Evaluation of high-risk clinicopathological indicators in gastrointestinal stromal tumors for prognosis and imatinib treatment outcome

Gastrointestinal stromal tumor (GIST) accounts for more than 80% of all gastrointestinal mesenchymal tumors [1]. As it ranks below only gastric and colorectal cancers, GIST is among the most common types of gastrointestinal tumors. Recently, the incidence of GIST has gradually increased [2‐4] and there are more than 5000 newly diagnosed cases each year since 2011 in the United States [5].

Modified NIH criteria based on NIH consensus criteria is wildly accepted as risk-stratification scheme for GIST and four categories from very low to high risk are used to predict prognosis of GIST patients. The mitosis count, tumor size, tumor site and tumor rupture are important prognostic predictors in this scheme [6, 7]. However, the clinical behaviors and the outcomes of GIST still vary even in the same group of the risk, especially in the patients with high-risk of recurrence. With wide application of imatinib mesylate (IM) in clinical practice for GIST, the mortality rate of GIST patients has decreased significantly [8]. Nevertheless, the recurrence and metastasis rates, especially for the patients at high-risk stage, remain high [8‐10].

Because unclear biological behaviors and high recurrence rates in high-risk GIST patients, some of them suffer worse prognosis than others even they are classified into the same category with the same treatment. To more precisely predict prognosis and possible association with efficiency of imatinib adjuvant therapy for high-risk GIST patients, we tried to sub-divide high-risk GIST patients with some “very high-risk” factors, such as primary sites not from stomach, tumor size > 10 cm, mitosis count > 10/50HPF and serosal invasion, a common pathological diagnosis in malignant tumors. Related recurrence-free survivals (RFS) were analyzed in test and validation cohort.

GIST has a wide various biological behaviors with malignant potential, so it can not be precisely distinguished as benign or malignant lesions. Mitotic index, tumor size, tumor site and tumor rupture which are from modified NIH criteria can be important prognostic predictors of GISTs [6, 7, 11]. According to the NIH guidelines, all GISTs might have malignant potential. Moreover the recurrence risk in high-risk cases was significantly higher than that in intermediate-, low- and very low-risk cases, and even in the same high-risk classification, the clinical outcomes of GIST patients are always variety in our approximate 10 years’ follow-up database [12, 13]. For example, patients with GIST invading local tissue or organ even if receiving R0 resection always appear poor prognosis. On the contrary, some cases with large tumor size but less mitosis count and tumor well-encapsulated are no sign of recurrence for a long time follow up (>5 years) without imatinib adjuvant therapy. As we all know, there is no perfect criteria which can predict the prognosis of the disease with 100% accuracy, and there must be some unrevealed room for improving or complementing the current criteria.

The aim of this study is to find “very high-risk” factors which can effectively sub-divide high-risk patients after R0 resection for more precisely predicting prognosis. Because our purpose was for clinical application, the factors we chose must be easily understandable, well-accepted and feasible variables. Primary sites not from stomach, tumor size > 10 cm and mitosis count > 10/50HPF were selected by referring to modified NIH criteria [7], serosal invasion was also selected in our study as a common pathological diagnosis in malignant tumors.

Tumor rupture is a poor prognostic factor indicated by modified NIH criteria. Tumor rupture are divided into two clinical conditions, one is spontaneous tumor rupture prior to operation, and another is a result of the manipulation at surgery [14, 15]. Tumor rupture was not enrolled in our study because insufficient data in our clinical records. This situation was common in other centers as in Joensuu et al.’s multi-center research in which data of tumor rupture were unavailable from 53.2% cases in pooled population-based cohort and 100% cases in validation [11]. Actually most patients with spontaneous tumor rupture before surgery frequently found having already accompanied with miliary nodules as implantation metastasis and impossible for R0 resection were excluded in our study. Another condition, if iatrogenic tumor rupture, mainly depends on surgeon’s subjective judgment and active reporting. Serosal invasion is a common pathological diagnosis in malignant tumors but few mentioned in GIST before [16], the merits of serosal invasion we selected in this study were less interference with subjective factors and surgical matters compared with tumor rupture, easily observed in surgery and feasibly confirmed by pathological diagnosis. But considering serosal invasion is not a standard prognostic factor in GIST enrolled in the guidelines yet, it mostly depends on detection and reporting by pathologists. Mitosis count is also a strong prognostic factor in GIST and enrolled in NIH criteria, but it still has limitations and its reliability is controversial. Identification of mitoses should be subjective, and the number detected depends on the tissue fixation time and the magnification of the field under the microscope [11].

Through univariate and multivariate analyses of the factors associated with RFS in test and validation cohort with GIST, mitosis count > 10/50HPF and serosal invasion were confirmed as the independent prognostic factors for the RFS. The Kaplan-Meier survival analysis with log-rank test showed sub-dividing high-risk GIST patients by mitosis count > 10/50HPF and serosal invasion yielded significantly different outcomes and more effectively differentiated the groups of GIST patients.

We further focused on whether mitosis count > 10/50HPF or serosal invasion could affect efficiency of imatinib adjuvant therapy. The results showed that GIST patients with serosal invasion might suffer a poorer prognosis with imatinib therapy, but there was no difference between patients with mitosis count > 10 and mitosis count ≤ 10/50HPF in the RFS. Because of the limitation of the sample numbers and follow-up time in our study, it still needs more works to verify this result, but the high-risk GIST patients with serosal invasion should be noticed in clinical follow-up because of higher possibility in recurrence even with imatinib adjuvant therapy.

How to improve outcomes of GIST patients with serosal invasion even after R0 resection is still a serious problem. Should this kind of patients need more than 3-year imatinib therapy? The real benefits and optimal time to stop treatment still need further study and it still remains the possibility of recurrence after stopping taking the drugs. Neoadjuvant imatinib therapy, which has been recommended by current ESMO and NCCN guidelines for locally advanced GIST [17, 18], may help to improve the outcomes of GIST patients with serosal invasion. Neoadjuvant imatinib therapy can shrink the size of locally advanced GISTs and increase R0 resection rate, which significantly prolong the RFS and OS comparing with the inoperable patients or patients with palliative operation [19‐23]. But there are still some problems that need to be solved in future study: first, how to verify serosal invasion of GISTs before surgery? Serosal or subserosal invasion are as superficial infiltration different from typical locally advanced GIST which can be judged by CT or MRI easily. It is hard for imaging examination to distinguish the real invasion or tumor just leaning against adjacent organs or tissues; for effective neoadjuvant therapy, aspiration biopsy is necessary for not only diagnosis but also gene mutation detection for KIT and PDGFR, but conducting biopsies in such highly malignant GIST may increase the risks of tumor rupture or implantation metastasis.

In this study, we analyzed several “very high-risk” factors in high-risk group of GIST patients after R0 resection. Serosal invasion appears to improve the modified NIH criteria and predicts an unfavorable outcome in high-risk GIST patients, with or without imatinib treatment. Our study demonstrated the possibility of personalized medical strategy for different GISTs by sub-dividing high-risk patients.