Superiority of mucosal incision-assisted biopsy over ultrasound-guided fine needle aspiration biopsy to diagnose small gastric subepithelial lesions:A propencity score matching analysis

Abstract

Background

Gastric subepithelial lesions (SELs) are often found incidentally during routine gastroscopy, and such lesions are reportedly found in approximately 0.4%–3% of patients who undergo the procedure [1] [2] [3]. Gastrointestinal stromal tumors (GISTs) and leiomyomas are the most common types of gastric SELs. Because GISTs have malignant potential, even small gastric SELs should not be dismissed. Many guidelines recommend the histological evaluation of gastric SELs ≥ 20 mm in size [4] [5] [6]; however, we sometimes encounter gastric SELs < 20-mm diameter with the tendency to grow. While endoscopic ultrasound-guided fine-needle aspiration biopsy (EUS-FNAB) is considered the gold standard for histologically evaluating gastric SELs, with small SELs, it is sometimes difficult to obtain samples large enough for histological analysis, even when using more recently-developed FNAB needles or newly developed forward-viewing endoscopes. Indeed, while 83–100% of EUS-FNAB samples were reportedly adequate for cytological evaluations, only 50–83% of such samples were accepted for further histological evaluation [7] [8]. If FNAB does not provide adequate samples or EUS systems are not available, it is very difficult to diagnose SELs, histologically.

“Open biopsy” of SELs can be performed by partially removing the covering mucosa and exposing the lesion. Devices developed for endoscopic surgery to treat superficial gastrointestinal neoplasms can be used for such procedures. Earlier studies reported the usefulness of electric snares developed for endoscopic mucosal resection or EUS-guided heat-probe resection for the “unroofing” process to expose SELs [8]. Following the development of endoscopic submucosal dissection, which has advantages over endoscopic mucosal resection when resecting large superficial lesions en bloc, endoscopic submucosal dissection knives are increasingly used to perform open biopsies of SELs [9] [10] [11]. We named this biopsy technique, which was originally reported by Lee et al., [11] but which did not have a specific name, mucosal incision-assisted biopsy (MIAB) [12]. In our previous study, we evaluated the usefulness of MIAB to diagnose gastric SELs and showed that MIAB was useful for SELs with intraluminal, but not extraluminal, growth patterns. Our more recent study[13] suggested a comparable usefulness of MIAB and EUS-FNAB for the diagnosis of SELs; however, the number of patients enrolled (23 patients in MIAB group) was small and was not enough to evaluate the efficacy of MIAB for SELs based on the lesion size. Thus, in the current study, we collected medical records of larger number of SEL cases with intraluminal growth pattern and compared the usefulness, diagnostic yield, procedural time, and associated adverse events, of MIAB vs. EUS-FNAB.

Methods

Patients

This was a retrospective comparative analysis of MIAB and EUS-FNAB using data for patients with gastric SELs with intraluminal growth patterns, who underwent either MIAB or EUS-FNAB at five hospitals in Japan (Kyushu University Hospital, Kyushu Medical Center, Harasanshin Hospital, Kyushu Rosai Hospital, and Kitakyushu Municipal Medical Center) between January 2010 and January 2018. No patients who met the above criteria were excluded from the study. The study population included 177 consecutive patients (men, n = 87; women, n = 90). The decision to use MIAB or EUS-FNAB was left to the primary physician for each patient. As a result, 71 patients underwent MIAB, and 106 patients underwent FNAB. In patients undergoing FNAB, 69 patients underwent endoscopic ultrasound-guided fine-needle aspiration (FNA), and 37 patients underwent endoscopic ultrasound-guided fine-needle biopsy (FNB).

The intraluminal growth patterns of the SELs was confirmed by preoperative gastroscopy and EUS, and SEL size was measured on the EUS images. Written informed consent for these procedure was obtained from all patients. This study was approved by the ethics committees of all five hospitals.

MIAB and EUS-FNAB procedures

For MIAB, to lift the mucosa covering the SEL and to create a safer incision, normal saline or glycerol supplemented with diluted epinephrine was injected into the submucosal layer above the lesion. The target mucosal and submucosal tissues were incised with an endoscopic submucosal dissection knife (Needle knife, Olympus, Tokyo, Japan; Flush knife, Fuji Film, Tokyo, Japan) using electrosurgical current generated by a high-frequency power supply (ICC or VIO300D; ERBE, Tubingen, Germany). After exposing the lesion, tissue samples were obtained by biopsy forceps (Radial jaw, Boston Scientific, Natick, MA, USA). Approximately 3–7 biopsy samples were obtained from each lesion.

For EUS-FNAB, 19- to 25-gauge FNAB needles (SonoTip, Mediglobe GmbH, Rosenheim, Germany; Expect, Boston Scientific; Echo-Tip Procore, Cook Medical, Tokyo, Japan; Acquire, Boston Scientific) were used to obtain SEL samples through the mucosa under the guidance of oblique-view EUS imaging (GF-UCT 260, Olympus). All EUS-FNAB procedures were performed using rapid on-site evaluation by pathologists. A 19-G needle was used in 10 patients, 22-G needle in 74 patients, and 25-G needle in 22 patients.

Procedures were repeated a maximum of six times until samples containing spindle cells were obtained, which indicated that the needle had penetrated the SEL. Those multiple attempts were performed without waiting for the on-site evaluations by pathologists, to minimize the procedural time.

All samples in both groups were evaluated histologically by pathologists. All patients were monitored daily for symptoms and signs of hematomesis and hematochezia. Major bleeding was defined as a ≥ 2 g/dl drop in blood hemoglobin.

Comparison between MIAB and EUS-FNAB

We compared three aspects of MIAB and EUS-FNAB: diagnostic yield, procedural time, and adverse event rate. The procedural time was defined as the time from the start to finish of the biopsy procedures. The data were collected from the operational records of patients.

Statistical analysis

All statistical analyses were performed using the JMP software program version 13.0 (SAS Institute, Cary, NC, USA). Comparisons between MIAB and EUS-FNAB were performed before and after propensity-score matching of the lesion sizes in the two groups (Fig. 1). The chi-squared test or Fisher’s exact test were used to compare the categorical data (patients’ characteristics, lesion locations, and histology types). Student’s t-test was used to compare continuous data (age, lesion size, and procedural time) before propensity-score matching. We used a multivariate logistic regression analysis to evaluate the relationship between the diagnostic yield and lesion size. After propensity-score matching, Student’s paired t-test was used to compare continuous data in the two groups. P < 0.05 indicated statistical significance, for all tests.

To estimate propensity scores, lesion sizes (mm) were entered as independent variables into a multivariate logistic regression model. This model yielded an area under the receiver operating characteristic curve score of 0.67. Once the propensity scores were estimated, we matched patients in the two groups by setting calipers, using the stringency scores in the JMP software program, at a width equal to a distance of 0.2 from the standard deviation of the logit of the propensity score, without replacement. The effect of matching was evaluated in terms of the absolute standardized difference.

Results

Comparisons between MIAB and EUS-FNAB

A total of 177 SELs from 177 consecutive patients were included in this study. The characteristics of the patients and lesions in both groups are summarized in Table 1. There were no significant differences between the groups for sex, age, lesion size, lesion location, or histological type. No procedure-related adverse events, including late-onset bleeding after discharge from hospital, major bleeding, or gastric perforation, occurred in either group. The success rate of tissue sampling was 95.6% with MIAB and 86.8% with EUS-FNAB. For SELs ≥ 20-mm diameter, the success rate of sampling was 96.1% with MIAB and 90.0% with EUS-FNAB (Table 3). However, for SELs smaller than 20-mm diameter, the success rate was 97.8% with MIAB and 85.7% with EUS-FNAB (Table 4).

The total diagnostic yield using MIAB was significantly higher than that for EUS-FNAB (94.3% vs. 79.3%, respectively; P = 0.013). For SELs ≥ 20-mm diameter, the diagnostic yield with MIAB was comparable with EUS-FNAB (92.3% vs. 88.0%, respectively; P = 0.56) (Table 3). For SELs < 20-mm diameter, the diagnostic yield with MIAB was significantly higher than with EUS-FNAB (97.8% vs. 85.7%, respectively; P = 0.34) (Table 4). However, MIAB took significantly longer to perform than EUS-FNAB (31.5 min vs. 21 min, respectively; P< 0.0001).. Among the SELs successfully diagnosed by either MIAB or EUS-FNAB, 69 lesions were surgically resected, and all were confirmed GISTs.

The effects of SEL size and location on the diagnostic yields of EUS-FNAB and MIAB

As shown in Table 2, the diagnostic yield with EUS-FNAB for SELs < 20-mm diameter was significantly lower compared with SELs ≥ 20-mm diameter (88.0% vs 71.4%, respectively; P = 0.048). The diagnostic yield with MIAB, on the other hand, was not affected by lesion size (92.3% vs 93.3%, < 20-mm vs ≥ 20-mm diameter, respectively; P = 0.51). The diagnostic yields for samples from the upper/middle/lower parts of the stomach were 92.5%/88.9%/100% with MIAB and 84.5%/76.9%/57.1% with EUS-FNAB, respectively. SEL location did not affect the diagnostic yield with either procedure (P = 0.48 with MIAB and P = 0.067 with EUS-FNAB).

Comparison of MIAB and EUS-FNAB after propensity-score matching

Because the initial analyses suggested the superiority of MIAB over EUS-FNAB, especially to diagnose SELs < 20-mm diameter, we divided the SELs into two groups (≥ 20-mm and < 20-mm diameter), and compared MIAB and EUS-FNAB using propensity-score matching of the lesion sizes between the two groups (Fig. 1, Table 3 and 4). As shown in Table 3 and 4, procedural times for MIAB and EUS-FNAB for SELs ≥ 20-mm diameter were 32 min and 20.5 min, respectively. Procedural times for MIAB and EUS-FNAB for SELs < 20-mm diameter were 31 min and 20 min, respectively. MIAB took significantly longer to perform (on average, 12–14 minutes longer) than EUS-FNAB, regardless of the lesion size. For SELs ≥ 20-mm diameter, the success of obtaining a histological diagnosis and the diagnostic yields with the two procedures did not differ significantly (P = 0.55) (Table 3). However, for SELs smaller than 20-mm diameter, MIAB yielded a significantly higher successful diagnosis rate than with EUS-FNAB (93.5% vs. 61.2%, respectively; P = 0.011) (Table 4).

Discussion

GISTs are one of the most frequently-found SELs with malignant potential, and their malignant potential increases with tumor growth. To obtain FNAB samples of gastric SELs, EUS is required, and EUS-FNAB is the gold standard for diagnosing gastric SELs. To diagnose GISTs, immunohistochemical staining for several antigens, such as c-Kit, DOG1, and S–100, is also necessary [4] [14] [15] [16] [17]. Obtaining samples large enough to perform several immunohistochemical evaluations, using EUS-FNAB, is sometimes very difficult, especially when the lesion is small [18]. This leads to failure in making a diagnosis despite time-consuming procedures and on-site evaluations by pathologists. The designs of aspiration needles have been modified to collect larger biopsy samples, and the so-called fine needle biopsy (FNB) needles have been developed. Although the superiority of FNB needles over conventional FNA needles for the diagnosis of pancreatic lesions have been reported, their usefulness for the diagnosis of gastric SELs is controversial[19–21]. The reported diagnostic yield of EUS-FNAB for small gastric SELs is 62%–82% [18] [22]. Furthermore, metastasis or invasion of GISTs < 20 mm in size is considered very rare [23] [24]. With these considerations, omitting biopsies for SELs < 20-mm diameter is clinically accepted, although follow-up gastroscopy is recommended every 6–12 months [4] [5]. However, we encountered a patient with a metastatic GIST of approximately 15 mm in size [25]. Many guidelines also recommend surgically resecting GISTs, regardless of the lesion size, despite the fact that the guidelines neither encourage nor discourage biopsies for small SELs. To minimize the risk of losing the chance for successful treatment, earlier histological evaluation should always be considered. Options to obtain SEL samples without FNAB are also needed, considering possible diagnostic failure following FNAB or situations where EUS systems are unavailable.

In the current study, we showed the superiority of MIAB over EUS-FNAB to diagnose gastric SELs < 20-mm diameter. Recently it has been reported that there is no significant difference in the diagnostic ability between FNA needle and FNB needle for small SELs, though FNB needle requires small number of the puncture session[19]. Thus we classified the FNA cases and FNB cases in the same group and compared superiority of MIAB for the small SELs with them.

As limitations, this study had a retrospective design, our findings must be confirmed in a prospective randomized trial; however, our data provide reasonable support for open biopsy as an option to obtain samples from gastric SELs. MIAB does not require EUS. Furthermore, MIAB does not require on-site evaluation by a pathologist, and whether the operator obtains a sufficient sample for histological evaluation is evident immediately, using MIAB.

Our findings are partially inconsistent with a previous study that reported comparable diagnostic yields with MIAB and EUS-FNAB for gastric SELs [9]. However, the previous study did not classify the lesions into small and large groups; MIAB is especially useful for obtaining samples from small SELs.

Our study also revealed that MIAB, as well as EUS-FNAB, is a very safe technique. No major or minor adverse events were reported in our hospitals. Although MIAB uses skills and devices developed for endoscopic submucosal dissection, the adverse event rate following MIAB was much lower than with those reported for endoscopic submucosal dissection. The incidence of bleeding in patients undergoing endoscopic submucosal dissection for gastric mucosal tumors is reportedly 2%–15% [26] [27] [28] [29] [30] [31]. The lower rate with MIAB is likely because MIAB requires only a partial incision into the normal mucosa covering the SEL, while endoscopic submucosal dissection resects an entire tumor of epithelial origin (i.e., adenoma or adenocarcinoma). Such epithelial tumors are usually fed by thick vessels from the submucosal layer, and endoscopic submucosal dissection requires transecting those vessels, which could lead to major or late-onset bleeding. Our data suggest that MIAB is a safe and reliable approach; however, one concern about MIAB is that it exposes tumor cells. Tumor cells are usually encapsulated by fibrous tissue in GISTs, and MIAB disrupts the pseudocapsule. EUS-FNAB also pierces the pseudocapsule, but the area that is disrupted (a pinhole) is much smaller than that with MIAB. Thus, in MIAB, more cells could be released into the gastric lumen from the biopsied area. It would be unlikely that the freed tumor cells would attach to and grow on other parts of the gastrointestinal tract; however, when the stomach is perforated during an inadequate procedure and gastric contents are released into the abdominal cavity, the chances of tumor seeding may increase. Although we have not experienced MIAB-associated perforation or tumor seeding, great care should be taken regarding this point.

Conclusions

In conclusion, although MIAB takes approximately 13 min longer to perform than EUS-FNAB, MIAB provides significantly better diagnostic yields for gastric SELs smaller than 20-mm diameter with intraluminal growth, regardless of the gastric location. MIAB could be a good option to diagnose small gastric SELs. In our study, diagnostic yields with MIAB and EUS-FNAB were comparable for gastric SELs ≥ 20-mm diameter. Considering the shorter procedural time required, EUS-FNAB should remain the standard to diagnose larger lesions.

Abbreviations

SEL: subepithelial lesion

GIST: gastrointestinal stromal tumor

EUS-FNAB: endoscopic ultrasound-guided fine needle aspiration/ biopsy

MIAB: mucosal incision-assisted biopsy

EGD: esophagogastroduodenoscopy

EMR: endoscopic mucosal resection

ESD: endoscopic submucosal dissection

ROSE: rapid on-site evaluation

PPI: proton pump inhibitor

Declarations

Acknowledgments

We thank Jane Charbonneau, DVM, from Edanz Group for editing a draft of this manuscript.

Ethics approval and consent to participate

The study was conducted in accordance with the Declaration of Helsinki, and the study protocol was approved by Ethics Committee of the Kyushu University hospital (Approval No. 29–465), Ethics Committee of the Kyushu medical center (Approval No. 17C366), Ethics Committee of the Kyushu Rosai Hospital (Approval No. 17–27), Ethics Committee of the Harasanshin Hospital (Approval No. 2017–31), and Ethics Committee of the Kitakyushu Municipal Medical Center (Approval No. 201801056).

Funding

None.

Competing interests

The authors have no conflicts of interest to declare.

Author Contributions

YM designed the study, analyzed the data and wrote the manuscript. TC edited and reviewed the manuscript. EI collected data and critically reviewed the manuscript. All other authors have contributed to the collection of the data.

Consent for publicaiton

Not applicable.

Availability of data and material

The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.

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Tables

Table 1. Patients’ demographics and lesion characteristics.

Table 2. Relationships between lesion size and location, and diagnostic yields with MIAB and EUS-FNAB.

Table 3. Comparison of MIAB and EUS-FNAB to diagnose SELs ≥ 20-mm diameter.

Due to technical limitations, table 4 is only available as a download in the supplemental files section