In our study, we aimed to elucidate the relationship between KI-67 expression and the progression of pituitary neuroendocrine tumors (PitNETs). Our findings reveal the unreliability of KI-67 as a progression marker, as well as the variability in different lineages with different clinical types.
The correlation between KI-67 and tumor progression has garnered significant attention from researchers in recent years. While a study from 2010[30] cast doubt on the predictive power of KI-67 in assessing tumor progression, it is noteworthy that such systematic reviews might be prone to selection and information biases. A later study in 2017[31]observed a correlation between KI-67 expression on intraoperative cytology smears and pituitary tumor invasiveness, albeit with a limited sample size. More recently, a 2019 study[32] utilized a sufficient sample volume to conclude that the predictive value of KI-67 and p53 in indicating tumor invasiveness and recurrence was not statistically significant. However, due to its timing, this study did not incorporate the currently popular transcription factor lineage classifications into its discussion. Drawing from these previous studies, we have undertaken a comprehensive effort to gather samples since the implementation of cell lineage classification in our center. We have systematically followed up with patients to gain a deeper understanding of the relationship between KI-67 and tumor progression, aiming to address some limitations of previous research.
Our study found no significant differences in preoperative tumor characteristics or postoperative prognostic outcomes among patients with high or low KI-67 expression levels. The study performed immunohistochemical staining of invasive and non-invasive pituitary tumor tissues, and again, no difference was observed between the two groups[33]. This is inconsistent with the conventional view of KI-67 expression as a reliable predictor of tumor progression in PitNETs, i.e., that high KI-67 expression is associated with larger tumor volume, higher recurrence rate, and poorer prognosis.[31, 34–36]. The 3% threshold labeling index of KI-67 for pituitary tumors has been widely used since a 1996 study suggested that it could help to differentiate invasive from noninvasive adenomas[37], but our study found that the reliability of the 3% threshold labeling index of KI-67 to differentiate between the two was poor. Our study suggests that tumor hyperproliferation represented by high KI-67 expression may not be the main cause of PitNETs infiltration of the cavernous sinus and surrounding structures. Some scholars believe that a class of high-invasive but low-proliferative tumor cells exists in tumors to evade surgical resection as well as radiotherapy and cause recurrence[38]. Our study also suggests that tumor hyperproliferation represented by high KI-67 expression may not be the main cause of infiltration of PitNETs into the cavernous sinus and its surrounding structures.
Contrary to the widely held view that high KI-67 expression is associated with tumor infiltration and poor prognosis in all types of PitNETs, our study suggests a more subtle relationship. While we observed a significant association between high KI-67 expression and the infiltrability of T-PIT lineage PitNETs, no such association was found in PIT-1 and SF-1 lineage tumors. Furthermore, no such association was identified between the various types of PitNETs classified according to their clinical manifestations. In this 2017 study, researchers found that ACTH-secreting adenomas had higher KI-67 expression than other types of PitNETs[31]. In addition, in a pan-genomic study, researchers found that pituitary tumors of different genotypes in the same lineage had different invasive abilities[39]. This highlights the heterogeneity of PitNETs and emphasizes the importance of considering tumor subtypes when evaluating prognostic indicators such as KI-67.
Our study has several important implications for clinical practice and future research. First, our findings highlight the need for more comprehensive prognostication in patients with PitNETs, taking into account tumor subtype, molecular features, and other clinicopathological factors. Second, our study highlights the need for further research to identify novel progression markers and therapeutic targets for PitNETs, especially the need to take into account different lineage classifications when searching for markers versus therapeutic targets.
However, some limitations must be recognized. The relatively short follow-up period may limit the assessment of long-term outcomes. There are no standardized rules for defining criteria for invasive PitNETs. In addition, the study was conducted in a single center, which may limit the generalizability of the results.
In conclusion, this study offers a deeper comprehension of the intricate biology of PitNETs, broadening our understanding of the prognostic implications of KI-67 expression beyond conventional perspectives. Reliable markers that reflect the progression of PitNETs are urgently needed[40] and to elucidate the underlying mechanisms that drive tumor infiltration and treatment response in patients with PitNETs.