| Abstract|| |
Background: Meningiomas are the most common benign central nervous system tumors. However, a sizeable fraction recurs, irrespective of histological grade. No molecular marker is available for prediction of recurrence in these tumors. Materials and Methods: We analyzed recurrent meningiomas with paired parent and recurrent tumors by fluorescence in situ hybridization for 1p36 and 14q32 deletion, AKT and SMO mutations by sequencing, and immunohistochemistry for GAB1, progesterone receptor (PR), p53, and MIB-1. Results: 18 recurrent meningiomas (11 grade I, 3 grade II, 4 grade III) with their parent tumors (14 grade I, 2 grade II and 2 grade III) were identified. Overall, 61% of parent and 78% of recurrent meningiomas showed 1p/14q co-deletion. Notably, grade I parent tumors showed 1p/14q co-deletion in 64% cases while 82% of grade I recurrent tumors were co-deleted. AKT mutation was seen in two cases, in both parent and recurrent tumors. SMO mutations were absent. GAB1 was immunopositive in 80% parent and 56.3% recurrent tumors. MIB-1 labeling index (LI), PR and p53 expression did not appear to have any significant contribution in possible prediction of recurrence.
Conclusion: Identification of 1p/14q co-deletion in a significant proportion of histologically benign (grade I) meningiomas that recurred suggests its utility as a marker for prediction of recurrence. It appears to be a better predictive marker than MIB1-LI, PR and p53 expression. Recognition of AKT mutation in a subset of meningiomas may help identify patients that may benefit from PI3K/AKT pathway inhibitors, particularly among those at risk for development of recurrence, as determined by presence of 1p/14q co-deletion.
Keywords: 1p 14q, AKT, co-deletion, fluorescence in situ hybridization, meningioma, recurrent
|How to cite this article:|
Kakkar A, Kumar A, Das A, Pathak P, Sharma MC, Singh M, Suri A, Sarkar C, Suri V. 1p/14q co-deletion: A determinant of recurrence in histologically benign meningiomas. Indian J Pathol Microbiol 2015;58:433-8
|How to cite this URL:|
Kakkar A, Kumar A, Das A, Pathak P, Sharma MC, Singh M, Suri A, Sarkar C, Suri V. 1p/14q co-deletion: A determinant of recurrence in histologically benign meningiomas. Indian J Pathol Microbiol [serial online] 2015 [cited 2018 Jun 21];58:433-8. Available from: http://www.ijpmonline.org/text.asp?2015/58/4/433/168852
| Introduction|| |
Meningiomas are the most common neoplasms of the central nervous system (CNS), accounting for 35.6% of primary CNS tumors. Based on histomorphological features, the WHO classifies meningiomas into grades I to III. This grading system aims to predict biological behavior with higher grades exhibiting worse outcomes. While most slow growing, benign tumors correspond to grade I, more aggressive tumors belong to grade II (atypical) and III (anaplastic) and have a tendency to recur. However, as this grading system is based on subjective histopathological criteria, its reliability and reproducibility are limited. Thus, there remains considerable variability in biological behavior and clinical outcome within a given histologic grade. More importantly, even histologically benign (grade I) meningiomas have been seen to recur in as many as 25% of cases, leading to significant morbidity.,,,,,,
To date, extent of surgical resection is the most important factor influencing patient outcome in meningiomas.,, A number of markers have been explored to assess the biological behavior of these neoplasms, including age, sex, tumor location, proliferation rate, and progesterone receptor (PR) and p53 immunoreactivity., 7, ,,,,, However, studies have shown conflicting results, and these do not prove useful for prognostication in all instances. Moreover, markers like PR expression and MIB-1 labeling index (LI) are not independently predictive of outcome, as prognostic differences reported are not evident within a given tumor grade. Thus, there is no objective marker that can accurately determine the propensity for development of recurrence in a histologically innocuous appearing tumor.
Loss of the neurofibromatosis type 2 (NF2) gene is the most frequent genetic alteration and represents an early event in meningioma pathogenesis., Deletion of 1p and 14q and co-deletion, in particular, is considered a marker of malignant progression in meningiomas, as it increases in frequency with increasing tumor grade.,,, Association of 1p/14q co-deletion with lower survival rates and high risk of recurrence has also been described., However, there is no large study in which 1p/14q co-deletion has been analyzed in paired samples (fromfirst and second surgeries) in recurring meningiomas.
Whole genome sequencing studies have identified oncogenic mutations in the AKT and SMO genes in meningiomas., AKT and SMO mutations correlate with activation of the PI3K/AKT and Hedgehog (SHH) signaling pathways, respectively, with GAB1 immunoreactivity being a marker of SHH pathway activation. However, the role of these mutations in the pathogenesis of meningiomas, their progression and development of recurrence has not been evaluated. We, therefore, conducted this study to determine the frequency of 1p/14q co-deletion, AKT and SMO mutations, and GAB1 immunopositivity in recurring meningiomas in parent and recurrent tumors, and to correlate results obtained with histological grade, MIB-1 LI, PR and p53 expression.
| Materials and Methods|| |
Recurring meningiomas with paired parent and recurrent tumors having adequate tissue in paraffin blocks were identified (2002-2013). Only cases in which Simpson grade I or II excision had been achieved at the time offirst surgery were included. Approval was obtained from Institutional Ethics Committee for conducting experiments on human patient samples.
Hematoxylin and eosin stained slides were reviewed by three neuropathologists, and diagnoses reconfirmed.
Fluorescence in situ hybridization
Dual-probe fluorescence in situ hybridization assay was performed on paraffin-embedded tumor sections, with locus-specific probes for 1p36 and 14q32 paired with reference probes for 1q25 and 18q21, respectively (Vysis, Downers Grove, IL, USA), as described previously.
Sequencing for identification of AKT and SMO mutations
DNA was extracted from paraffin-embedded tumor tissue. Primers for PCR amplification and sequencing of exon 4 of AKT1 had the following sequence: Forward 5'-CTGGCCCTAAGAAACAGCTCC-3' and reverse 5'-CGCCACAGAGAAGTTGTTGA-3'. Primers for PCR amplification and sequencing of exon 6 and exon 9 of SMO had the following sequence: Forward 5'-GTGGCGCAGGTATAGTGACTG-3'and reverse 5'-GCCCTATAGGAGCTAGCTGGG-3', and forward 5'-AGTTGGAAGCTGCAGTGGG-3' and reverse 5'-CAAGGCTGTGCTAGAGGCAG-3', respectively. Reaction conditions for PCR amplification were 40 cycles at 95°C for 30 s, 60°C for 1 min and 72°C for 1 min. PCR products were purified using ExoSAP-IT (Affymetrix, Santa Clara, CA, USA) and analyzed on an automated DNA sequencer (ABI 3130, Applied Biosystems, Foster City, CA, USA). Data analysis was carried out using DNASTAR software.
Immunohistochemistry was performed using the following monoclonal antibodies: GAB1 (Abcam, Cambridge, UK; dilution, 1:100), PR (Neomarkers, Fremont, CA, USA; dilution, 1:50), p53 (Santa Cruz Biotechnology, Inc., CA, USA; dilution, 1:200), and MIB-1 (Dako, Glostrup, Denmark; dilution, 1:200). Universal labeled streptavidin-biotin kit was used as detection system (Dako, Glostrup, Denmark). Diaminobenzidine was used as a chromogen. Cytoplasmic positivity was ascertained for GAB1. PR and p53 staining was considered positive when nuclei of >10% of tumor cells were stained. MIB-1 LI was calculated in the highest proliferating areas as the percentage of labeled nuclei per 1000 tumor cells.
| Results|| |
Eighteen recurrent meningiomas with their corresponding primary tumors were identified [Table 1]. Mean age of patients at the time offirst surgery was 39.4 years (range: 5-64 years). A slight male preponderance was noted (male:female = 1.25). Nine tumors were supratentorial, eight were located at the skull base, and one was in the orbit. Mean time to recurrence was 46.3 months (range: 11-94 months). Majority of patients (n = 16; 89%) had undergone Simpson grade II excision for the parent tumor. Most parent tumors belonged to WHO grade I (14/18; 78%) and recurred as grade I (11/18; 61%). Malignant progression to a higher grade occurred in 4 cases (22%): Grades I to II in 2 cases, grades I to III in 1 case and grades II to III in 1 case. There was no change in grade in 14 cases.
|Table 1: Clinicopathological features, 1p/14q co--deletion status, AKT mutation and immunohistochemistry in paired parent and recurrent meningioma|
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1p/14 co-deletion [Figure 1] was identified in 11 out of 18 (61.1%) parent tumors and 14 out of 18 (77.8%) recurrent tumors. Of all the co-deleted parent tumors, 9 were grade I, and one belonged to grades II and III each. On correlating with tumor grade, we found that 11 of the 14 grade I tumors from the first surgery (64.3%) and 9 of 11 grade I tumors (81.8%) from the second surgery were 1p/14q co-deleted. Grades II and III tumors included four parent and seven recurrent tumors, which showed co-deletion in 50% and 71.4% of cases, respectively. No significant association of 1p/14q co-deletion was noted with Simpson grade or with location of the tumors. Mean time to recurrence was 46.9 months in 1p/14q co-deleted group while it was 44.8 months in the non-co-deleted group (P > 0.05).
|Figure 1: Fluorescence in situ hybridization for 1p/14q: Photomicrographs from parent meningioma showing deletion of 1p (one red test and two green control signals) (left; ×1000) and deletion of 14q (one green test and two red control signals) (right; ×1000)|
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AKT E17K mutation [Figure 2] was seen in 2/18 (11.1%) paired tumor samples, that is, in both, parent and recurrent tumors. Tumors showing AKT mutation were located at the base of the skull, one at the medial sphenoid wing and the other at the foramen magnum. On histopathology, both tumors were transitional meningiomas, corresponding to WHO grade I, and recurred as grade I. Mean time to recurrence was 39.5 months in these tumors. One case showed concurrent 1p/14q co-deletion in the parent as well as recurrent tumor. Mean MIB-1 LI was 2% in the parent tumors; PR was positive and p53 negative.
|Figure 2: AKT mutation: Electropherograms showing wild-type AKT, and AKT with E17K mutation in a case of meningioma|
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SMO mutations were not seen in any of the cases. GAB1 was performed on 31 tumors (15 pairs and one recurrent tumor) as tissue was insufficient in the rest. GAB1 was immunopositive [Figure 3]a in 12 out of 15 parent tumors (80%), and in 9 out of 16 recurrent tumors (56.3%). Majority of the paired tumors (13/15; 86.8%) showed similar staining pattern in both the primary and the recurrent tumors. One of the AKT mutated tumors was positive for GAB1 in the primary tumor but not in the recurrent tumor. The other AKT mutated tumor did not show GAB1 positivity in either parent or recurrent tumor.
|Figure 3: Immunohistochemistry: Photomicrographs of a grade I parent tumor that recurred showing strong immunopositivity for GAB1 (a; ×200), low MIB-1 labeling index (b; ×400), diffuse strong progesterone receptor positivity (c; ×200), and weak, focal p53 positivity (d; ×400)|
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Mean MIB-1 LI [Figure 3]b showed an increasing trend in tumors from the second surgery as compared to parent tumors (4.2% vs. 3.0% in grade I, 16.3% vs. 10.5% in grade II and 14.0% vs. 13.0% in grade III; P > 0.05). Similarly, loss of PR expression [Figure 3]c and p53 immunopositivity [Figure 3]] were more frequent in recurrent tumors than parent tumors, but no statistical significance was noted. When present, p53 immunopositivity was focal and weak (1+).
| Discussion|| |
Although majority of meningiomas are benign, slow-growing tumors, the most important clinical complication is tumor recurrence. Even after complete resection, recurrences occur in a significant proportion of grade I tumors.,,,,,, In spite of the substantial advances being made towards understanding their biology and identification of factors responsible for aggressive behavior, no single marker has been identified which is of utility in predicting the propensity for tumor recurrence in any given patient, particularly in benign tumors. Thus, there is a need for comprehensive understanding of the genetic abnormalities in meningiomas, not only to identify adjuncts to standard histopathological grading, but also to allow better risk stratification of patients and prediction of patient outcome, in terms of tumor recurrence.
Loss of the NF2 gene localized to chromosome 22q12.2 is the an early event in meningioma pathogenesis but is not associated with malignant progression.,,, 1p, 10q, and 14q have been identified as loci that are rarely altered in grade I, but are often lost in grades II and III meningiomas, and are suspected to contain tumor suppressor genes associated with tumor progression.,,, 1p/14q co-deletion is seen in majority of grades II and III tumors, and its frequency increases with increasing tumor grade.,,, Thus, malignant progression appears to be associated with the sequential accumulation of genetic abnormalities, most often deletions at 1p and 14q. However, the role of 1p/14q co-deletion in the development of recurrences is not established. To the best of our knowledge, this is the largest study to analyze 1p/14q co-deletion in paired samples (fromfirst and second surgeries) in recurring meningiomas.
Previous studies on recurrent meningiomas have not compared chromosomal alterations in the parent and recurrent tumors or have included only a few cases in a large series, some of which have been analyzed by conventional cytogenetics alone.,, Maillo et al. showed that grade I meningiomas demonstrating the coexistence of monosomy 14 and del(1p36) in the ancestral tumor cell clone displayed a higher frequency of relapses. Al-Mefty et al. analyzed successive tumor specimens from four patients with recurrent meningiomas: Three of the four lower grade samples (two grade I and one grade II) showed 1p/14q co-deletion prior to progression to higher grade. Espinosa et al. analyzed primary and recurrent tumors from 19 patients and established that tumors which relapsed showed multiple chromosomal aberrations and that recurrent tumors harbored the same chromosomal losses as parent tumors, along with additional aberrations. They identified combined 1p loss and monosomy 14 in 5 out of 25 (20%) primary tumors, of which 4 were grade I and one was grade II. In our study, the majority of recurrent meningiomas showed 1p/14q co-deletion in the parent and recurrent tumors. We compared our results to those from 64 nonrecurrent meningiomas previously analyzed at our Institute. Of these, a notable proportion of grade II (28.5%) and grade III (30%) tumors showed 1p/14q co-deletion. However, none of the nonrecurrent grade I tumors showed this alteration. This is in stark contrast to grade I parent tumors that recurred, in which 1p/14q co-deletion was significantly more frequent (64.3%) (P< 0.001). Thus, the frequency of 1p/14q co-deletion identified in grade I tumors is low, and that seen in recurring tumors in our study is much higher than that quoted for grade I tumors in literature (only 7-25%), providing compelling evidence that co-deletion has utility as a determinant of recurrence in this subset of histologically benign meningiomas.,,,, Similar to our results, Cai et al. identified 1p/14q co-deletion in three benign meningiomas, of which two recurred. Barbera et al. demonstrated that benign tumors harboring 1p and 14q alterations are similar to atypical meningiomas in terms of potential for recurrence. Pfisterer et al. reported that all three completely resected grade I tumors in their series which recurred had 1p/14q co-deletion. Thus, along with being a good supplement to histopathological grading of meningiomas, 1p/14q co-deletion emerges as an important marker for prediction of recurrence and indicates inherent aggressive behavior in a subset of benign tumors. Mean MIB-1 LI, loss of PR expression and p53 immunopositivity did not show a significant difference between parent recurring and nonrecurring tumors suggesting that while they might be useful in grading, they do not have much role to play as predictive markers.
In a recent genome sequencing study, Brastianos et al. identified mutations in AKT (5%) and SMO (5%) genes, which were mutually exclusive from NF2 alterations. These mutations were seen in tumors from therapeutically challenging locations like skull base and were of meningothelial subtype. AKT and SMO mutations correlated with activation of PI3K/AKT and SHH signaling pathways, respectively. GAB1 immunoreactivity was seen in seven cases, three of which harbored SMO mutations. Similarly, Clark et al. identified AKT mutations in 14% and SMO mutation in 3.7% of cases. They reported that AKT/SMO-mutated meningiomas were usually benign, located in the medial skull base, displayed chromosomal stability, and had a gene expression profile different from NF2-altered meningiomas. Sahm et al. described AKT E17K mutations in 6.8% of cases and established that these mutations cluster with meningothelial and transitional subtypes. We identified AKT mutations in parent as well as recurrent tumor samples from two patients (11%). Both these tumors were grade I transitional meningiomas and recurred as grade I. Similar to the results of Clark et al., both tumors had a medial skull base location. No correlation was noted between 1p/14q co-deletion and AKT mutation. However, a larger number of cases need to be analyzed for a definitive comment on the same. None of our cases showed SMO mutations in the exons examined. However, GAB1 immunopositivity was frequent suggesting that there might be mutations in the remaining exons of the SMO gene or activating mutations in other regulators of the SHH pathway. The latter hypothesis is supported by results of gene expression profiling of the SHH pathway in meningiomas, which have shown overexpression of mRNA levels of 16 different genes involved in SHH pathway activation and cell proliferation, including SMO. Thus, while AKT mutations are rare and seem to be an early event in meningioma tumorigenesis, they may not be associated with malignant progression, as both cases showing AKT mutation in our series were grade I and there was no change in grade in the recurrent tumors. The role of SMO mutation in meningioma tumorigenesis, on the other hand, could not be ascertained from our study. However, identification of these novel mutations has therapeutic implications, and may be relevant in planning targeted therapy for patients with incompletely resected tumors, particularly at challenging locations like skull base., This suggests that the inclusion of mutation analysis in pathological work-up of meningiomas may be of value in the future.
| Conclusion|| |
1p/14q co-deletion is an important marker for prediction of recurrence in benign meningiomas, as it is seen in a sizeable fraction of grade I tumors. It appears to be a better marker than MIB1-LI, PR and p53, and has utility in guiding management of meningioma patients. Recognition of AKT mutation in a subset of meningiomas may help identify patients that can benefit from PI3K/AKT pathway inhibitors, particularly those at risk for development of recurrence, as identified by 1p/14q co-deletion, and those with incompletely resected skull base tumors. Thus, identification of these genetic alterations in histologically benign meningiomas will ultimately aid in defining management protocols for follow-up and early intervention in patients that are likely to develop tumor recurrence, and should therefore be incorporated into routine pathological evaluation of meningiomas.
Financial support and sponsorship
This study was funded by Intramural Grant, All India Institute of Medical Sciences.
Conflicts of interest
There are no conflicts of interest.
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Dr. Vaishali Suri
Department of Pathology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi - 110 029
Source of Support: None, Conflict of Interest: None
[Figure 1], [Figure 2], [Figure 3]