Case 4 -

Radiation And Chemotherapy-Associated Gastric Ulcers Vs Gastric Carcinoma/Dysplasia Robert E. Petras, M.D., FASCP, FACG Associate Professor of Pathology Northeastern Ohio Universities, College of Medicine National Director for Gastrointestinal Pathology Services, AmeriPath, Inc.

Clinical History The patient, a 46 year old man, presents with marked epigastric pain. Upper endoscopy reveals a very large gastric ulcer involving most of the anterior wall of the body and antrum of the stomach. The ulcer is described as clean-based with smooth edges. Description of Slide and Discussion The biopsy specimen from this case demonstrates epithelial atypia mimicking dysplasia/adenocarcinoma but shows many of the features described with HAIC-associated atypia. These findings prompted a phone call to the referring gastroenterologist for a more detailed clinical history. Twenty days prior to his presentation with severe epigastric pain, the patient had received selective internal radiation therapy (SIRT) for metastatic colonic adenocarcinoma involving the liver. His hepatic artery had been injected with an infusion of 35 micron, radioactive yttrium-90 microspheres made of biocompatible resin (SIR-Spheres, SIRTeX Medical Inc., Lake Forest , IL ). This history helps explain not only the epithelial atypia but the presence of the small black microspheres within the mucosal capillaries. Case 4 - Slide 1 Click to view with ImageScope Click to view with a Web-Based Viewer SIRT can be a useful palliative measure for metastatic carcinoma in liver [10, 11, 12, 13, 14]. By using selective hepatic arterial infusion, forty times the radiation dose can be delivered to the tumor (vs. conventional radiation techniques) while minimizing side effects. SIR-Spheres employ yttrium-90 which emits beta irradiation with a half-time of 64 hours. Reported side effects of this therapy include lethargy, anorexia, nausea, fever, pancreatitis and right upper quadrant pain. Gastrointestinal hemorrhage has been reported in less than 2% of patients [10, 12, 13, 14, 15, 16]. Rare examples of gastric and duodenal ulcer, cholecystitis and interstitial pneumanitis have been reported, some in association with embolization and migration of the radioactive microspheres into extrahepatic organs [12, 13, 14, 16, 17, 18]. Based on our experience with two patients with gastric ulcer caused by SIRT, the gastric lesion appears self limiting. With a relatively short half-time, the radiation dose to the tissues becomes negligible in 2-3 weeks. Proton pump inhibitors may be effective as an aid in healing. Our patient was treated with esomeprazole (40 mg bid) with relief of the epigastric pain in one week. Follow-up endoscopy done 6 weeks later revealed near complete healing of the ulcer. The atypia seen in gastric brushings and biopsy specimens from patients treated with hepatic arterial infusion chemotherapy/radiation therapy may be prominent and alarming. Care must be taken to avoid misinterpretation of the findings as adenocarcinoma/dysplasia. Documentation of a clinical history of prior treatment with hepatic arterial infusion chemotherapy/radiation therapy should alert the pathologist to this potential pitfall in interpretation [8]. Diagnosis Gastric epithelial atypia associated with hepatic arterial infusion of SIR-Spheres mimicking gastric dysplasia/carcinoma. Regional forms of chemotherapy and radiation therapy are used clinically with increasing frequency. Many employ hepatic arterial infusion and are used to treat primary and metastatic carcinoma involving the liver. A number of complications can occur with these forms of therapy [1, 2, 3, 4, 5], including gastric ulcers [1, 6]. These ulcer can closely mimic primary gastric carcinoma clinically, endoscopically, and sometimes in biopsy and gastric brush cytology specimens [1, 6, 7, 8]. Similar atypia has been seen in small intestinal epithelium in patients receiving this form of regional chemotherapy [6, 9]. In order to identify features useful in distinguishing hepatic arterial infusion chemotherapy (HAIC)-associated atypia from gastric carcinoma, we reviewed gastric ulcers associated with HAIC. For comparison we used a control group of 20 patients with early gastric carcinoma of intestinal type, the lesion most likely to be confused with chemotherapy-associated ulcer. The chemotherapy-associated lesion showed a marked resemblance to irradiation effect. The Table lists those features that were most helpful in distinguishing chemotherapeutic effect (and radiation effect) from carcinoma/dysplasia in histologic sections [6]. Table 1: Differential Features Between HAIC-associated Atypia and Early Gastric Adenocarcinoma HAIC ATYPIA GASTRIC CARCINOMA/DYSPLASIA Mucosal architecture Preserved Distorted Location of atypia Glands Foveolar Cellular features Bizarre Marked enlargement Uniform anaplasia N/C ratio Low High Cytoplasmic eosinophilia Present Absent Cytoplasmic vacuolization Present Absent Mitotic figures Few or none Numerous Atypia in granulation tissue Present Absent Intestinal metaplasia Usually absent Present Similar bizarre cytologic atypia may be seen in gastric brushing specimens in patients receiving HAIC [7, 8]. The atypical features of the epithelial cells resemble pronounced radiation effect. Atypical cells in gastric brushings can exist singly or in small clusters or flat sheets. Papillary formations or three-dimensional cellular aggregates were not observed in the specimens we studied. The most consistent feature of HAIC atypia was marked enlargement of the cytoplasm and nucleus. In spite of large size, the nuclear-cytoplasmic size ratio remained relatively low. The cytoplasm of the atypical cells was often foamy or vacuolated. The enlarged nuclei were vesicular, round to oval, and often eccentrically placed in the cytoplasm. Nuclear contours were smooth. Massive round or angulated nucleoli, either single or multiple, were characteristic. Binucleation and multinucleation were common. References Weidner N, Smith JG, Lavanway JM. Peptic ulceration with marked epithelial atypia following hepatic arterial infusion chemotherapy. A lesion initially misinterpreted as carcinoma. Amer J Surg Pathol 7:261-268, 1983. Nakhleh RE, Wesen C, Snover DC , Grace T. Venoocclusive lesions of the central veins and portal vein radicals secondary to intraarterial 5-flouro-2-deoxyuridine infusion. Human Path 20:1218- 1220, 1989. Marymont JV, Dakhil SR, Travers H, Housholder DF. 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