Gastrointestinal stromal tumor (GIST) is a group of tumors of mesenchymal origin of the gastrointestinal tract, which belongs to soft tissue sarcoma. According to the statistics of western countries, the annual incidence of GIST is about 1-2/100,000, accounting for about 1/5 of all sarcomas, and has become the most common single type of sarcoma.
The reconceptualization of this disease is based on the discovery of its pathogenesis by Japanese scholars in 1998, which distinguished this rare tumor with relatively specific expression of KIT protein from many tumors of gastrointestinal mesenchymal origin for more than 15 years now. In recent years, with the increase in the number of cases seen and experience gained, it is not uncommon to find small GISTs that are asymptomatic or found incidentally during surgery.
Since 2006, several pathological studies have confirmed that gastric GISTs less than or equal to 1 cm in diameter are common in middle-aged and elderly people, with a detection rate of up to 3%-35%. This is significantly higher than the incidence of clinical GISTs. These small volume GISTs have attracted the attention of clinicians in recent years. In this paper, we discuss our views on the current understanding of small GIST.
I. Evolution of the concept and epidemiology of small GIST
How to define small GIST itself is controversial. Western scholars have long found that Cajal interstitial cell ofcajal (ICC) hyperplasia is prevalent in familial GIST or GIST-related syndromes including F-I neurofibromatosis and Carney’s triad, and these microscopically visible bands of continuous ICC proliferating cells are all GD117 positive.
As early as 1988, Japanese scholars found that the detection rate of microleiomyomas was 16.4% ( 46/286) by serial sectioning of gastrectomy specimens. Inspired by this, in 2006, Kawanowa et al. examined 100 total gastrectomy specimens for gastric cancer by serial sectioning at 5 mm intervals and found 50 microscopic GIST nodules in 35 cases (35%).
The authors called them “microscopic GISTs”. These GISTs had an average diameter of 1.5 ( 0.2-4.0) mm, 90% were located in the upper part of the stomach, were composed of spindle cells, no nuclear division was found, and were positive for CD117. In the same year, German pathologist Agaimy et al. found that the detection rate of CD117-positive “ICC hyperplastic” nodules in lower esophageal cancer specimens was 9.1% (7/77).
In 2007, Agaimy et al. also reported that gastric GIST nodules were more commonly detected by autopsy, at 22.5% (22/98), and these small nodules were detected by careful macroscopic examination and then confirmed by staining of sections. All nodules were located in the upper middle part of the stomach and were also spindle-shaped cells and CD117 positive. To distinguish these GIST nodules, the authors referred to those found by microscopic examination as “ICC hyperplasia” and those found by macroscopic examination as “GIST tumorlets” (GIST tumors).
These tumors have a KIT mutation rate of 46% and a PDGFRA rate of 4%. Immediately after, the Department of Pathology at the Mayo Clinic, in conjunction with the University of Pittsburgh and MD Anderson Cancer Center, re-examined 150 specimens of lower esophageal and combined esophagogastric cancers and confirmed that GIST tumorlets were common in 10% (15/150) of these specimens, with an average diameter of 1.3 (0.2-3.0) mm, all of which were spindle cells and stained positive for CD117 and CD34 staining positivity.
They described such microscopic GIST nodules as “seedling” as Takubo et al. described in 1981 for esophageal smooth muscle tumors less than 7 mm in shape (millet seeds), and equated it with “ICC hyperplasia” as described by Agaimy et al. “They further noted that these disseminated, isolated “seedling GISTs” are distinct from the generalized ICC hyperplasia that is continuous in a band with familial GISTs carrying germline mutations or GIST-related syndromes.
To further understand the distribution of small GISTs in other parts of the GI tract, in 2008, Agaimy et al. again reexamined pathological sections from nearly 7,000 colorectal resection specimens (an average of 5 hematoxylin-eosin stained slides with intrinsic muscle layer per case), including ileal tissue from right hemicolectomized specimens, and showed that the detection rate of microscopic GISTs from the distal ileum and colon was only approximately 0.1%. Therefore, Agaimy et al. abandoned the use of ICC hyperplasia in favor of MicroscopicGIST to define these incidentally detected microscopic GISTs.
In 2010, 170 small GISTs less than 2 cm in diameter were screened from 929 clinically resected primary GISTs at 35 pathology centers in Italy, including 115 in the stomach, 39 in the small intestine, and 10 in the colorectum, with a median size of 1.1 (0.2-2.0) cm. This study is one of the few retrospective studies with a large sample size and compared the clinicopathological characteristics of small GISTs less than or equal to 1 cm with those of 1-2 cm.
The authors referred to those less than or equal to 1 c.m. as “micro GIST” and those 1-2 cm as “milli GIST.” In 2011, Swiss pathologists used a method similar to that of Agaimy et al. In 2011, using a method similar to that of Agaimy et al, Swiss pathologists performed a careful macroscopic examination of 578 autopsy gastric specimens and identified 17 cases (2.9%) of tiny GISTs, which they called “Minute GISTs”.
These GISTs had an average diameter of 9.8(5-55) mm, except for one GIST of 5.5 cm, and the rest of the “Minute GISTs” were also spindle-shaped cells with benign microscopic morphological features of no nuclear anisotropy and nuclear division, and had a 64% (11/17) KIT mutation rate and a 6% (1/17) PDGFRA mutation rate. The mutation rate was 64% (11/17) for KIT and 6% (1/17) for PDGFRA.
The NCCN guidelines first suggested the management of small GISTs in 2010, referring to gastric GISTs smaller than 2 cm as “very smallGIST”. In the newly revised 2013 edition of the Chinese Expert Consensus, the definition of micro GIST is clearly defined for the first time (see pp. 393-398 in this issue), and it is proposed that GIST with a diameter less than or equal to 1 cm is called micro GIST. “is reasonable. The GIST less than 2 cm is collectively called “small GIST”.
II. Biological behavior of small GIST
Although the aforementioned pathologists from different countries have different methods for studying small GISTs, we found that almost all micro or small GISTs from the stomach are composed of spindle cells, with no nuclear anomalies or nuclear divisions microscopically, and are morphologically benign, whether from gastrointestinal cancer specimens or autopsy specimens, and whether by macroscopic examination, microscopic reexamination, or microscopic examination of whole specimens in serial sections.
Moreover, Agaimy et al. found that 49% of the postmortem gastric micro-GISTs had central atrophic calcification, and in some cases, simple atrophic calcified nodules were seen in the fundic tissue, and it is suspected that the latter evolved from the former, so it is assumed that the vast majority of such benign micro-GISTs will eventually regress and resolve. We already know that KIT and PDGFRA mutations are key events in the development of GIST.
Corle ss et al. in 2002 performed the first mutation testing for micro GISTs in order to investigate whether the mutational status of GISTs correlated with tumor progression and grade.Thirteen specimens were obtained from autopsy or incidental clinical findings with benign microscopic morphology (no nuclear anomalies or nuclear divisions);
The results showed that mutations in the KIT gene were detected in 84.7% (11/13). These studies suggest that KIT or PDGFRA mutations are key early events in the development of GIST, as in the case of colorectal adenomas caused by deletion of the APC gene: while the progression from subclinical micro-GIST to clinical lesions should have other unknown factors that may involve additional oncogene activation, oncogene inactivation or epigenetic alterations. In turn, the apparent tendency of micro-GIST to occur in the upper middle part of the stomach may involve other unknown factors both internally and externally.
Clinically, there are not many long-term follow-up studies focusing on small GISTs. A series of bulk case follow-up studies from the Armed Force Institute ofPathology (AFIP) has shown that the risk of recurrence varies among sites of primary limited GIST, as shown in Table 1.Miettinen et al. retrospectively analyzed 1765 gastric GISTs, of which 116 had GISTs less than or equal to 2 cm and nuclear fission images less than or equal to 5/50 HPF, none had recurrence or GIST-related death: 8 cases with GIST less than or equal to 2 cm and nuclear schizograms greater than 5/50 HPF also had no recurrence or death, but the number of cases was small and difficult to evaluate.
In a retrospective study of 906 jejunal GISTs, 69 patients with less than or equal to 2 cm and nuclear schizograms less than or equal to 5/50 HPF had no recurrence or death: while 2 patients with less than or equal to 2 cm and nuclear schizograms greater than 5/50 HPF had 1 death; therefore, the latter were classified as high risk, but the number of cases noted was low.
A retrospective analysis of 170 small GISTs from Italy found that the nuclear division index of all micro GISTs was extremely low, at 0.07_0.18/mm2 (equivalent to approximately 10 high-powered fields of view), while to small GISTs above 1 cm, the nuclear division index increased to 0.43 -1 .04/mm2, close to that reported in the group with a median diameter of 8 cm ( 0.56/ mm2).
Long-term follow-up revealed that only one 1.5 cm rectal GIST (nuclear schism >5/50 HPF) and one 2 cm small bowel GIST (nuclear schism 0) had recurrent metastases after surgery.
We have previously assumed that all GISTs are potentially malignant or malignant. It is likely that this subclinical portion of small GISTs was overlooked. the 2013 edition of the NCCN guidelines first cited the AFIP risk assessment classification (consistent with the data in Table 1) to evaluate the risk of recurrence after surgery for primary limited GISTs in the stomach and small intestine separately, and proposed for the first time that small GISTs of less than 2 cm in the stomach and small intestine with nuclear schizograms less than or equal to 5/50 HPF are all benign GISTs.
And our 2013 edition of GIST consensus followed suit, with the pathology section citing the WHO definition of GIST covering benign to malignant, while adding AFIP risk assessment as a reference (see pp. 393-398 in this issue). From the available literature, we can easily find that there are more reports and a good number of cases of small GIST in the stomach found incidentally; however, there are fewer data on follow-up of small GIST in other sites.
From the limited data available, we can conclude that for small GIST of the stomach, if the nuclear splitting image is less than or equal to 5/50 HPF can be considered benign with no risk of postoperative recurrence: while those with nuclear splitting image greater than 5/50 HPF are insufficient to evaluate the risk of malignancy due to the small number of cases. For small GIST in the small intestine and rectum, despite the small number of cases, nuclear schizograms less than or equal to 5/50 HPF also have a low risk of recurrence; while those with nuclear schizograms greater than 5/50 HPF, despite the small number of cases, have a clear case record of recurrence and should be regarded as a high risk of recurrence.
III. Clinical disposition of small GIST
The above study by Agaimy et al. confirms our usual clinical observation that small GISTs in the stomach are significantly more common than those in the intestine, and the NCCN proposed a separate disposition for gastric GISTs smaller than 2 cm in 2010. Our 2013 edition consensus is also basically similar to its disposition: ultrasound gastroscopy should be performed for these proposed small GISTs, and surgical resection should be considered if combined with adverse factors of endoscopic ultrasound (irregular margins, ulceration, strong echogenicity and heterogeneity).
Otherwise, ultrasound endoscopy may be repeated at 6-12 month intervals and surgery may be withheld (see pp. 393-398 of this issue). In conjunction with the preceding, the vast majority of small gastric GISTs have a non-invasive morphology microscopically and exhibit self-limiting growth in their biological behavior. It should be safe and reasonable to resect only those small GISTs that present with adverse factors on endoscopic ultrasound that suggest more active growth, while the majority of the rest are followed up for observation.
Most small gastric GISTs may be lifelong or degenerate on their own with atrophy and do not require aggressive surgical intervention. In contrast, for small GISTs in the small intestine or colorectum to be diagnosed, the author believes that they should be aggressively surgically resected. However, our knowledge of small GISTs at these sites is still limited, except for the small number of cases and the fact that many previously reported small GISTs at the small bowel site were found incidentally during surgery for abdominal malignancies, and patients often died of other tumors without a true understanding of the malignant risk of these small GISTs.
Moreover, small GIST resection in the small intestine has a history of recurrent metastases, regardless of the number of nuclear split images. Therefore, a more aggressive early surgical treatment is favored for small GISTs at these sites. In contrast, for incidental intraoperative findings of suspicious small GISTs, they should be resected whenever possible, regardless of the site.
Local excision is the main surgical modality for small GIST, but the specific procedure should be decided according to the tumor site and growth pattern. The surgical principle remains to ensure complete resection of the tumor and negative margins. Regardless of whether laparoscopic surgery is applied, endogenous small GIST of the stomach can be endoscopically localized preoperatively or intraoperatively for accurate resection. In recent years, there has been a lively discussion on the endoscopic treatment of small GIST of the stomach in China.
Theoretically, GIST differs from gastric cancer in that its tissue originates from the intrinsic muscular layer, and it is difficult to ensure negative margins with general endoscopic resection, and there is a risk of perforation if resection is too deep. In China, Yao Liqing et al. have made a lot of exploration and attempts to endoscopic and bimicroscopic resection of GIST in the gastric and esophagogastric junction.
Regardless of whether endoscopic, laparoscopic, combined bimicroscopic or conventional open surgery is used, the basic requirement for the surgical treatment of GIST is to ensure surgical safety while meeting the principles of surgical resection of GIST. Given the lack of long-term follow-up data on endoscopic treatment of GIST, our consensus suggests that this technique should be limited to exploratory treatment and research in experienced endoscopic centers and is not routinely recommended.
In summary, we still have little understanding in the face of small GIST, a special subclass of GIST, and the clinical disposition is still controversial. It is believed that the keen interest in small GIST in China is bound to bring about new research findings that will help to understand the occurrence of small GIST at different sites in our population and eventually solve the mystery of the specific process of how micro GIST develops into a clinical lesion.