Introduction

Peptic ulcer (PU) is a common gastrointestinal (GI) disease mainly involving the stomach and duodenum. Benign peptic ulcer (BPU) is defined as an inflammatory defect that penetrates the muscularis mucosae or reaches deeper levels in the gastric and duodenal wall. BPU is mainly associated with the imbalance between the digestion effect of pepsin and gastric acid and the restitution of mucosal injury1,2,3, and according to the literature, a significant portion of BPU are related to Helicobacter pylori infection4. Gastroscopy combined with biopsy is the gold standard for diagnosing and staging BPU. However, it is often inappropriate to perform gastroscopy in resource-limited areas, and patients may also refuse or be contraindicated from receiving an invasive diagnostic test for benign disease.

At present, there are few reports on the ultrasonic diagnosis and staging of BPU5,6. This is mainly because traditional abdominal ultrasonography faces difficulty distinguishing the structure of the gastric wall, resulting in an unacceptable high rate of misdiagnosis.

Oral contrast-enhanced gastric ultrasonography (OCUS) is a novel contrast-enhanced abdominal ultrasound diagnostic technique under development for diagnosing various GI diseases, including BPU and gastric cancer. OCUS is showing promising results in some areas4.

In this study, we evaluated the feasibility of OCUS as an alternative method for diagnosing and staging BPU by comparing it with conventional gastroscopy.

Methods

Participants

The charts of patients who underwent OCUS were followed by endoscopic biopsy, and were finally diagnosed with BPU between July 2018 and December 2020, were retrospectively reviewed. Patients whose gastric wall layers cannot be clearly defined by ultrasonography, or failure to obtain the pathological diagnosis, were excluded from this review. This study was approved by the Ethics Committee of the Second Affiliated Hospital of Shandong University of Chinese Medicine (2022–020). The ethics committee of the Second Affiliated Hospital of Shandong University of Chinese Medicine dropped its requirement for informed consent. The authors confirm that all methods were carried out in accordance with relevant guidelines and regulations.

OCUS procedure

For OCUS, 50 g of an natural branched starch-based oral contrast agent (Visoun Ultrasound Gastrointestinal Contrast Agent, Hangzhou Huagong Benxiang Pharmaceutical Technology Co., Ltd.) was prepared into a 500 ml homogeneous suspension according to the manufacturer’s protocol. This oral contrast agent is a viscous liquid. Its main component is branched starch extracted from natural grains, with a pH of approximately 7.0–7.5 when prepared. Each dose of the contrast agent contains less than 200 kcal of energy. All patients have fasted for 8 h before the examination. After oral administration of the contrast agent, abdominal ultrasonography was immediately (no more than 20 min) performed using 1–5 MHz convex probes C5-1 of the diagnostic ultrasound system (EPIQ 7, Philips Ultrasound, Inc., Texas, USA), perform dynamic continuous scanning of the patient from multiple positions and angles, sequentially examining the cardia, fundus, body, antrum, duodenum, and abdominal segment of the esophagus. Observe and record the thickness and structural layers of the gastric wall at the lesion sites, as well as the location, extent, and depth of infiltration of the lesions, and the condition of the perigastric lymph nodes. If the sign of the presence of lesions found, lesions were zoomed in to observe the size, morphology, internal echo accurately, and affected area7. For patients with unclear gastric wall layer display due to obesity or abdominal distention, a second ingestion of 500 ml of water may be administered to re-fill the gastric cavity with contrast agent, further expelling gas and enhancing the clarity of gastric wall layers (Figs. 1 and 2). Endoscopic biopsies were subsequently performed for all the patients, and the endoscopic biopsy specimens were compared with OCUS findings. The sonographers and pathologists do not know each other's diagnoses until the study is concluded.

Figure 1
figure 1

Comparison of the stomach cavity and gastric wall structure before and after the re-filling with water. (A) After the patient orally ingested 500 ml of contrast agent, the presence of excessive gas in the anterior wall caused the gastric wall and stomach cavity to be displayed unclearly. (B) After drinking an additional 500 ml of water, the gas in the stomach was further expelled. In the same section, the gas in the anterior wall of the stomach was significantly reduced, and the gastric wall and cavity were clearly displayed.

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Figure 2
figure 2

The long-axis (A) and short-axis (B) structures of the gastric wall.

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Measurement and manifestations of BPU lesions under OCUS

The stage of BPU lesions was classified using a six-stage Sakita–Miwa classification as follows: active (A1, A2), healing (H1, H2), and scarring (S1, S2)8. Both ultrasound and pathological staging were performed on each patient, which was confidential to the gastroenterologist and pathologist.

BPU in different stages have differentiated manifestations under OCUS, and the summary is as follows:

  1. (1)

    Active Stage (Stage A): Localised thickening of the GW can be seen at the lesion area with ulceration, interruption and depression occurring in the thickened mucosa. Ulceration can penetrate the muscularis mucosa or an even deeper layer. Lesions are perpendicular to the GW, showing a “deeply chisel-like” change. Lesions have smooth bottoms, and the bottom and surrounding tissue have no hypoechoic area. The GW at the depression area is destroyed, and the remaining area is thickening while the layers of GW can be clearly distinguished. In stage A1 ulcers, the hypoechoic, thickening lamina propria around the ulcer or the thickening submucosa formed a protruding edge of the ulcer, which could be called “the lip-like sign” (Fig. 3). In stage A2 ulcer, the GW thickening at the edge of the ulcer was relatively reduced and the “lip-like sign” was not readily observable (Fig. 4).

  2. (2)

    Healing Stage (Stage H): The ulcer is shrunken and shallower compared to Stage A. The bottom of the ulcer depression area and the area surrounding GW were hypoechoic. The thickening area with the layers of GW could not be clearly distinguished. In stage H1, the mucosal surface of the depression area of the ulcer can be seen with either or both point-like and strip-like hyperechoic areas attached (Fig. 5). In stage H2, the depression area of the ulcer is gradually not easily observable, and either of both of the point-like and strip-like hyperechoic area attached to this area may not occur (Fig. 6).

  3. (3)

    Scar Stage (Stage S): The original GW of the healed ulcer was a thickened hypoechoic area, and its layer could not be clearly distinguished. The hyperechoic linear of the third layer was interrupted, which could be called a “broken bridge sign”, but the mucosal was complete. S1 and S2 ulcers are difficult to distinguish under OCUS, and gastroscopy may be needed to confirm the classification (Figs. 7 and 8).

Figure 3
figure 3

Stage A1 BPU under OCUS and gastroscopy. (A) Stage A1 ulcer. OCUS shows the ulcer was deeply sunken. There was no hypoechoic area surrounding the bottom and periphery. The edge of the ulcer was a high, hypoechoic area because of the thickening of mucosal oedema in the acute stage ulcer. (B) The same ulcer as in (A) under gastroscopy. A large ulcer can be seen with thick yellow fur at the bottom, and congestion and oedema of the surrounding mucosa.

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Figure 4
figure 4

Stage A2 BPU under OCUS and gastroscopy. (A) Stage A2 ulcer. OCUS shows the ulcer was sunken less deeply than in Fig. 1A, with no hypoechoic area surrounding the bottom and periphery. The mucosal oedema at the edge of the ulcer gradually subsided. (B) The same ulcer as in (A) under gastroscopy. There was thick, yellow-and-white coloured fur at the bottom of the ulcer, and the congestion and oedema of the surrounding mucosa were relieved.

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Figure 5
figure 5

Stage H1 BPU under OCUS and gastroscopy. (A) Stage H1 ulcer. OCUS shows the ulcer was small and shallow, with a thick hypoechoic area surrounding the bottom of the depression (granulation tissue and repair-related hyperplastic fibrous tissue), and attachment of punctate-like hyperechoic area can be seen in the depression. (B) The same ulcer as in (A) under gastroscopy. The ulcer is small, with yellow-and-white colour, and with thin fur.

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Figure 6
figure 6

Stage H2 BPU under OCUS and gastroscopy. (A) Stage H2 ulcer. OCUS shows that the depression of the ulcer became shallow, and a thick hypoechoic area surrounded the bottom of the ulcer. There was no obvious point-like or strip-like hyperechoic area in the depression. (B) The same ulcer as in (A) under gastroscopy. The ulcer is small, and the fur becomes thin and white.

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Figure 7
figure 7

Stage S1 BPU under OCUS and gastroscopy. (A) Stage S1 ulcer. OCUS shows that the mucosal surface of GW has been completely repaired, the original ulcer damage has been replaced by a hypoechoic area (repair-related hyperplastic fibrous tissue), and the hyperechoic linear of the third layer was interrupted, which could be called “broken bridge sign”. (B) The same ulcer as in (A) under gastroscopy. Gastroscopy showed a red stain in the ulcer area.

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Figure 8
figure 8

Stage S2 BPU under OCUS and gastroscopy. (A) Stage S2 ulcer. OCUS shows the same manifestations as Fig. 3A. (B) The same ulcer as in (A) under gastroscopy. Gastroscopy showed a white spot in the ulcer area.

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Statistical analysis

Data were further analysed using the Statistical Package for Social Sciences IBM (SPSS-IBM), version 24 (SPSS Inc., Chicago, Illinois, USA).

Ethics approval and consent to participate

This study was approved by the Ethics Committee of the Second Affiliated Hospital of Shandong University of Chinese Medicine (2022–020). The ethics committee of the Second Affiliated Hospital of Shandong University of Chinese Medicine dropped its requirement for informed consent. The authors confirm that all methods were carried out in accordance with relevant guidelines and regulations.

Result

Diagnostic accuracy of OCUS in BPU patients

A total of 44 patients were enrolled, including 25 males and 19 females. The median age of patients was 47 years old (range from 14 to 78 years old). In 44 patients with BPU, 45 ulcers were confirmed by endoscopic biopsy, including 43 cases with single ulcer and one case with with two ulcers. In 44 BPU patients, there were 37 cases of gastric ulcer (GU) and 8 cases of duodenal ulcer (DU). Amount the 45 ulcer lesions, OCUS could detect 44 lesions, The overall rate of detection of gastric ulcers by OCUS was 97.8% (44/45), and there were no false positive results among the OCUS exams. 32 case of BPU were located in the gastric angle, 3 in the sinus, 1 in the cardia and 7 in the duodenum, comparable with the finding from gastroscopy. OCUS misdiagnosed two ulcer lesions, with one ulcer in the fundus due to its deep location and posterior wall positioning, and one ulcer in the antrum caused by frequent gastric motility and the inconspicuous depression of the thickened gastric wall and ulcer. With OCUS, 14 out of 15 ulcers were correctly classified as stage A1, 6 out of 6 ulcers were correctly classified as stage A2, 7 out of 7 ulcers were correctly classified as stage H1, 5 out of 7 ulcers were correctly classified as stage H2, and 8 out of 10 ulcers were correctly classified as stage S. The specificity of OCUS in the classification of BPU vary across each stage. (Tables 1 and 2).

Table 1 Comparison between ultrasonic staging and gastroscopic staging.
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Table 2 Efficacy of ultrasound in staging peptic ulcer.
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Discussion

BPU has a characteristic four-layer structure in histology: the first layer is composed of debris and neutrophils; the second layer is a coagulative necrosis area; the third layer is granulation tissue; the fourth layer is fibrous tissue or scar tissue, which can reach the muscular layer, or even the serosa9,10.

Our study analysed the finding of OCUS of 44 patients with PU. Compared to previous studies11,12 using pure water or cellulose as contrast agents for gastric cavity filling, our research has shown an increased detection rate of BPU and a reduced misdiagnosis rate. In the classifition of PU, we was further classified using a six-stage Sakita–Miwa classification as follows: active (A1, A2), healing (H1, H2), and scarring stage (S1, S2). According to the pathological staging of BPU13, the scar stages of S1 and S2 are only different in colour but not shape. Thus, distinguishing S1 and S2 stage ulcers under abdominal ultrasonography, including OCUS, is difficult. In contrast, gastroscopy can distinguish S1 and S2 stage ulcers by the fresh, red-colour scar representing S1 stage ulcers and the old, white-colour scar in the S2 stage. Therefore, gastroscopy has more advantages in differentiating S1 and S2 stage ulcers. In some scar-stage ulcers, there was no apparent red or white colour scar on the mucosal surface, but a hypoechoic area caused by post-repaired fibrous tissue in the GW wall can be found. Although these parts of the ulcers in the scar stage are without signs of BPU under gastroscopy, OCUS could correctly detect it. Post-treatment BPUs were not included in our study. Further study is needed for ulcers in the healing stage to clarify manifestations of this group of BPU under OCUS.

Active stage ulcer behaves as a large, profoundly involved lesion, and the mucosal surface of the ulcer is often accompanied by large, hypoechoic necrotic tissue, which makes ulcer easily detected under OCUS. In our study, OCUS detected all A1 and A2 ulcers, and incorrect staging only occurred in a minor part of active-stage ulcers. However, in the healing stage and the scarring stage ulcer, the lesion shrinks and becomes shallow, and the ulcer’s mucosal surface is often not accompanied by hyperechoic area. In rare cases, they can be accompanied by small, spot-like or strip-like hyperechoic areas. When the small ulcer is located in the duodenal bulb, a relatively deeper site for ultrasound probes, misdiagnosis due to GI gas interference, the performance of radiologists, clinicians performing ultrasound, and other factors occur more frequently than the diagnosis of other types of BPUs. In our study, one ulcer in healing and scarring stage misdiagnosed by OCUS were occured. Gastroscopy is not affected by GI gas interference14 and the location of the ulcer. Thus, the diagnostic accuracy of duodenal bulb ulcer in gastroscopy’s healing and scarring stage may be superior to OCUS.

Ultrasonography staging of PUs improved the probe of manifestations of each stage of PUs. It eased the diagnosis and staging of PUs, which can provide more accurate diagnostic information for radiologists and correctly guide disease-specific treatment. The analysis of the manifestations of each stage of PUs is also helpful in differentiating benign and malignant ulcers. Both active-stage benign and cancerous ulcers behave as large, profoundly involved lesions. However, the cancerous ulcer is formed by necrotic tissue that falls from the centre of a fast-growing tumour. Therefore, the cancerous ulcer is formed by neoplasm in the GW, showing as a “mound-trenching sign”, while the benign ulcer is a result of direct damage from the inflammation in the GW, showing as a “flat-digging sign”. The two different signs can be used to distinguish benign ulcers from cancerous ulcers. The healing stage ulcer should be differentiated from Borrmann type III gastric cancer15. Both hyperplastic fibrous tissues induced by cancer cells and the hyperplastic fibrous tissue formed by the repairing and proliferating procedure in the bottom and periphery of the healing ulcer behaved as a hypoechoic area, and the layers of GW in this area could not be clearly distinguished. The healing stage ulcer showed small and shallow depression and an extensive range of hypoechoic areas at the bottom and periphery. Therefore, when the lesion has a large and deep depression with an unsmooth bottom and an extensive range of hypoechoic areas at the bottom and periphery, the diagnosis of Borrmann type III gastric cancer should be considered. It is difficult to differentiate some scar-stage ulcers from diffuse gastric cancer that induces fibrous tissue hyperplasia only by OCUS. However, by combining with the medical history, OCUS or endoscopic biopsy, it is not difficult to identify the underlying disease16. By summarising the results of ultrasonography staging, the differential diagnosis between benign and malignant ulcers could be efficiently completed. Furthermore, the diagnostic accuracy of benign and malignant ulcers can be improved.

In our study, OCUS demonstrates a high detection rate and zero false positive rate, with similar efficacy in ulcers localization to that of gastroscopy. Perhaps another advantages of OCUS is in monitoring the healing of peptic ulcers. Endoscopy follow-up programs are invasive and not easily agreed to by patients. And OCUS is an examination that not severity dependent to ultrasound physicians' experience, doctors who have undergone systematic training and mastered this examination technique are usually proficient in diagnosing gastroduodenal diseases, including BPU. Therefore, this examination can be widely promoted. Also, our stuty have some limitations. All included patients had gastric lesions previously detected in gastroscopic examinations, and this may have influenced the higher accuracy rates for the detection of the lesions. Additionally, OCUS examination requires the use of specific contrast agents and necessitates short-term specific training including OCUS theory and practice for ultrasound physicians to effectively identify lesions.

In summary, OCUS provides a fast, non-invasive way to detect and stage PU. It provides more accurate diagnostic information for radiologists, especially for patients that are contradicted to or refuse gastroscopy procedures, and to observe the prognosis of ulcers frequently17.