 distinct concepts of radiation-induced injury in the brain. Pseudoprogression is considered to be a subacute radiation effect and can appear weeks or up to 3 months after radiation.¹⁷ Radiation necrosis is rather a late effect and can appear 3–12 months after radiotherapy but also can occur years later.^18,19 In a series of 51 gliomas inducing astrocytomas and oligodendrogliomas, Forsyth et al. reported a 6% rate of radiation necrosis with a median time from surgery to diagnosis of 28 months.²⁰ Ahmad et al. conducted a retrospective review of 319 adults with lower-grade diffuse gliomas over a 10-year span and identified radiation necrosis radiologically or histologically in 41 patients (12.9%), among which were 28 patients (21.3%) with oligodendroglioma and 13 (6.9%) with astrocytoma.²¹ In our series, radiation necrosis occurred after a median interval of 4 months (range 3–40 months) after radiotherapy in patients with glioblastoma and 20 months (range 4–37 months) in patients with oligodendroglioma. The risk of developing radiation necrosis was significantly higher in patients with oligodendroglioma and negligible in patients with astrocytoma or glioblastoma. Oligodendroglioma was previously reported to confer a higher risk of radiation necrosis.²¹ Our results clearly confirm this finding and present histopathological evidence of the risk of developing radiation necrosis in patients with oligodendrogliomas.

The concept of radiation-induced contrast enhancements (RICE) was discussed by Eichkorn et al. in the context of the treatment of WHO grade I to III gliomas. This concept includes both symptomatic and non-symptomatic lesions that are considered non-tumor related.^22,23 They defined RICE as “an umbrella term for findings characterized by radiation-induced contrast enhancements, which may include radiation necrosis, pseudoprogression, and radiation-induced blood–brain barrier disruption.”²³ In our patient cohort, only cases with confirmed radiation necrosis were included in the analysis. The histopathological diagnosis was made independently of whether patients exhibited symptoms and regardless of radiological findings.

Sampling Error

Sampling error denotes the discrepancy between initial histological findings from a tissue sample and the final, comprehensive histopathological diagnosis that accurately captures the lesion’s pathology. This concept is particularly relevant in the context of biopsies, which are typically conducted prior to definitive surgical interventions.²⁴ Within this study, 2 notable cases highlighted the potential for sampling error. The first involved a patient who underwent a biopsy and was subsequently diagnosed with tumor recurrence 3 months later, suggesting a high likelihood of sampling error during the biopsy process. Conversely, the second patient underwent a gross total resection and received a diagnosis of tumor recurrence 5 months postoperatively, making sampling error less probable in this instance. However, there are many reports that highlight the risk of diagnostic undergrading due to small pathological tissue samples or inadequate tissue collection.^25–27 This phenomenon might account for the perceived sampling error in the case involving gross total resection. Nonetheless, quantifying the actual incidence of sampling error remains challenging, given the inherent unpredictability of recurrence timings in primary brain tumors.

Management Strategies for Radiation Necrosis

The clinical course of radiation necrosis is typically benign and manageable, as supported by existing literature. Bevacizumab has been increasingly favored for treating radiation necrosis, given its demonstrated efficacy and safety in primary brain tumors and metastases across several studies.^28–32 The treatment outcomes with Bevacizumab have been shown to surpass those of corticosteroid-based treatments with a comparable safety profile.³³ Other therapeutic modalities, such as laser interstitial thermal therapy³⁴ and hyperbaric oxygen therapy³⁵ have also been explored. In our patient cohort, the necessity for medical intervention post-surgery was relatively low, primarily because most patients were asymptomatic and a significant portion underwent gross total resection. Importantly, we observed no further progression in cases of radiation necrosis, suggesting that gross total resection might be a viable treatment option for symptomatic lesions suspected of being radiation necrosis. However, the validation of this approach requires further exploration through prospective randomized studies.

Limitations

The retrospective design of our study and instances where preoperative radiological evaluations were incomplete for some patients might restrict the generalizability of our findings. Furthermore, sourcing our patient cohort exclusively from a neuropathology database and basing our incidence rates on presumed recurrent tumors could impact the comparability of our results with those of other studies. In addition, there might be a significant cohort of suspected findings who did not undergo surgery but were deemed as reactive by imaging/morphology only and were not considered in the current study. This could be a significant bias that should be taken into consideration while interpreting our results.

Conclusions

Radiation necrosis is a notable complication following radiotherapy therapy for primary brain tumors, especially in patients with oligodendroglioma, who exhibited a significantly higher incidence compared to patients with astrocytoma. The latency period varied from 3 to 40 months, highlighting the need for long-term monitoring. Most patients were asymptomatic and showed no progression of necrosis, suggesting conservative management may be sufficient. However, vigilant follow-up is necessary to detect potential tumor recurrence. These findings emphasize the importance of accurate diagnosis and tailored follow-up protocols to optimize patient outcomes.

Supplementary Material

Supplementary material is available online at Neuro-Oncology Practice (https://academic.oup.com/nop/).

Conflict of interest statement: The authors declare that they have no competing interests.

Funding

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

Author Contributions

M.H., T.A., V.M., L.S., and T.H. collected clinical data. M.H. and T.A. interpreted the data and drafted the manuscript. I.M., C.S., L.H.D., R.E.S., D.M., and V.R. critically revised the manuscript. All authors approved the last version of the manuscript.

Data Availability

Data are available from the corresponding author upon reasonable request.