|Year : 2021 | Volume
| Issue : 2 | Page : 29-37
Prognostic significance of modified Pignatti score in patients with World Health Organization grade II diffuse astrocytomas
Edmond J Gandham1, Wilson P D’Souza1, Gowri Mahasampath2, Ranjith K Moorthy1, Vedantam Rajshekhar1
1 Department of Neurological Sciences, Christian Medical College, Vellore, Tamil Nadu, India
2 Department of Biostatistics, Christian Medical College, Vellore, Tamil Nadu, India
|Date of Submission||21-Apr-2021|
|Date of Acceptance||16-Feb-2022|
|Date of Web Publication||20-Apr-2022|
Dr. Edmond J Gandham
Department of Neurological Sciences, Christian Medical College, Vellore 632004, Tamil Nadu
Source of Support: None, Conflict of Interest: None
The aim of this study was to validate the modified Pignatti scoring system as a predictor of survival in patients with World Health Organization (WHO) grade II diffuse fibrillary astrocytomas (DFAs). In this retrospective cohort study, data were collected from 135 consecutive patients who underwent excision/biopsy of WHO grade II DFAs from January 2000 to December 2015. The effect of the following prognostic variables on overall survival (OS) and progression-free survival (PFS) was studied: Pignatti score (PS = 1–4, low versus high risk), location of tumor (lobar versus nonlobar), extent of resection (subtotal resection [STR] versus <STR), and presence of enhancement (yes versus no). The median age was 42 years (range = 13–81 years) with male to female ratio of 1.8. A total of 99 patients had taken radiation therapy and had a follow-up >1 year (median follow-up = 5.2 years, range = 1–16 years). In all, 80 patients (81%, PS = 1–2) were in the low-risk group. The median PFS in the low-risk group (PS = 1 and 2) was 120 months (95% confidence interval [CI] = 72, 128). The median PFS in the high-risk group (PS = 3 and 4) was 72 months (95% CI = 18, not applicable [NA]). The median OS in the low-risk group was significantly higher at 128 months (95% CI = 72, NA) as compared to 72 months (95% CI = 18, NA) in the high-risk group (P = .005). The modified PS can be used to prognosticate survival in patients with WHO grade II DFAs, with patients of the low-risk category having a better OS but not PFS.
Keywords: Diffuse fibrillary astrocytoma, Pignatti score, prognosis, radiation therapy, surgery, survival
|How to cite this article:|
Gandham EJ, D’Souza WP, Mahasampath G, Moorthy RK, Rajshekhar V. Prognostic significance of modified Pignatti score in patients with World Health Organization grade II diffuse astrocytomas. Int J Neurooncol 2021;4:29-37
|How to cite this URL:|
Gandham EJ, D’Souza WP, Mahasampath G, Moorthy RK, Rajshekhar V. Prognostic significance of modified Pignatti score in patients with World Health Organization grade II diffuse astrocytomas. Int J Neurooncol [serial online] 2021 [cited 2022 Jun 29];4:29-37. Available from: https://www.Internationaljneurooncology.com/text.asp?2021/4/2/29/343568
| Introduction|| |
Diffuse fibrillary astrocytoma (DFA) is a category of low-grade glioma (LGG) that is slow growing and classified as a World Health Organization (WHO) grade II tumor.,,,,, It is infiltrative in nature and exhibits malignant transformation, which accounts for mortality in these gliomas.,,,
Several prognostic factors affecting median survival (MS) in LGG have been described in literature.,,,, In 2002, Pignatti et al. on behalf of the European Organization for Research and Treatment of Cancer (EORTC, 22844) published a scoring system that included age, largest tumor diameter, tumor crossing midline, histopathology (astrocytoma versus oligodendroglioma), and preoperative neurological deficit. This scoring system was intended to prognosticate MS in WHO grade II gliomas. Age >40 years, tumor diameter >6 cm, tumors crossing the midline, presence of neurological deficit, and astrocytoma histology were associated with a worse outcome. This scoring system was subsequently validated in cohorts that included patients with different pathologies such as oligodendrogliomas, oligoastrocytomas, and astrocytomas.,,,
Oligodendroglial tumors have a distinct molecular signature and have been shown to have a better outcome compared to astrocytomas., Therefore, clubbing them with DFA is not appropriate.
A study of prognostic factors for patients with DFA should focus on a pure cohort of DFA without contamination from those with oligodendrogliomas and those diagnosed as oligoastrocytomas. To the best of our knowledge, there is no published study validating the Pignatti score (PS) in a pure cohort of DFAs. We, therefore, investigated the prognostic significance of Pignatti scoring system in a cohort of patients who were homogenous for a diagnosis of WHO grade II DFA.
| Materials and methods|| |
In this retrospective cohort study, all patients who underwent excision/biopsy of WHO grade II DFA between January 2000 and December 2015 and with at least one clinical and radiological follow-up at 12 months or more following diagnosis were included. Only patients who had undergone adjuvant radiation therapy following the diagnosis were included.
Surgery for WHO grade II DFA was performed in 135 patients during the study period. Of these, 36 patients were lost to follow-up, had follow up <12 months, or had not received radiation therapy and were excluded from the study. Therefore, 99 patients who met the inclusion criteria formed the cohort group for this study. The median age at diagnosis was 42 years (range = 13–81 years). Most of these patients (74 patients, 75%) were ≤40 years of age at presentation. There were 63 males and 36 females. Seizure was the most common presenting symptom (63 patients, 63%). Preoperative neurological deficit was seen in 24 (24%) patients.
Tumor was classified as lobar when the tumor was located predominantly in the frontal, temporal, parietal, and occipital lobe. The tumor was classified as nonlobar when located predominantly in the insula, thalamus, basal ganglia, cerebellum, and brainstem. In our cohort, the tumor was lobar in 71 (72%) patients and nonlobar in 28 (28%) patients. The largest tumor dimension was ≤6 cm in 69 (70%) patients and >6 cm in 30 (30%) patients. The tumor was seen to cross the midline in seven (7%) patients. The details are summarized in [Table 1].
Magnetic resonance (MR) images were reviewed to determine the presence or absence of contrast enhancement. Contrast enhancement was noted in 19 (19%) patients.
Extent of resection
Extent of resection (EOR) was determined using the early postoperative contrast-enhanced computed tomography (CT) in 74 patients. Radiation therapy (RT) planning MR images were used to determine the EOR in 25 patients (mean duration for the MRI after the surgery was 2.48 months, range = 1–5 months). RT planning was done using the contrast-enhanced CT scan in majority of the patients due to financial constraints. EOR was based on the reading of the images by two independent observers (RKM and EJG). There was good concordance between the EOR determined on the early postoperative CT and the RT planning MR in the 25 patients in whom both images were performed.
EOR was categorized as gross total resection (GTR) when no tumor residue was visualized on the early postoperative CT or RT planning MR and subtotal resection (STR) when the tumor residue was ≤10% of the initial tumor volume [Figure 1]. When the residue was >10%, the EOR was categorized as less than STR group [Figure 2].
|Figure 1: MR brain T2-weighted (T2W) fluid-attenuated inversion recovery (FLAIR) image showing a right insular DFA, Pignatti 1. (a) RT planning MR T2W flair image (3 months after the surgery) showing a subtotal excision (STR). (b) MR brain T2W FLAIR image showing very good disease control at 5-year follow-up. (c) Patient received adjuvant radiation therapy and temozolomide-based chemotherapy|
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|Figure 2: MR brain T2W FLAIR images (a and b) showing a large right insular DFA, Pignatti 2. Three months postoperative radiation therapy planning MR showing less than an STR excision (c). MR brain T2W FLAIR image (d) showing good response to adjuvant radiation therapy and temozolomide-based chemotherapy at 3-year follow-up|
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None of our patients underwent GTR. A total of 28 (28%) patients underwent STR, whereas most of our patients (71, 72%) underwent less than an STR.
Grade 2 astrocytomas were differentiated from oligodendrogliomas based on morphology till 2006, but since then, 1p/19q deletion studies were used to differentiate the two tumors.
All patients received RT (54 Gy in 30 fractions) as a standard of care. In all, 37 (37%) patients had taken adjuvant chemotherapy with RT. No patient received concurrent chemotherapy. A total of 12 patients operated between 2000 and 2008 received 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea-based chemotherapy and procarbazine, 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea, and vincristine chemotherapy. From 2008, temozolomide was used for adjuvant chemotherapy.
The median follow-up was 5.2 years (range = 1 year–16 years). The mean follow-up was 4.5 years. Follow-up was obtained through review of outpatient medical records, radiological images, telephonic conversations, and emails.
Progression-free survival (PFS) was calculated as the time from diagnosis (surgery) to clinical or radiological worsening, whichever occurred first. Overall survival (OS) was calculated as the time from diagnosis (surgery) to death. In the absence of events, PFS and OS were censored to the last follow-up date.
Additional prognostic variables
In addition to the variables reported in the Pignatti criteria, the following variables were analyzed for their effect on PFS and OS: location of the tumor (lobar versus nonlobar), presence of enhancement, and EOR.
Categorical data were expressed using frequency and percentage. The MS in months was determined with 95% confidence interval (CI). PFS and OS among the predictor variables categorized were compared using the log-rank test. Cox regression analysis was performed, and estimation of effect size was given as hazard ratio (HR) with 95% CI. The survival data were analyzed using the Kaplan–Meier curves. Difference in survival between the low-risk group and the high-risk group was tested for statistical significance using the log-rank test. A P value of ≤.05 was considered significant. Data were analyzed using Stata 13.1/IC software.
| Results|| |
Based on the PS, the patients were stratified into low-risk (PS = 1–2, n = 80, 81%) and high-risk (PS = 3–5, n = 19, 19%) groups [Figure 3]. None of our patients had a PS of 5.
|Figure 3: MR brain T2W and T2W FLAIR axial images (a and b) depicting a patient in our series with Pignatti 3 (age—0, diameter >6 cm—1, crossing midline—1, histology—1, deficit—0). MR brain T2W axial images (c and d) showing a diffuse left frontal and temporal astrocytoma with right hemiparesis, Pignatti 4 (age—0, diameter >6 cm—1, crossing midline—1, histology—1, deficit—1)|
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In the entire patient cohort, the 5-year PFS was 72% and 10-year PFS was 38%. The 5-year OS was 78%. This is summarized in [Table 2].
Prognostic factors for progression-free survival and overall survival
On univariate analysis, the MS for patients with age <40 years was 126 months (95% CI = 72–132 months), whereas it was 67 months (95% CI = 36–72 months, P = .008) for patients with age >40 years. Patients with tumor crossing the midline had a significantly lower PFS of 33 months as compared to patients with tumors not crossing the midline who had PFS of 120 months (95% CI = 72–127 months, P = .009). Patients who underwent STR had a statistically significant longer OS as compared to patients who underwent less than an STR (P = .01). None of the other variables had a correlation with PFS or OS. These results are summarized in [Table 3] and [Table 4].
On multivariate analysis, age >40 years (HR = 2.41, 95% CI = 1.2–6) and tumors crossing the midline (HR = 5.46, 95% CI = 1.5–19.8) were found to be independent predictors of shorter PFS and shorter OS. EOR was not a significant predictor of outcome in multivariate analysis (P = .08). These results are summarized in [Table 3] and [Table 4].
Survival and Pignatti score
The median OS in the low-risk group was 128 months (95% CI = 72, not applicable [NA]) as compared to 72 months (95% CI = 18, NA) in the high-risk Pignatti group (P = .005, [Table 4] and [Figure 4]). The PFS in the low-risk group was 120 months (95% CI = 72–128) and the PFS in the high-risk group was 72 months (95% CI = 18, NA; P = .15; [Table 3] and [Figure 5]).
|Figure 4: Kaplan—Meier curves showing the OS in the entire cohort. The low-risk Pignatti group (1–2) had significantly better OS as compared to the high-risk Pignatti group (3–5; P = .005)|
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|Figure 5: Kaplan–Meier curves showing the PFS in the entire cohort. The low-risk Pignatti group (1–2) had longer PFS than the high-risk group (3–5). However, this was not statistically significant (P = .15)|
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| Discussion|| |
LGGs constitute 40% of all glial neoplasms. Many prognostic factors affecting the MS in LGG are described in literature.,,,,, In 2002, Pignatti et al. on behalf of the EORTC study incorporated variables such as age, largest tumor diameter, tumor crossing midline, presence of neurological deficit, and histopathology into a scoring system that could predict MS. Our results establish the value of this scoring system in a cohort of patients with DFAs.
Previous studies have reported age, tumor size, EOR, presence of preoperative neurological deficit, presence of contrast enhancement, and astrocytic histology versus oligodendroglial histology as prognostic variables for PFS and OS in LGGs.,,,,, Some of these variables have been incorporated into the Pignatti scoring system. In our patient cohort, age <40 years and tumors confined to one hemisphere and not crossing the midline were associated with longer PFS and OS. Contrary to other series, we did not find that EOR was an independent predictor of PFS.,,,
The influence of age at presentation on PFS and OS has been recognized as an important prognostic variable with patients <40 years of age having a longer MS.,,,,,, This was confirmed in our study. Daniels et al. however observed that when age was analyzed as a continuous variable, it was a prognostic factor, whereas analyzing it as a categorical variable (cutoff of 40 years) resulted in it not being a prognostic factor.
Extent of resection
EOR has been reported to improve survival in several series of LGGs that have included tumors with oligodendroglial and astrocytic histologies.,,, In one series, elderly patients were offered less aggressive surgical resection, thus confounding the effect of surgical resection. However, not all studies report a correlation between EOR and survival in patients with LGG. Although the EORTC 22844 study reported improved survival with more aggressive tumor resection, the EOR was evaluated based on the surgeon’s estimate rather than on the postoperative imaging findings., In our patient cohort, EOR as defined on postoperative imaging was a prognostic factor in univariate analysis but not in multivariate analysis.
Adjuvant RT has been demonstrated to prolong PFS but not OS., Karim et al. concluded that there was no difference in survival whether RT was given in the immediate postoperative period or delayed till the time of recurrence. In another study on patients with lobar astrocytoma grade II, RT was administered to only those who underwent incomplete surgical resection, had tumors with contrast enhancement and were older patients, and it was found to have negative effect on survival. This could be due to the confounding effect of RT being administered to a subgroup with other unfavorable prognostic factors. The long-term results of the Radiation Therapy Oncology Group (RTOG) 9802 study concluded that patients who received RT and chemotherapy (procarbazine, lomustine, and vincristine) experienced a longer PFS and OS than those who received RT alone. Many studies in the recent past have studied the role of temozolomide in the treatment of grade II astrocytomas. With temozolomide, the objective radiological response rate to the chemotherapy was 33–71%.,,,,, Long-term results from RTOG 0424 concluded that patients who received RT and temozolomide had longer PFS and OS as compared to historical controls who received RT alone. They found that the 3-year OS in patients with high-risk WHO grade II gliomas of astrocytic, oligodendroglial, or mixed lineage (defined as equivalent of PS >3) who received RT and temozolomide was 73.5% (95% CI = 65.8–81.1%), which was significantly higher than that of historical controls (54%). Presence of isocitrate dehydrogenase 1 (IDH1), two mutations, and 1p/19q codeletion increased the chemosensitivity of LGGs to temozolomide with better PFS and OS.,,,
Better preoperative neurological status/function as measured by the Karnofsky Performance Status score, Mini-Mental State Exam (MMSE) score, Medical Research Council (MRC) grade, as well as absence of preoperative neurological deficits have all been associated with improved survival.,,,,,,
Pignatti score and its validation
Pignatti et al. in 2002 derived a prognostic scoring system from 322 patients recruited in the EORTC 22844 trial and validated this score on 288 patients from the EORTC 22845 trial. Pilocytic astrocytomas were excluded. Age ≥40 years, astrocytoma histology, tumor size ≥6 cm, tumor crossing the midline, and neurological deficit prior to surgery were found to be unfavorable prognostic factors. Patients with <2 factors were classified into the low-risk group, whereas those with >2 factors were classified into the high-risk group. This was the first prognostic scoring system for LGGs to be validated. In their cohort, the number of patients with score 4/5 was only 9%, which is similar to the findings in our patient cohort. EOR was determined based on the surgeon’s estimate rather than on postoperative imaging findings. Despite these limitations, the scoring system could establish different survival in the low-risk and high-risk groups.
Daniels et al. validated these EORTC prognostic factors for adults with LGG (astrocytomas and oligodendroglial tumors) among 203 patients with LGGs treated in a North Central Cancer Treatment Group-led trial. All patients had central review of their pathology, and the median follow-up was 7.7 years. Among all the variables defined by Pignatti et al., astrocytoma histology was an independent predictor of PFS but not OS. Tumor size and MMSE score were the only independent predictors of PFS and OS. The other criteria such as age, tumor crossing midline (being probably seen earlier on MRI that was used for diagnosis in this series than on CT that was used in the EORTC cohort), and preoperative neurological deficit were not found to be prognostic factors. As was seen in our patient cohort, the low-risk group had better median OS and PFS than the high risk group despite very small number of patients (n = 5), being in PS 4 or 5.
Gorlia et al. analyzed pooled data from two EORTC cohorts and the North Central Cancer Treatment Group. A central pathology review resulted in 21% of the patients being excluded as they were not classified as grade II tumors, with most of them being reclassified into high-grade gliomas. EOR and age were not found to be prognostic factors. Both OS and PFS were influenced by duration of symptoms, neurological status/MRC score, tumor size >5 cm, and astrocytic histology. Immediate RT resulted in improved PFS but not OS. On subclassifying their patients into low risk, intermediate risk, and high risk, the low-risk group patients were found to have a better OS/PFS compared to the intermediate- and high-risk groups. This group stratification was then validated using the data from the North American group. It was commented that the duration of symptoms being uniformly shorter in the North American cohort, this might not play a significant role as a prognostic factor.
Our findings have validated the utility of this scoring system in a cohort of South Asian patients with DFAs.
Several studies have confirmed that lower PSs are associated with improved survival in patients with LGGs.,,,, However, previous studies that have validated the Pignatti scoring have done so in a mixed group of oligodendroglial and astrocytic tumors, whereas our patient cohort is homogeneous with only DFAs being included. In our patient cohort, a lower PS was associated with higher PFS and OS [Figure 4] and [Figure 5]. In another study on prognostic variables for lobar WHO grade II astrocytomas, contrast enhancement was also found to be associated with poor survival, although we did not observe this association.,
The MS of LGG is between 5 and 10 years, disease progression contributing to death in 50–70%.,,,,,,, Durmaz et al. in their study on LGG (oligodendroglial and astrocytic neoplasms being included) reported an MS of 141 months following surgical excision alone.
In our series, the MS in the low-risk group (based on PS) was 128 months and the MS in the high-risk group was 72 months. As shown in [Figure 4], we observed a consistent decline in the median OS with an increase in the PS. There seems to be a value in assigning a PS even within the low-risk group. In patients within the low-risk group, those with a PS of 1 had a better OS than those with a PS of 2. In the high-risk group, the lone patient with a score of 4 had lower PFS than those with a score of 3.
Role of isocitrate dehydrogenase 1 and 1p/19q codeletion
Daniels et al. found that patients with a low-risk PS with 1p/19q codeletion had longer PFS and OS. These would essentially be oligodendroglial neoplasms (as per the revised WHO classification of 2016). Other authors have also corroborated these findings, and it is accepted that 1p/19q codeletion is an independent nontreatment-related prognostic factor associated with increased OS.,,,
Waqar et al. reported that presence of IDH1 mutation in low-grade astrocytomas was associated with improved OS (P = .006, HR = 3.310, 95% CI = 1.416–7.738). Gozé et al. found that diffuse LGGs with IDH1 mutation had longer PFS and OS (P = .019, HR = 2.39, 95% CI = 1.19–4.66).
In our study, we have not studied the impact of molecular features of DFA on OS and PFS, as these data were not available for a large number of patients operated on early in the series.
| Conclusion|| |
PS (low-risk or high-risk category) was a good predictor of OS of patients with WHO grade II DFAs. However, it did not correlate with the PFS. Age >40 years and tumors crossing the midline were associated with both poor OS and lower PFS.
Financial support and sponsorship
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the Declaration of Helsinki 1964 and its later amendments or comparable ethical standards.
For this type of study, formal consent is not required.
Conflicts of interest
All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge, or beliefs) in the subject matter or materials discussed in this manuscript. The authors declare that they have no conflicts of interest.
| Editor notes|| |
The special supplement of International Journal of Neurooncology was published in November 2021.
We wish to state that the office bearers of Executive committee members of the Indian Society of Neurooncology ( ISNO) on the Editorial board page in that issue was incorrectly mentioned. We sincerely apologize for the same.
The correct office bearers of the executive committee of the Indian Society of Neurooncology ( ISNO) is as follows:
Indian Society of Neuroncology (Executive committee)
President: Purna Kurkure President-Elect: Neelam Shirsat
Honorary Secretary: Tejpal Gupta Honorary Joint Secretary: Epari Sridhar
Honorary Treasurer: Sona Pungavkar
Honorary Joint Treasurer: Anandh Balasubramaniam
Editor, International Journal of Neuroncology: Dattatraya Muzumdar
Dr. Dattatraya Muzumdar. FRCSI, FRCSEd, FACS (USA)
Editor, International Journal of Neurooncology
Department of Nerosurgery
Seth G.S.Medical College and King Edward VII Memorial hospital
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2], [Table 3], [Table 4]