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ORIGINAL ARTICLE
Year : 2022  |  Volume : 18  |  Issue : 6  |  Page : 1616-1622

Malignant transformation in low-grade astrocytoma for long-term monitoring


Division of Neurosurgery, Department of Surgery, Faculty of Medicine, Prince of Songkla University, Hat Yai, Songkhla, Thailand

Date of Submission06-Oct-2020
Date of Acceptance29-Jul-2022
Date of Web Publication16-Nov-2022

Correspondence Address:
Thara Tunthanathip
Division of Neurosurgery, Department of Surgery, Faculty of Medicine, Prince of Songkla University, Hat Yai, Songkhla, 90110
Thailand
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_1469_20

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 > Abstract 


Background: Malignant transformation (MT) of low-grade astrocytoma (LGA) produces a poor prognosis in benign tumors. Currently, variables linked with MT of LGA have proven equivocal. The present study aims to evaluate the risk variables, indicating that LGA gradually differentiates to malignant astrocytoma.
Methods: Retrospective cohort analysis of LGA patients was performed. Both univariate and multivariate studies were used to discover variables connected to MT using the Cox regression method. As a result, the cumulative incidence of MT for each covariate survival curve was built after the final model.
Results: In the current study, 115 individuals with LGA were included in the analysis, and MT was found in 16.5% of cases. In the case of MT, 68.4% of patients progressed to glioblastoma, whereas 31.6% progressed to anaplastic astrocytoma. Significant factors included supratentorial tumor (hazard ratio (HR) 3.41, 95% CI 1.18–12.10), midline shift > 5 mm (HR 7.15, 95% CI 2.28–34.33), and non-total resection as follows: subtotal resection (HR 5.09, 95% CI 0.07–24.02), partial resection (HR 1.61, 95% CI 1.09–24.11), and biopsy (HR 2.80, 95% CI 1.18–32.52).
Conclusion: In individuals with LGA, MT dramatically altered the disease's natural history to a poor prognosis. The present study's analysis of the clinical features of patients indicated supratentorial LGA, a midline shift greater than 5 mm, and the degree of resection as risk factors for MT. The more extensive the resection, the greater the reduction in tumor load and MT. In addition, more molecular study is necessary to elucidate the pathophysiology of MT.

Keywords: Diffuse astrocytoma, high-grade glioma, low-grade glioma, malignant transformation, pilocytic astrocytoma


How to cite this article:
Tunthanathip T. Malignant transformation in low-grade astrocytoma for long-term monitoring. J Can Res Ther 2022;18:1616-22

How to cite this URL:
Tunthanathip T. Malignant transformation in low-grade astrocytoma for long-term monitoring. J Can Res Ther [serial online] 2022 [cited 2022 Dec 2];18:1616-22. Available from: https://www.cancerjournal.net/text.asp?2022/18/6/1616/361202




 > Introduction Top


According to the 2016 World Health Organization (WHO) central nervous system tumor classification, astrocytomas are categorized into four classes. Typically, these tumors are classified as either low-grade or high-grade astrocytomas. Low-grade astrocytomas (LGAs), which include pilocytic and diffuse astrocytomas (WHO I and II, respectively), are benign tumors with a considerably better prognosis than high-grade tumors. Diffuse astrocytoma has a median survival time between 44 and 57 months, whereas anaplastic astrocytoma (WHO III) and glioblastoma prognosis (WHO IV) have median survival times between 15 and 24 months and 11 and 14 months, respectively.[1],[2],[3]

It has been observed that 19.5 to 21% of low-grade gliomas undergo malignant transformation (MT), which includes fibrillary astrocytoma, diffuse astrocytoma, oligodendroglioma, mixed oligoastrocytoma, and ganglioglioma.[4],[5],[6],[7]

The 10-year cumulative incidence of MT was 3.8%, and the median duration of MT was 5.1 years, according to Broniscer et al.[7] The causes of MT are unclear; however, researchers have identified certain risk factors. Common genetic profile of MT includes TP53 overexpression, deletions of RB1, CDKN2A, and PTEN pathway abnormalities, whereas Murphy et al.[6] indicated that age, male gender, multiple tumors, chemotherapy alone, and the degree of resection were probable predictors of MT.[7] Previous research indicated, however, that the sample population was rather diverse. All types of glioblastoma were taken into account, including oligodendroglioma, oligoastrocytoma, and mixed glioma.[4],[5],[6],[7],[8]

Moreover, when the patients have to wait for long-term follow-up, benign tumors have a greater risk of developing into MT. Therefore, the present study aims to describe MT prevalence of LGA and explore clinical factors that are linked with MT during long-term follow-up.


 > Materials and Methods Top


Study population

The patients in the study were all newly diagnosed with pilocytic astrocytoma or diffuse astrocytoma between January 2003 and July 2022, and the research was carried out in a tertiary hospital in southern Thailand. The research was based on a review of medical records. The multicenter central nervous system (CNS) tumor registry of Thailand included some patients, and it was published with death as the study's endpoint.[1] A pathologist validated the histopathological diagnosis in accordance with the 2016 WHO classification of CNS tumors.[9],[10],[11]

The patients with mixed oligoastrocytomas or other gliomas as well as the patients without access to imaging were excluded. Additionally, the patients who underwent a stereotactic biopsy were not excluded from the current research; however, the patients who underwent a free-hand biopsy or an ultrasound-guided biopsy were. A neurosurgeon looked through the magnetic resonance imaging (MRI) taken before, during, and during the follow-up period to assess the tumor's size, position, side, and midline displacement. Additionally, a tumor volume calculation was done using data from a previous Tunthanathip et al. investigation.[12]

Postoperative imaging was used to determine the degree of resection, which was then categorized into four categories: entire resection (no visible remaining tumor in both enhanced and unenhanced sections), subtotal resection (>90% of resection), partial resection (>50% of resection), and biopsy.[13],[14],[15]

MT was defined as a tumor that had gradually differentiated to high-grade astrocytoma and had histology-confirmed evidence of at least WHO III astrocytoma.[4],[5],[6],[7] In addition, information obtained from the Office of Central Civil Registration on July 31, 2022 was used to determine whether or not the patients had passed away. The current investigation was authorized by a human research ethics committee. Because the current study used a retrospective design, the patients were not required to provide informed permission. Furthermore, before processing, the patients' identity numbers were encoded.

Statistical analysis

The study's endpoint was the MT, and the starting date was the day LGA was diagnosed. The study's endpoint was the day a pathologist diagnosed the malignant transformation, or until July 2022 as the departing date.

The baseline features of the patients were described using descriptive statistics. The prognosis between the MT group and the non-MT group was compared using the Kaplan–Meier curve and the log-rank test. The impact of MT on survival time was examined using the Cox regression analysis, and the results were presented as a hazard ratio (HR) with 95% CI. Therefore, a multivariable model with backward stepwise selection was used to investigate the candidate variables that had a P value of 0.1 or less in the univariate analysis.[16],[17],[18],[19] Statistical analysis was performed using R version 4.0.1 and Stata version 16 (StataCorp, Texas, USA).


 > Results Top


A total of 131 individuals with a recent diagnosis of low-grade astrocytoma were first examined. With no accessible imaging and a final diagnosis of mixed glioma, sixteen individuals were disqualified. As a result, the baseline clinical features of 115 patients were examined and summarized, as shown in [Table 1].
Table 1: Baseline characteristics of patients newly diagnosed low-grade astrocytoma (n=115)

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Male and female percentages were nearly equal at 53.9% and 46.1%, respectively. The first and third most frequent clinical manifestations of the qualifying individuals were seizures, progressive headaches, and hemiparesis. Frontal lobe was common location, and tumors at eloquent area were found in 40.9%.

All the eligible patients received histological diagnosis surgery. As a result, the most common diagnoses were diffuse astrocytoma (84.3%), pilocytic astrocytoma (12.3%), gemistocytic astrocytoma (1.7%), and pleomorphic xanthoastrocytoma (1.7%). Total tumor resection was reported in 38.3% of patients, with more than two-thirds receiving postoperative adjuvant radiation. In addition, seven patients were given postoperative chemotherapy.

When the median period of follow-up was 20 months (interquartile range (IQR) 45 months), 16.5% of the study population experienced MT. [Table 2] shows the clinical features of individuals who acquired MT during the follow-up period. [Figure 1]a, [Figure 1]b, [Figure 1]c, [Figure 1]d, [Figure 1]e, [Figure 1]f and [Figure 2]a, [Figure 2]b, [Figure 2]c, [Figure 2]d indicate that more than two-thirds of the MT converted into glioblastoma, whereas 31.6% transitioned into anaplastic astrocytoma. Furthermore, almost MT patients had never undergone radiation previously, and all MT patients had never received adjuvant chemotherapy prior to MT.
Table 2: Characteristics of patients with malignant transformation (n=19)

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Figure 1: Illustrative cases of malignant transformation of diffuse astrocytoma. (a) Preoperative T1W post-contrast MRI showing homogeneously enhanced left frontal mass. (b) H and E stain showing moderate cellularity with nuclear atypia of astrocytes. (c) T1W post-contrast MRI at 6 months later showing heterogeneously enhanced left frontal mass. (d) H and E stain showing an anaplastic transformation, including astrocytes with pleomorphism. (e) T1W post-contrast MRI at 11 months later showing heterogeneously enhanced left frontal tumor with central necrosis. (f) H and E stain showing glioblastoma features, including hypercellularity of astrocytes and endothelial proliferation (arrow)

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Figure 2: Anaplastic transformation illustrative case of pilocytic astrocytoma. (a) Preoperative T1W post-contrast MRI showing a homogeneously enhanced suprasellar mass. (b) H and E stain showing astrocytic cells neoplastic astrocytes in the glial fibrillary background. (c) T1W post-contrast MRI at three years later showing the larger residual tumor with heterogeneous enhancement. (d) Ki-67 stain showing 10–15% in pseudo-oligodendroglial area that was then observed as focal anaplasia

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[Figure 3] shows that the MT of LGA was strongly related with a poor prognosis (log-rank test, P = 0.02). MT substantially impacted survival time as HR 1.89 (95% CI 1.08–3.30, P value 0.02) using the Cox regression analysis.
Figure 3: Kaplan–Meier curve showing malignant transformation group had a significantly poorer prognosis than non-malignant transformation (log-rank test, P = 0.02)

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As demonstrated in [Figure 4]a, MT was the failure event in the current study that is likely to occur over time. The 1-year risk of MT in patients with LGA was 10.8%, while the 2-year risk of MT in patients was 17.4%. [Table 3] shows that the MT risk remained stable at 19.7% when the patients were followed up on in the third year.
Table 3: Risk of malignant transformation in patients with low-grade astrocytoma overtime

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Figure 4: Survival curve of the cumulative incidence of MT each factor. (a) Malignant-free survival curve. (b) Tumor location. (c) Midline shift on preoperative imaging. (d) The extent of resection. Abbreviation: 95% CI = 95% confidence interval, EOR = extent of resection

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Factor associated with MT

The univariate analysis looked at a variety of clinical variables. Significant factors included supratentorial tumor (HR 7.92, 95% CI 1.80–32.2), preoperative imaging midline shift of more than 1 cm (HR 9.19, 95% CI 2.09–33.70), and non-total resection as follows: subtotal resection (HR 2.31, 95% CI 0.09–37.44), partial resection (HR 1.83, 95% CI 1.15–29.31), and biopsy (HR 3.38, 95% CI 2.01–37.32).

Moreover, backward stepwise selection was used to assess potential variables for multivariable analysis. As shown in [Table 4], the model with the lowest AIC included supratentorial tumor (HR 3.41, 95% CI 1.08–19.10), midline shift of more than 1 cm from preoperative imaging (HR 7.15, 95% CI 2.28–34.33), and non-total resection as follows: subtotal resection (HR 1.29, 95% CI 0.17–24.0282), partial resection (HR 1.61, 95% CI 1.09–24.11), and biopsy (HR 2.80, 95% CI 1.18–32.52). Following that, the model's relevant covariates produced the survival curve for calculating the cumulative incidence of MT in each covariate, as illustrated in [Figure 4]b, [Figure 4]c, [Figure 4]d.
Table 4: Univariate and multivariable analysis for malignant transformation of low-grade astrocytoma

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 > Discussion Top


The transformation of benign astrocytes into malignant astrocytes is referred to as the MT of LGA. When MT appeared, the prognosis of patients with LGA rapidly deteriorated, and these individuals had a survival time that was much lower than the group that did not have MT. In the current study, the onset of MT of LGA occurred in 14.4% of patients, and the median amount of time it took to develop MT was 13 months. The findings of the current study were consistent with those found in earlier research. It has been observed that the incidence of MT in low-grade gliomas ranges between 3.8 and 21%.[6],[7] However, the literature assessment revealed a variety of approaches and terminology from earlier investigations. While the research population of the current study was focused on astrocytoma, heterogeneity of low-grade gliomas such as fibrillary astrocytoma, oligodendroglioma, and mixed glioma may be an effect on MT rate and time to MT. Additionally, MT in earlier studies included instances with a histological diagnosis as well as cases with imaging characteristics,[6] but MT in the current analysis excluded cases without one.

In the current investigation, supratentorial LGA, a preoperative midline displacement of more than 1 cm, and degree of resection were identified as clinical predictors linked with MT. Supratentorial astrocytoma was much more likely to progress to MT; this may be connected to how LGA was graded by the WHO. LGA with WHO grade II tended to be MT's risk factor, even though the WHO grading was not substantially connected with MT. According to the 2007 CNS tumor categorization system used by Chaichana et al.,[4] fibrillary astrocytoma, a WHO grade II tumor, was substantially related with MT.

In the current investigation, a midline movement of more than 1 cm was one of the MT predictors. To the author's knowledge, no one has ever reported this characteristic as an MT predictor; however, multiple studies showed larger tumor size or volume was linked to MT.[4],[20],[21] Peritumoral edema has been reported as a typical finding of malignant gliomas and contributed as a prognostic factor.[22] Due to a disruption in the blood–brain barrier, which may be the mechanism behind MT, these locations encourage the invasion of tumor cells.[23],[24] Therefore, it is recommended that future research using a larger cohort or meta-analysis analyzes our findings that a midline displacement of more than 1 cm increased the risk of MT.

In earlier research, the degree of resection was taken into account as a predictor connected to MT. Total tumor resection was found to be a risk factor for MT by Kiliç et al. and Murphy et al. The crucial element that altered the patient's prognosis and MT event was total tumor excision since residual tumors might change over time.[6],[25] Additionally, complete tumor removal is well recognized as a prognostic indicator for longer life.[26],[27],[28] The patients who experience a death event that also happens to be an MT event will directly interfere with MT likelihood.

A number of neurosurgical disorders, including meningioma, metastases, and cerebral aneurysms, have been described as a result of the novel survival analysis paradigm.[29],[30],[31] Furthermore, multiple low-grade glioma tumors have, furthermore, been linked to MT as a preventative factor of MT.[6] The results might be a result of concurrent occurrences in individuals who have several lesions that are linked with a poor prognosis.[32],[33]

Several variables have been reported as MT predictors, but these are still inconclusive. Tom et al. reported that males were associated with MT, while females were a risk factor of MT in the study of Murphy et al. Moreover, greater age was revealed to be associated with MT,[6] but Rotariu et al. showed that MT occurs often in younger individuals.[34],[35]

There are also certain limitations with the study that should be pointed out. First, the biopsy procedure may cause inadequate tissue for MT diagnosis. However, the stereotactic biopsy was used in this study because it had been used in previous studies to get enough tissue to make a diagnosis.[6],[18],[35] Secondarily, the study design was set up and could cause bias in retrospective studies. However, the prospective study also has challenged for MT's time-consuming surveillance. We adjusted the outcomes and covariates using the multivariable analysis to reduce bias.[36],[37],[38] Thirdly, according to the findings of this study, only clinical predictors of MT and genetic research should be done. The pathophysiology of MT has been found and clinical predictions explained using molecular results.[39]


 > Conclusion Top


In individuals with LGA, MT dramatically altered the disease's natural history to an adverse prognosis. The present study's analysis of the clinical features of patients indicated supratentorial LGA, a midline shift greater than 1 cm, and the degree of resection as risk factors for MT. The more extensive the resection, the greater the reduction in tumor load and MT. In addition, more molecular study is necessary to elucidate the pathophysiology of MT.

Financial support and sponsorship

The study was supported by the Health Systems Research Institute (Thailand; Grant No. 63-078).

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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