Chronic ulcer diagnosis and perforation risk with oral agent contrast-enhanced ultrasound: A case report and review of literature

Abstract

BACKGROUND

Gastric ulcer (GU) perforation is an acute condition with a high mortality rate, typically requiring emergency surgical intervention. Early warning of perforation risk before it occurs would enable earlier and more aggressive intervention. This case report describes a patient undergoing comprehensive treatment for hepatocellular carcinoma (HCC) who developed a chronic GU. Endoscopy and computed tomography (CT) scans failed to determine ulcer depth due to blood crust coverage and gastric wall edema. Oral agent contrast-enhanced ultrasound (OA-CEUS) visualized full-thickness involvement of the chronic ulcer and predicted perforation risk.

CASE SUMMARY

A 47-year-old male patient presented to our hospital for the next course of comprehensive treatment for HCC. He had previously received anti-Helicobacter pylori therapy. Gastroscopy prior to liver cancer treatment revealed chronic non-atrophic gastritis with erosion. During treatment, the patient experienced one episode of bloody stool and self-administered oral medication. Subsequent gastroscopy revealed multiple ulcers attached with necrotic tissue and coffee-ground material, surrounded by edematous mucosa. The diagnosis was compound ulcer (A1-H1 stage, radiation-associated gastroenteritis), and treatment included spraying sucralfate during gastroscopy and oral administration of omeprazole. Abdominal CT did not reveal GU. OA-CEUS demonstrated irregular gastric wall thickening with ulcers extending to the serosal layer at their deepest point, filled with hyperechoic material, indicating perforation risk. Due to negative fecal occult blood test results, the patient requested to continue oral treatment with lenvatinib plus omeprazole. Two weeks later, sudden abdominal pain led to surgical intervention, where acute GU perforation with acute diffuse peritonitis was diagnosed intraoperatively.

CONCLUSION

OA-CEUS can serve as an effective monitoring tool for GU complications during comprehensive treatment of HCC, aiding in the early warning of perforation.

Key Words: Gastric ulcer; Multidisciplinary treatment; Hepatocellular carcinoma; Oral agent; Ultrasound; Perforation; Case report

Core Tip: Gastric perforation is a rare yet severe complication of abdominal radiotherapy, occurring more frequently when combined immunotherapy and tyrosine kinase inhibitor therapy are administered. Most patients require emergency surgical intervention. This study reports a case where, within the complex context of comprehensive hepatocellular carcinoma treatment (involving radiotherapy, chemotherapy, immunotherapy, and targeted therapy), traditional methods (gastroscopy, contrast-enhanced computed tomography) could not accurately assess ulcer infiltration depth due to blood crust coverage and gastric wall edema. Oral agent contrast-enhanced ultrasound as a novel monitoring tool, clearly demonstrated that the ulcer had reached the serosal layer, thereby successfully predicting impending perforation.

INTRODUCTION

Gastric perforation is a full-thickness injury of the stomach wall, which may result from trauma, severe peptic ulceration, tumor progression, drug or radiation injury, and endoscopic procedures[1-4]. Gastric perforation allows bacteria, gastric acid, and partially digested food to enter the abdominal cavity, subsequently triggering severe peritonitis, and approximately one-fifth of perforated patients develop sepsis[5]. Despite the availability of various treatment options, including non-surgical and surgical approaches, the mortality rate for gastric perforation remains at 30%. Cases complicated by diffuse peritonitis carry an even higher mortality rate of 70%[6-8]. Therefore, preventing perforation remains our primary goal. Deep gastric wall injuries often involve complications like bleeding and edema, this is particularly true in patients with chronic gastric ulcer (GU) caused by comprehensive cancer treatment, where ulcer depth can penetrate the muscularis mucosae layer and, in severe cases, reach the serosal layer[9,10]. However, the actual depth is difficult to assess via conventional gastroscopy or computed tomography (CT) scans as the ulcer surface is often filled with necrotic material. Oral agent contrast-enhanced ultrasound (OA-CEUS) is a gastric examination technique utilizing an orally administered echo-enhanced cellulose contrast agent produced in Yanbian, China. Its application in diagnosing and monitoring gastric tumors and ulcers has increased in recent years. This modality not only significantly improves ultrasound diagnostic accuracy but also clearly displays the layered structure of the gastric wall. Due to its safety, convenience, and suitability for repeated examinations, it has gained high patient acceptance[11]. However, current research on its role in chronic ulcer monitoring and complication prediction remains limited. This case demonstrates that OA-CEUS not only assesses ulcer depth of invasion but also provides early warning of perforation risk, further expanding its diagnostic and therapeutic applications in gastrointestinal diseases.

CASE PRESENTATION

Chief complaints

A 47-year-old male patient presented to Department of Oncology of the First People’s Hospital of Nanning for the next round of treatment, 26 days after his last immunotherapy session, having been diagnosed with liver cancer over five months previously.

History of present illness

The patient was diagnosed with hepatocellular carcinoma (HCC) in the Department of Gastroenterology at our hospital in May 2024 after experiencing abdominal pain. On June 25, 2024, the patient underwent transcatheter hepatic artery embolization followed by intra-arterial chemotherapy. The specific regimen was: Oxaliplatin 140 mg d1 + calcium folinate 700 mg d1 + fluorouracil 700 mg + fluorouracil 4000 mg via micro-infusion pump for 48 hours. On June 3, 2024 and June 28, 2024, immunotherapy with camrelizumab 200 mg was administered. Oral lenvatinib targeted therapy was commenced on June 15. Portal vein tumor thrombus radiotherapy initiated on July 22 with the specific dosage of plan clinical target volume 45 Gy/15 f. Immunotherapy with camrelizumab 200 mg was administered on July 26, 2024, August 23, 2024, and September 13, 2024.

History of past illness

From October 28, 2022 to November 4, 2022, the patient was admitted to the Department of Gastroenterology of the First People’s Hospital of Nanning due to liver function impairment. Diagnoses at the time were: (1) Chronic hepatitis C; (2) Composite ulcer (A2-H1); (3) Liver fibrosis; and (4) Helicobacter pylori (H. pylori) infection. After receiving treatment for liver protection, gastric protection, and anti-H. pylori therapy, the patient’s condition improved and he was discharged. Preoperative gastroscopy for hepatic artery embolization on May 27, 2024 showed chronic non-atrophic gastritis with erosion. In late June 2024, the patient reported bloody stools and self-administered oral medication, although specific details are unavailable. On July 22, 2024, gastroscopy revealed a composite ulcer (stage A1-H1, radiation-associated gastroenteritis). Treatment was initiated with endoscopic spraying of sucralfate plus oral omeprazole for 6 weeks.

Personal and family history

The patient had a history of smoking for 20 years (one pack per day), alcohol consumption for 10 years (1-2 bottles of beer per occasion) and consuming raw fish. His father had a history of bladder cancer.

Physical examination

Physical examination showed no abnormalities. No abdominal tenderness or masses were observed. The spleen, liver and enlarged lymph nodes were not palpable.

Laboratory examinations

Blood analysis showed red blood cells 4.98 × 10¹²/L and hemoglobin 152 g/L. Biochemical results indicated alanine aminotransferase 88.3 U/L, aspartate aminotransferase 67.1 U/L, alkaline phosphatase 346.5 U/L, gamma-glutamyl transferase 697 U/L, and prealbumin 140 mg/L. Coagulation function revealed fibrinogen 4.98 g/L, and D-dimer 1.77 μg/mL. Alpha-fetoprotein was 122 ng/mL. No significant abnormalities were noted in other blood tests. Fecal occult blood tests in August 2024, September 2024 and October 2024 were negative. C₁₄ was negative. Electrocardiogram and urinalysis were normal.

Imaging examinations

Gastroscopy revealed multiple ulcers, some with white coating at the base, others attached with necrotic tissue, and some with coffee-ground material. The surrounding mucosa was edematous, with visible minor bleeding. Preliminary diagnosis was compound ulcer (A1-H1 stage, radiation-associated gastroenteritis; Figure 1). Abdominal CT with contrast enhancement revealed post-treatment changes consistent with HCC; abnormal lymph nodes in the hepatic hilum, abdominal mesentery and para-aortic region; and liver cirrhosis with mild splenomegaly. No ulcers were reported (Figure 2). OA-CEUS revealed irregular thickening of the anterior wall of the greater curvature (maximum thickness approximately 11 mm) with interrupted mucosal continuity. The deepest depression measures approximately 8 mm, penetrating the muscularis layer and locally reaching the serosal layer. The depression contained hyperechoic filling material, with slight protrusion of the serosal surface, indicating a risk of perforation (Figure 3 and Video 1).

Figure 1 Gastric folds show edema and thickening. The surface of the deep ulcer reveals old blood crusts. Orange arrows indicate endoscopically visible large deep ulcer and blood crusts. Blue arrows indicate swollen and thickened gastric wall.

Figure 2  Computed tomography reveals a slightly irregular local gastric wall (arrows).

Figure 3 Oral agent contrast-enhanced ultrasound findings. A: The short-axis section; B: The long-axis section. The thickened and edematous gastric wall surrounding the chronic gastric ulcer is clearly visible, with distinct layers discernible. The ulceration and its attachments extend from the mucosal layer to the serosal layer. The typical edematous hypoechoic base of the ulcer is absent, appearing only as a blurred linear hypoechoic line. Orange arrow: Ulcer; Blue arrow: Thickened gastric wall; Yellow arrow: Gastric lumen.

FINAL DIAGNOSIS

The final diagnosis was liver malignancy; hepatitis C-related cirrhosis; chronic hepatitis C; and GU.

TREATMENT

Given negative fecal occult blood tests along with normal hemoglobin levels, and no active bleeding and no abdominal pain symptoms, the patient only consented to continue antineoplastic therapy plus oral omeprazole conservative treatment.

OUTCOME AND FOLLOW-UP

Two weeks after discharge, the patient suddenly developed upper abdominal pain. Emergency CT findings indicated free gas in the abdominal and pelvic cavities, with small amounts of fluid accumulation in the abdomen and pelvis. The gas shadow traversing the greater curvature of the gastric body was thought to be a perforation. Immediate laparoscopic examination + GU perforation repair + abdominal paracentesis and drainage were performed. Intraoperatively, purulent exudate adhering to the abdominal wall, pelvic cavity, and perihepatic region were observed. Ulcer perforation measuring approximately 0.5 cm × 0.5 cm was identified on the anterior wall of the greater curvature of the gastric body, with marked hyperemia and swelling of the gastric wall overlaid by purulent exudate. Intraoperative diagnosis was GU with bleeding and acute perforation (greater curvature side of gastric body) and acute diffuse peritonitis. The timeline information in this case report is shown in Figure 4.

Figure 4 The timeline information in this case report. TACE: Transarterial chemoembolization; HGB: Hemoglobin; CT: Computed tomography; OA-CEUS: Oral agent contrast-enhanced ultrasound.

DISCUSSION

Gastric perforation is a life-threatening acute abdominal emergency. Due to its sudden and insidious onset, treatment is often delayed[12]. GUs are the most common cause of perforation. Although the incidence of GU has declined annually owing to the significant efficacy of H2 blockers, proton pump inhibitors (PPIs), and H. pylori eradication therapy, complications such as bleeding and perforation still occur. Perforation accounts for nearly 40% of peptic ulcer disease-related deaths. Most perforations require surgical intervention, and the mortality rate associated with perforation surgery remains relatively high, ranging from 10% to 40%[13].

Radiation therapy is one of the commonly used treatments for tumors. Reports indicate that total radiation doses exceeding 45 Gy may increase the risk of gastrointestinal perforation[14]. Chemotherapy, immunotherapy, and targeted drug therapy can all cause varying degrees of gastric damage[14-17]. As cancer patients gain access to more novel treatment options, an increasing number of studies suggest potential overlapping gastrointestinal toxicities[18]. Research has pointed out that the incidence of gastrointestinal perforation associated with abdominal radiation therapy increases following the use of anti-angiogenic drugs[18].

Gastroscopy is the gold standard for ulcer diagnosis. However, for patients with chronic GU or refractory GU, on the one hand, its invasiveness leads to poor patient compliance and frequency of re-examination cannot be guaranteed. On the other hand, due to the persistent presence of triggers such as disease or medication, ulcers recur and are difficult to heal, ulcers may penetrate into the muscularis layer or deeper, while the ulcer surface is often filled with old blood clots and necrotic material, making it difficult to determine the lesion depth[10,19,20]. Although endoscopic ultrasound has been used to assess the interior of ulcers, its prevalence and practical application remain limited[21,22]. In this case, gastroscopy revealed a deep, large ulcer on the anterior wall of the greater curvature. However, the ulcer surface was covered with a significant amount of old blood clots, and gastric folds were edematous, making it difficult to observe the internal condition of the ulcer. The patient declined further endoscopic ultrasound examinations, partly due to intolerance and the high cost of the procedure. Therefore, continuous observation is required.

Barium swallow was the earliest imaging method used for gastrointestinal examinations. Its sensitivity in diagnosing peptic ulcers remains relatively low, ranging from approximately 54%-81%[23,24]. It also has limitations in distinguishing diverticula, visualizing gastric wall layers, and assessing ulcer penetration depth[25]. Studies evaluating peptic ulcers using CT have also been conducted. CT is considered to be of limited diagnostic value for non-perforated peptic ulcers[26], with sensitivity ranging from 29.6% to 54% and an average visible ulcer size of 25 mm. Diagnosis primarily relies on gastric wall thickening, enhanced mucosal discontinuity, and protrusion. This makes differentiation from hypoalbuminemic thickening and contraction difficult. Consequently, even large ulcers may remain invisible on CT, necessitating careful multiplanar examination and attention to secondary features like perilesional fat edema to identify deep or penetrating ulcers[27,28]. The contrast-enhanced CT scan in the present case did not indicate GU.

In recent years, with the increasing maturity of OA-CEUS technology, its application in gastrointestinal examinations has become increasingly widespread. Relevant literature has documented its use in gastric cancer screening, differentiation of submucosal tumors, diagnosis, staging, and follow-up of GUs, as well as detection of gastrointestinal fistulas. OA-CEUS significantly enhances the accuracy and reliability of gastrointestinal ultrasound diagnosis[11,23,29,30]. Leveraging ultrasound’s high resolution for soft tissues, OA-CEUS imaging reveals intramural layering, providing crucial radiographic evidence for assessing lesion extent and depth of invasion. Studies have confirmed that in preoperative assessment of colorectal cancer, contrast-enhanced ultrasound demonstrates superior diagnostic value compared to CT and magnetic resonance imaging for tumor T staging and lesion length determination[31]. In our case, ultrasound not only revealed immunotherapy-associated gastric wall thickening[32], but also demonstrated the depth of chronic ulcers. The sonographic appearance at the ulcer base enabled timely warning of perforation risk, providing objective evidence for prompt clinical intervention. Although side effects of this technique are rarely reported, as contrast agent contains food products like soybeans and Chinese yam, some individuals may experience food allergies or abdominal distension.

With negative fecal occult blood tests for three consecutive months, normal hemoglobin levels, and no abnormal symptoms or signs, the ulcer was considered to be stabilizing. Ultimately, the patient only consented to conservative treatment with oral omeprazole, which still failed to prevent the occurrence of perforation. While PPIs offer protective effects against chemotherapy-related gastropathy, their efficacy in radiation therapy, immunotherapy, and lenvatinib-related gastropathy remains unconfirmed and is typically used empirically[14,33,34]. In this case, tumor-treatment-related gastric injury resulted from antineoplastic agents and radiotherapy, which directly or indirectly disrupted the gastric mucosal barrier and impaired endothelial cell regenerative capacity. This led to delayed ulcer healing and recurrent, difficult-to-heal lesions. Although no evidence of active bleeding was observed during monitoring in this case, PPI monotherapy is insufficient for managing imaging-confirmed ulcers penetrating to the serosal layer. More aggressive interventions are required, such as fasting, nasogastric tube decompression, or surgical intervention. At the same time, the case serves as a reminder that fully informing patients about the unpredictability and potential changes in their condition can lead to more active cooperation with physicians in treatment.

In summary, for patients undergoing comprehensive cancer treatment, early monitoring and more proactive interventions remain essential to prevent perforation.

CONCLUSION

Gastric perforation is a rare yet potentially life-threatening complication of comprehensive liver cancer treatment, typically arising from treatment-related chronic GU. OA-CEUS serves as an affordable, convenient and effective monitoring method due to its reproducibility and ability to provide transwall visualization, and can serve as an important supplement to endoscopy and CT.

ACKNOWLEDGEMENTS

The authors would like to thank the reviewers for their critical review and constructive suggestions. We also thank all participants in this study.