Even though GG patients have the best prognosis among all GIST patients, nearly 30% of GG cases eventually relapse or metastasize after curative resection of the primary tumor.22 The most important recurrence factors are tumor size, tumor rupture and mitotic rate per 50 high-power fields. For example, the recurrence rate is 0% for GG patients with lesions ≤ 2 cm.23 Generally, a smaller GG often means a lower mitotic rate, a lower chance of rupture, a higher chance of receiving less invasive surgery and a better prognosis with TKI therapy.24 Early detection has been proven to improve the treatment outcomes of GG in Japan.19 However, there is still a lack of a reliable noninvasive GG detection method. The reason may be that there are no specific symptoms or GG secreting factors. In fact, 48% of GG patients in our study were asymptomatic. Based on our Positive-Gastric-GIST-PG criterion, the serum PG test showed high sensitivities in both asymptomatic GG patients (63%) and small GG patients (14 out of 17 patients with lesions ≤ 2 cm). The benefit of detecting GGs ≤ 2 cm is still unclear. However, 11·4% of GISTs < 2 cm were metastatic (regional/distant).25 Guidelines recommend different strategies for GG lesions < 2 cm. The National Comprehensive Cancer Network recommended conservative follow-up for GGs < 2 cm without high-risk features. The European Society for Medical Oncology and Japanese guidelines recommend resection for all GISTs < 2 cm. However, studies found that some GGs < 2 cm would enlarge after years of follow-up.26,27
Some medicines, such as PPIs and NSAIDs, and diseases (gastric ulcer, non-AG, Hp. infection) would increase the PG level. To minimize the drug impact on PG level, we excluded patients who received PPIs, NSAIDs, Hp. eradication therapy or TCM. Because most GG patients with GI bleeding received PPIs as first-aid medicine, only 1 patient with GI bleeding was included in our study. In fact, we also analyzed the impact of PPIs on the PG level of GG patients (data not shown). Only 2/11 and 3/16 patients fulfilled the Positive-Gastric-GIST-PG criterion among patients who received PPIs within 24 h and 2 weeks before the PG test, respectively. In clinical practice, PGI ≤ 70 ng/ml plus PGI/PGII < 3 are the most widely accepted values used in AG screening. The lower the PGI and PGI/PGII values are, the more severe the gastric atrophy. Therefore, our criteria can effectively discriminate GG from both AG and GC. As subjects routinely undergo endoscopy examination after PG levels suggest AG in health checkups, limited data about the PG level of endoscopically normal subjects were reported. One study conducted at an area of high incidence GC in China showed that only 1 out of 30 endoscopically normal subjects had PGI ≤ 70ng/ml.28 These data indicate that our criteria can efficiently distinguish GG from endoscopically normal subjects.
The PG reduction in the Positive-Gastric-GIST-PG criterion is a result of local gastric atrophy. One-time PG test may not efficiently distinguish GG from other diseases of local atrophy, such as early GC and AG. A Japanese study identified 27 previously Hp. infected patients in 271 patients with gastric neoplasms (early GC and adenoma). All 27 patients had endoscopic atrophy in the gastric corpus. Twenty-four out of the 27 patients fulfilled our Positive-Gastric-GIST-PG criterion.29 Considering that the true incidence of GG may be as high as 35% and early gastric neoplasms were undetectable, it is not surprising that another Japanese study found that 42·6% of asymptomatic middle-aged males with high-cancer risk fulfilled our Positive-Gastric-GIST-PG criterion.29 However, following the Correa cascade, PG levels will stepwise reduce in the process from AG to GC. Based on the finding that the sensitivity of Positive-Gastric-GIST-PG decreased from stage Ⅰ to stage Ⅳ (from 38–11%) in the subgroup analysis of GC and that neither PGⅠ level nor PGⅠ/Ⅱ differences were detected in different tumor size GG subgroups, periodic PG testing will help to discriminate GG from early AG and GC.
Based on the 22 per million prevalence of GISTs worldwide, the prevalence of clinically relevant GG should be 13·2 per million in the case of 60% of GISTs located in the stomach. According to Bayes' Theorem, the PPV and NPV were 0·0030799% and 99·9994429% with 70% sensitivity and 70% specificity. In fact, the actual incidence of all kinds of GGs is much higher than that. Three studies have reported that the incidence was 2·9%-35% for GGs ≤ 1 cm.12–14 The incidence was 9·54% (74/776) when we summarized the data of the three studies. The PPV and NPV were 19·75% and 95·68%, respectively. If subjects were double positive, the PPV and NPV would change to 36·47% and 90·46%, respectively.
The baseline characteristics were not balanced between the two groups. However, our study samples represented most patients. In the real world, the prevalence of GC in male patients is 2·38 times that of female patients in China. GG was also slightly predominant in females. GC is more antrum involved and metastatic, while GG seldom metastasizes and rarely occurs in the antrum. The PG test is a noninvasive, repeatable, ray-free, economical and highly acceptable method. Future studies can focus on its role as a biomarker to evaluate the effect of therapy and postoperative surveillance. Small GGs are often negative on CT scans and endoscopy. Endoscopic ultrasonography can be considered when subjects meet the Positive-Gastric-GIST-PG criteria twice, especially for subjects with high GG risk, such as those with familial GISTs and those with succinate dehydrogenase complex dysfunction.
There were some limitations in our study. The first limitation was its retrospective nature. The second limitation was that our study may still be influenced by selection bias, even though only 62 patients lost follow-up in the 199 followed GG patient. The third limitation of our results was that the PG tests were based on Abbot testing kits. Whether the criteria could be used with other manufacturer testing kits requires further study. A former study showed that the serum PG values using Japanese kits (LZ-test EIKEN; Eiken Chemical Co., Tokyo, Japan) were lower than those using the GastroPanel examination (Biohit Plc., Helsinki, Finland).30 The fourth limitation was that we did not evaluate the atrophy status of all included GG patients because some slides were unavailable and some resection specimens did not have proffer adjacent mucosa. Despite these limitations, our study offered a new strategy for GG detection and deserved further prospective study. Furthermore, because PG has been applied for AG detection for decades, the PG > 70ng/ml is a standard for healthy cases, we did not think it was a definitely requirement to compare GG with healthy cases.
In summary, our study identified local gland atrophy surrounding the mucosa as a characteristic feature of most GGs. Positive-Gastric-GIST-PG-CEA can effectively distinguish the most common gastric stromal tumor (GG) from the most common GC. The criteria showed high sensitivities in all GG subgroups. Integrating our criteria into the current PG test scheme of gastric precancerous screening will be helpful for the early detection of GG without additional expense. Actually, the age at diagnosis of more than 90% of GG patients is older than 40 years, which is also the age of subjects suitable for Japanese government-sponsored AG screening by PG.