A Woman with Black Beads in Her Stomach: Severe Gastric Ulceration Caused by Yttrium-90 Radioembolization

Radioembolization (RE) is a selective internal radiation therapy (SIRT) delivering targeted, high-dose, intra-arterial radiation directly to the vascular supply of liver tumors. Complications can occur due to aberrant deposition or migration of radiation microspheres into nontarget locations, including normal hepatic parenchyma, lungs, pancreas, and upper gastrointestinal (UGI) tract. We report a case of gastric ulcers due to yttrium-90 (90Y) seed migration to the stomach to alert clinicians to this rare cause of gastric injury. A 57-year-old woman with stage IV breast cancer with liver and lung metastases presented to the hospital with 2 months of worsening nausea and vomiting. Two months prior, she had received SIRT with 90Y microspheres without complications. Upper GI endoscopy showed diffuse gastritis and extensive antral ulceration. Biopsies revealed black, spherical foreign bodies, consistent with 90Y microspheres, documenting radiation injury. Radiation-induced UGI ulceration is caused by direct radiation injury from beta-radiation. Delay in diagnosis may be due to the nonspecificity of symptoms and temporal delay of symptom onset from SIRT, which was 2 months in our patient. Also, complaints may be attributed erroneously to adjuvant chemotherapy or widespread metastatic disease. Clinicians must consider radiation-associated toxicity in any SIRT-treated patient developing abdominal symptoms.


Introduction
Radioembolization (RE) is a selective internal radiation therapy (SIRT) technique which delivers targeted, precise, high-dose, intra-arterial radiation directly to the vascular supply of liver tumors [1]. A common SIRT protocol uses beta-emitting yttrium-90 ( 90 Y) microspheres, infused by intra-arterial catheters via the hepatic arteries. e procedure's rationale is that primary and metastatic liver tumors are vascularized by arterial blood flow, whereas normal hepatocytes obtain their blood supply from the portal venous network. e procedure aims to spare normal, contiguous hepatic parenchyma, and adjacent viscera [2,3].
However, complications can occur, predominantly due to aberrant deposition or migration of radiation microspheres into unintended nontarget locations, including normal hepatic parenchyma, lungs, pancreas, and upper gastrointestinal (UGI) tract [4]. We report a case of diffuse gastric ulceration due to radioactive yttrium seed migration to the stomach to alert clinicians to this exceptional cause of gastric injury and to the diagnostic difficulties of this underappreciated and potentially catastrophic complication of hepatic SIRT.

Case Report
A 57-year-old woman with stage IV breast cancer with liver and lung metastases presented to the hospital with 2 months of worsening intermittent nausea and vomiting. Two months prior, she had received SIRT with 90 Y resin microspheres. Successful hepatic arterial mapping was done for the planned 90 Y SIRT. Prophylactic gastroduodenal and right gastric arterial coil embolization were performed without complication. Preliminary scintigraphy was performed through a hepatic artery catheter with Technetium-99m Macroaggregated Albumin (99mTc-MAA). e scan revealed minimal activity in the lungs (7%) with 93% of measured activity in the liver. Yttrium-90 radioembolization of the right and medial segment of the left hepatic lobes was performed without complication. Posttreatment imaging with bremsstrahlung SPECT demonstrated heterogeneous activity in the liver. No significant activity was seen outside the liver including no gastric uptake of microspheres. At the time of SIRT treatment, the patient also had chemotherapy with 5-FU, gemcitabine, cyclophosphamide, and trastuzumab. e patient reported a hospitalization at another institution 4 weeks after SIRT for nausea and vomiting, which were treated symptomatically.
After discharge, her symptoms did not resolve completely. Repeat UGI endoscopy revealed hemorrhagic gastritis and multiple nonbleeding, gastric antral ulcers with clean bases. Gastric biopsy showed focal gastritis with an inflammatory reaction and degenerative connective tissue consistent with radiation injury. Biopsies of the ulcers were negative for Helicobacter pylori. e patient was placed on iron supplementation therapy and pantoprazole. Repeat endoscopy 6 weeks later revealed healing of gastric ulcers.

Discussion
In selective internal radiation therapy (SIRT), resin microspheres 25-45 µm in size impregnated with radioactive 90 Y are directly infused into the hepatic arterial circulation [5]. e microspheres become trapped in the tumor microcirculation, releasing targeted beta-radiation [5]. Optimal vascular flow and oxygenation are important in achieving the desired brachytherapy effects and avoiding complications. e average penetration of beta-radiation is 2.5 mm and a maximum of 11 mm of surrounding hepatic parenchyma when used to treat hepatic metastases [4].  Case Reports in Medicine e half-life of 90 Y is 64 hours, with 95% of the dose delivered by day 11 [4]. e tumoricidal effect of radioembolization is predominantly due to radioactivity rather than an ischemia-induced effect [6]. Targeted radioembolization produces shrinkage of tumor size in hepatic metastases from colorectal cancer, in as many as 79% to 91% of patients [4]. Comparable tumor shrinkage has been reported in other metastatic liver malignancies.
Yttrium-90 microspheres can cause tissue damage due to aberrant dissemination of radioactivity to nontarget parts of the GI tract or normal hepatic tissue (Figure 3). e reported incidence of GI complications after SIRT for hepatic neoplasia varies widely [7]. Procedure-related morbidity is as low as 5% with strict adherence to contemporary protocols [8]. As in our patient, radiation-induced gastric or duodenal ulceration is caused predominantly by direct mucosal radiation injury from pure beta-radiation. Additionally, mechanical occlusion of arterioles by the 30 µm microspheres can contribute to ischemic injury [1]. e finding that ulcerations typically do not occur after transarterial chemoembolization or when nonradioactive microspheres are injected into the hepatic arteries of experimental animals supports the hypothesis that radiation injury, rather than ischemia, is responsible for these mucosal ulcerations [6].
Gastroduodenal ulceration from nontarget seed distribution to unintended viscera can occur due to variations in hepatic artery anatomy, collateral vessels, or changes in flow dynamics during infusion [8]. A recent root cause analysis indicated that stasis during injection was the strongest independent risk factor for gastroduodenal complications [9]. Knowledge of the hepatic arterial network and its variations is required to identify hepaticoenteric or collateral splanchnic arterial circulation. Pretreatment assessment with digital subtraction angiography and nuclear scintigraphy helps direct specific treatment protocols and minimizes nontarget embolization of radiation [3,4]. Coil embolization treatment of communicating vessels can be performed if indicated. However, despite meticulous evaluation, these techniques occasionally do not detect small vessels perfusing structures other than the targeted, malignant hepatic tumor. After 90 Y radioembolization, evaluation of extrahepatic activity and liver dosimetry was performed for our patient by 90 Y bremsstrahlung SPECT images. However, this technique may have low resolution, which may be another reason for failure to detect sphere distribution in the stomach [10]. As such, some studies have suggested 90 Y PET as a more accurate method for postprocedure imaging [10,11].
Typically, as in our patient, the development of ulceration is delayed and has a longer time course than the short half-life of radiotherapy. At times, additional stressors to the gastric mucosa such a toxins, infections, and mechanical trauma may render the stomach more vulnerable to delayed mucosal ulceration. is may impair ulcer healing and may cause scar or adhesion formation [6]. Prior radiotherapy may also inhibit the inherent ability of the mucosa to repair, resulting in a diminished capacity to heal and recover from repeated radiation treatments. Unlike gastric ulcers due to other etiologies that develop at the mucosal surface, 90 Yinduced ulcers originate from the serosal surface [6].
Delay in diagnosis of gastroduodenal ulcers due to SIRT is common, due to diverse reasons. First, nonspecificity of symptoms such as abdominal pain, nausea, and vomiting mimic more common abdominal or systemic disorders. ese symptoms may be vague, insidious, and nonspecific and, thus, attributed erroneously to adjuvant chemotherapy, widespread metastatic disease, or preexisting or new-onset gastroesophageal reflux disease (GERD), thus posing a challenge to timely diagnosis. Second, temporal delay of symptom onset from the time of SIRT administration, as in our patient's two-month delay in symptom onset, lowers the index of suspicion to link these two events. Clinicians must consider radiation-associated toxicity in any SIRT-treated patient developing abdominal symptoms.
Clinicians should also be familiar with the diverse spectrum of multiorgan, acute, and delayed abdominal adverse events after targeted radioembolization to facilitate timely diagnosis and treatment. In addition to the aforementioned symptoms, this treatment can rarely result in cholecystitis, hepatic abscess, decompensation, and liver failure [12]. A postradioembolization syndrome (PRS) can occur, marked by fatigue, nausea, vomiting, abdominal pain of varied severity. Postradioembolization syndrome is common, with reported incidences range from 20 to 70% [1,6]. In our patient, symptoms of radiation-induced ulceration were delayed, appearing 2 months after the therapeutic procedure.
An important methodological issue in assessing SIRTrelated morbidity is that many relevant reports are of single cases or small case series of varying quality and subject to reporting bias. Also, scrupulous adherence to established  contemporary protocols associated with a decreased complication rate is not uniformly followed. Physicians treating patients who have received radioembolization therapy should be familiar with the spectrum of complications and have heightened suspicion for the sometimes delayed, nonspecific adverse effects. Clinicians must consider radiation-associated toxicity in any SIRTtreated patient developing abdominal symptoms.
Disclosure is work was published in an abstract form in e American Journal of Gastroenterology 105, S150-S388 (1 October 2010) by James L. Godwin, Alyn Adrain, and Edward Feller.