Volumetric growth rates of meningioma and its correlation with histological diagnosis and clinical outcome: a systematic review

Introduction Tumour growth has been used to successfully predict progression-free survival in low-grade glioma. This systematic review sought to establish the evidence base regarding the correlation of volumetric growth rates with histological diagnosis and potential to predict clinical outcome in patients with meningioma. Methods This systematic review was conducted according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Databases were searched for full text English articles analysing volumetric growth rates in patients with a meningioma. Results Four retrospective cohort studies were accepted, demonstrating limited evidence of significantly different tumour doubling rates and shapes of growth curves between benign and atypical meningiomas. Heterogeneity of patient characteristics and timing of volumetric assessment, both pre- and post-operatively, limited pooled analysis of the data. No studies performed statistical analysis to demonstrate the clinical utility of growth rates in predicting clinical outcome. Conclusion This systematic review provides limited evidence in support of the use of volumetric growth rates in meningioma to predict histological diagnosis and clinical outcome to guide future monitoring and treatment. Electronic supplementary material The online version of this article (doi:10.1007/s00701-016-3071-2) contains supplementary material, which is available to authorized users.


Introduction
Meningiomas originate from the arachnoid cap cells, which are found in the meninges that surround the brain and spinal cord. Meningiomas are thought to be the most common benign intracranial tumour [20]. The World Health Organisation (WHO) classification system for brain tumours, including meningiomas, was first published in 1979 with the latest edition published in 2016. This and the immediately preceding (2007) WHO classifications do not differ in their grading of meningiomas into benign (grade I), atypical (grade II) and anaplastic (grade III) [13]. A comparative table of histological grading of meningioma is shown in Table 1 [1,22]. Research has shown that higher-grade tumours are associated with a higher rate of recurrence and a poorer prognosis [24]. Histologically, these tumours have higher mitotic activity and cellular atypia [1]. However, in some cases, benign meningiomas have also been shown to have relatively rapid growth and recurrence after total removal [12,15].
In addition to histological diagnosis, growth rate has been found to serve as significant prognostic factor in low grade glioma [19]. We hypothesised that this could be similarly useful in the longitudinal management of patients with meningiomas. We thus sought to design a systematic review to ascertain the current evidence base for the prognostic value of spontaneous volumetric growth of meningiomas as seen on Electronic supplementary material The online version of this article (doi:10.1007/s00701-016-3071-2) contains supplementary material, which is available to authorized users. MRI. We also aimed to establish the relationship between the rate of meningioma growth and the underlying WHO meningioma histological grades and identify whether the combination of these two parameters has been used to predict recurrence, overall survival and anaplastic transformation.

Methods
This systematic review was conducted according to PRISMA guidelines and has been registered with the PROSPERO international prospective register of systematic reviews (registration number CRD42016027746).

Search strategy
A systematic search of keywords in Table 2 (Table S1).
Initially titles and abstracts were screened for relevant papers by two authors independently (DMF and WCS). Decisions were blinded and, where disagreements occurred, both authors discussed the disparities and resolved them throughout the selection process. The bibliographies of accepted papers were also examined for additional articles not identified in the systematic search. The inclusion criteria, designed using the PICO (Patient and Problem, Intervention, Comparators, Outcomes) process, were as follows: & Study design: Randomised controlled trials, controlled clinical trials, prospective and retrospective observational studies were included conditional upon a sample size > 10 patients from the population of interest. We excluded studies with smaller sample sizes, such as case reports and case series, on the grounds of a potential publication bias risk. Only full articles in English language were included, with articles in other languages, conference abstracts and grey literature excluded. & Population: All studies including human subjects with a meningioma. & Intervention: Patients underwent imaging with accompanied volumetric growth analysis. & Outcome: All studies investigating correlation rates of growth analysis with histological diagnosis, progressionfree and overall survival, recurrence rate and rates of anaplastic transformation were included.
Data extraction was also performed by two authors (DMF and WCS) to ensure reliability. Forward and backward searching of included studies provided one further study not identified in the database search.

Results
Our search strategy identified a total of 1,983 articles for screening. After excluding duplicates and irrelevant studies, we obtained 24 full articles for further assessment of eligibility. Of these, 21 were excluded mainly because the studies did not include volumetric growth rates or the volumetric growth rates were not directly correlated with the outcomes (Fig. 1). Four retrospective cohort studies with a total of 151 patients met the inclusion and exclusion criteria for the systematic review. As such, they were all classified as evidence level 2b [8]. Table 3 shows a summary of the four studies that have been included in the analysis.

Volumetric calculation methods
The methods used for volumetric measurements varied between studies. Jääskeläinen et al. [10] used computed planimeter to measure the volumetric growth rates on CT images whereas Nakasu et al. [16,17] performed volumetric measurements on CT and MRI images using the National Institutes of Health (Bethesda, MD) Image 1.62 software. Nakamura et al. determined the mean volume from three volumetric measurements using the National Institutes of Health Scion Image J programme [14].

Histology grades
Only Nakasu et al. 2011 [17]  Of the available histological grades, there were 81 grade I or benign meningiomas, 21 grade II or atypical meningiomas and 7 grade III or malignant meningiomas. Histology was not available in 38 cases as the patients were asymptomatic and did not undergo biopsy or resection of their tumours. Two studies undertook growth rate analysis post-operatively; whilst Jääskeläinen et al. reported growth rates following recurrence after radical removal [10], Nakamura reported growth rates following identification of remnant tumour post-operatively [14]. Whilst Nakasu et al. 2005 reported pre-operative volumes [16], Nakasu et al. 2011 analysed a combination of asymptomatic and post-operative meningioma, the latter either as a remnant or a recurrence [17]. Jääskeläinen et al. reported that four benign meningiomas transformed into atypical meningiomas and four atypical tumours transformed into malignant meningiomas [10]. In the 2005 study by Nakasu et al., the authors described eight out of nine Grade I and one out of four Grade II meningiomas presenting as regrowth, the remaining presenting as recurrence [16].

Mean growth rates and tumour doubling time
The mean growth rates (cm 3 /year) were only specified in Nakamura et al., reporting significantly higher rates in grade II meningioma relative to grade I [14]. The tumour doubling time in days were specified in three of the four studies. Jääskeläinen identified a significantly shorter tumour doubling time between grade I and grade II or III tumours, [10] which was consistent with findings in Nakamura reporting significantly higher growth rates in grade II meningioma [14].
The pattern of growth also showed evidence of utility in predicting histological grade. It was reported that atypical meningiomas tend to grow quasi-exponentially and a majority of benign or asymptomatic meningiomas had already passed the inflection point prior to diagnosis [10,17]. The majority of grade I meningiomas begun to slow their growth before the age of 80 years when compared with the growth of atypical meningiomas which did not significantly show deceleration (p = 0.04) [17]. Using regression analysis, the authors showed that the growth curves of meningiomas fitted the logistic and sigmoid Gompertzian curves. In addition, the authors also demonstrated that the growth rates of benign meningiomas may change in the long term and it is vital to apply the correct growth model to predict tumour growth and guide the decision-making process.

Other findings
Nakamura et al. highlighted that the growth rates of benign meningiomas vary widely even among grade I meningiomas [14]. Factors associated with an increased volumetric growth rate include younger age at diagnosis [14], lack of calcification on radiological scans [16] and the presence of hyper-intense T2 signals on MRI [14]. Table 4 presents twelve studies that did not meet the inclusion or exclusion criteria but we felt that the findings of the papers should be reviewed as volumetric growth rates were performed in these studies. The demographic data could not be summarised as they are not uniformly available. Two out of twelve studies investigated volumetric growth rates in neurofibromatosis type 2-associated meningiomas [3,5]. Evers et al. showed that in patients with NF2-associated meningiomas, tumours in the skull base have higher absolute growth rates when compared to convexity and 'other' meningiomas [5]. In the study by Dirks et al., the authors found that younger age at diagnosis (p = 0.01) and female gender (p = 0.05) significantly contributed to increased volumetric growth rates [3].
Two studies demonstrated that computer-aided volumetric growth analysis is significantly more superior to traditional methods in assessing tumour growth [2,27]. There were eight different methods used for performing volumetric growth rates in these studies as demonstrated in Table 4 [3,27]. Information on histological grading of the meningiomas was only reported in one study [9]. The mean relative growth rates and tumour doubling time are not comparable due to the heterogeneity of the reported data.

Discussion
The majority of meningiomas are generally benign and slowgrowing tumours. In clinical practise, tumour growth together with the presence of symptoms are the main determining factors of the frequency of follow-up, both pre-and post-operatively, and help guide the clinical management decisionmaking process. Nevertheless, there remains limited information in the literature regarding the growth rates of meningioma. A range of imaging methods is available for assessing and monitoring growth and disease progression [2,5,6,18]. Volumetric measurements have been found to be superior to traditional planimetric methods in assessing tumour growth kinetics. This has been proposed to be due to tumours being three-dimensional structures that may grow in various directions and not just in the planimetric axes [2,23]. When reviewing evidence on radiological follow-up of low-grade gliomas, Pallud et al. found that there remains a question as to whether growth should be monitored over time in diameter or in volume [19]. This is due to the fact that the tumour volumes do not usually increase linearly when compared with tumour diameter. The authors proposed that the linearity of diameter growth curves will allow the analysis of biological aggressiveness to be more straightforward. The tumour volumes can be converted into diameter using the formula Mean Tumour Diameter (MTD) = (2 × Volume) 1/3 . The MTD can then be used to calculate the velocity of diametric expansion (VDE) by plotting the MTD and performing a linear regression of VDE over time [19]. The authors concluded that spontaneous VDE carries a strong prognostic significance with regards to progression-free and overall survivals in patient with low-grade glioma. There is currently no evidence if this metric is applicable to meningiomas.
According to the CBTRUS statistical report, the incidence of meningioma increases with age but there is no specific mention as to whether older age at initial diagnosis correlates with higher-grade meningioma [4]. However, Park JS et al. has shown that the combined incidence of WHO grade II and III increases as age advances [21]. Several studies have demonstrated that a higher tumour volume at initial diagnosis is significantly associated with a higher rate of tumour recurrence [2,26]. However, little is known regarding the volume of the tumour and the probability that the tumour is of a higher grade. Using diffusion-tensor MR imaging, Wang et al. showed that there is significant difference in tumour volume between atypical and benign meningioma. Atypical meningioma tended to be larger when compared to benign meningioma [25].
Our review has indicated that the growth rates of meningiomas may evolve over time and vary even among grade I meningiomas [14,15]. Jääskeläinen et al. and Nakamura et al. showed that higher-grade tumours are significantly more likely to have higher growth rates and shorter tumour doubling times [10]. However, these studies have correlated the volumetric growth rates with the old WHO classification of meningiomas. None of the studies attempted to correlate the growth rates of meningiomas with the revised 2007 WHO classification of meningiomas. Moreover, the findings of these studies are limited by the small number of patients and their retrospective nature. A reliable method to evaluate spontaneous growth rates of meningiomas on MRI should be utilised to determine its usefulness in determining the frequency of follow-ups, determine progression-free survival, treatment efficacy and, possibly, the probability of recurrence or regrowth after resection. With regards to the growth rate of non-operated tumours, Zeidman et al. showed that there was no significant association between age, gender, or radiological characteristics and volumetric growth [27]. These results need to be considered in the context of the cohort size of only 21 patients. In a multi-variate analysis of a slightly larger series (N = 37) by Yoneoka et al., tumour growth was significantly higher in younger patients and in patients with a higher volume of tumour at initial diagnosis [26]. When looking at the natural history of 273 intracranial meningiomas, Oya et al. demonstrated that volumetric growth rate was seen in 74% of cases. Factors such as male sex, initial tumour diameter greater than 25 mm, MR imaging T2 hyperintensity, presence of symptoms and oedema are significantly associated with higher annual growth rate [18]. Interestingly, Evers et al. demonstrated that in patients with neurofibromatosis type-2 meningiomas, skull base tumours have higher growth rates compared with convexity and other locations whereas Hashimoto et al. demonstrated that in non-NF2 related meningiomas, tumour doubling-time was significantly lower in non-skull base tumours [5,7].

Limitations
The review was limited by the level of evidence in accepted studies, with four retrospective cohort studies accepted. Heterogeneity of patient demographics and the timing of volume measurement prevented pooled analysis of the data. None of the studies undertook statistical analysis to investigate the potential for volumetric growth rates to act as a predictor of histological diagnosis or clinical outcome, restricting to demonstrating significant differences between histological diagnoses.

Conclusion
Tumour volumetric growth rates were hypothesised to be a potentially useful indicator of histological diagnosis and prognosis in patients with meningioma. This systematic review of volumetric growth rates in patients with meningioma identified four retrospective cohort studies providing limited evidence in favour of the correlation of volumetric growth rates with histological diagnosis. None of the accepted studies extended this analysis to evaluate the potential to predict clinical outcome. This study highlighted a knowledge gap that is ready to be addressed as digital acquisition and storage of radiological imaging has been widely available for over a decade in most neurosurgical centres.

Compliance with ethical standards
Funding No funding was received for this research.
Conflict 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.
Ethical approval 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 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Informed consent This article does not contain any studies with human participants performed by any of the authors.
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