The meta-analysis revealed a significant difference in the aggressiveness of the adenoma size ≥10mm. The results of the meta-analysis support this by comparing the mean size of the adenoma and giant adenoma, both of which showed significant aggressiveness, with mean differences of 5.61 (3.29-7.92) and OR 2.21 (1.17-4.18), respectively (figure L2 and L3). The findings of Liang Lv et al.20 study, which compared adenomas' diameter and volume, are also intriguing. The findings were surprising because, despite a significant mean difference in diameter, there was no clinical difference (3.42±1.08cm and 2.80±0.84cm, p<0.0001). When measured by volume, however, there is a clinically significant difference (12.1 (0.06-76.20)cm3 and 6.00 (0.05-50.60)cm3, p<0,0001). This finding could help to reduce the risk of bias or error when measuring adenoma diameter.
The corticotroph type was more aggressive than the other types, while the somatotroph type was less aggressive. Figure L7 depicts the results of other types of meta-analysis. There are currently no guidelines that could determine which type of pituitary adenoma is more aggressive than the other. However, two of the five high-risk subtypes highlighted by WHO, namely crook's cell adenoma and silent corticotroph adenoma, are found to be part of the corticotroph type.19 The small number of studies evaluating this subtype could be due to the WHO's relatively recent recommendation in 2017 or certain difficulties in the examination, which is quite detailed and costly. However, as recommended by WHO, this should still be considered when evaluating patients with pituitary adenoma.19,21
In the case-control meta-analysis, the invasive trait variable showed a significant difference in aggressiveness. The significance of invasiveness could be seen through the assessment of grade 2a, which showed significant differences in aggressiveness compared to grade 1a in the Jang et al.29 study and similarly in the Raverot et al.17 study. Pituitary adenomas and other neoplastic diseases have long been assessed using this invasive technique. Based on Hardy and Knosp, pituitary adenoma is divided into two categories based on the level of invasion.32,33 In general, a higher level of invasion makes it more difficult for the surgeon to remove the mass completely, increasing the risk of the adenoma becoming aggressive.11 In 2004, WHO recommended the classification of atypical pituitary adenomas where it prioritizes proliferative properties over invasiveness in predicting pituitary adenomas' aggressiveness.18 Experts at the time were outraged, and this drew much criticism. The WHO abolished the atypical classification in 2017 after it was proven that many patients do not have proliferative traits but have an aggressive outcome.19,21
On the aggressiveness, the proliferative trait variable showed significance in the meta-analysis result. Because it requires a combination of two positives from three IHC tests (Ki-67, p53, and mitosis), each of these components is predicted to have a prognostic value for the aggressiveness of pituitary adenoma, this proliferative property has a fairly strong prognostic value.
The variable Ki-67 showed a significant meta-analysis result on the aggressiveness. This is also supported by the meta-analysis results of the mean aggressiveness difference, which shows a significant difference of 1.05 (0.87-1.22)% (Figure L4). No meta-analysis could be performed in the cohort study group; however, Jang et al.27 found that aggressiveness was associated with higher Ki-67 values. This procedure has long been used to diagnose endocrine tumors, particularly pituitary adenomas. Guadagno E et al.31 conducted a fairly large study on the significance of Ki-67 in pituitary adenomas, with mixed results. Ki-67 is one component in assessing the proliferative nature of pituitary adenoma, according to WHO guidelines, so it must be combined with other markers to provide a better prognostic value.18,19,21
In one of the three studies that looked at it, the variable of mitosis rate showed a significant difference in aggressiveness. Three studies with significant results on the aggressiveness were meta-analyzed.
In one of the four studies that looked at it, the p53 variable showed a significant difference in aggressiveness. A positive p53 was found to significantly impact the aggressiveness in the meta-analysis.
The variable of adenoma’s grade showed significant aggressiveness at grade 2b. The findings of a meta-analysis comparing grades 2b and 1a with significant differences in aggressiveness back this up (figure L5). Although no meta-analysis could be performed in a cohort study, Raverot et al.17 found aggressive aggression at grade 2b versus grade 1a. Trouillas et al.15 proposed this grade in their study evaluating prognostic factors for pituitary adenoma postoperative outcome. This grade is based on pituitary adenomas' invasive and proliferative nature, both of which have long been used to predict its’ prognosis. The higher the grade, the more positive prognostic factors there are, so this assessment becomes objective and means that the postoperative outcome is quite good.
Because it has been extensively studied in the selected literature, the postoperative residue is an additional component that is quite important in assessing the aggressiveness of postoperative pituitary adenomas. In studies that looked at the tendency to occur in adenomas with postoperative residues, this component showed significant differences in aggressiveness. This component is commonly used to assess postoperative outcomes in other organ malignancies. On patients where gross total resection cannot be performed, the unclean removal of the mass tissue will result in future recurrence. The meta-analysis found that aggressiveness was significantly increased in the presence of postoperative residues, with an OR of 2.86 (1.32-6.19). (Fig. L6).
The limitations include:
Wide range of study designs
The number of independent variables studied and research subjects.
The study's quality
Differences in definitions and variable data types resulted in a separated meta-analysis of each variable between studies with case-control and cohort designs.
The limited number of studies.
According to an assessment of case-control study quality, four studies had poor quality, and five studies had an unclear definition of control, indicating a selection bias possibility from the included studies. Meanwhile, the cohort study's quality assessment revealed a high dropout rate for no apparent reason, indicating the possibility of study outcome bias. The proliferative trait variable is one of the components of adenoma grade, where an anatomical pathology examination relies on the subjective assessment of anatomical pathologists—only one anatomical pathologist is examining in the studies, so the chance of assessment bias is there. Because pituitary adenoma has a low incidence, there may be unpublished studies. This publication bias could also be due to limited access to large databases like Embase.