Multifocal Gastric Carcinoid Tumor in a Patient with Pernicious Anemia Receiving Lansoprazole

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1 Digestive Diseases and Sciences, Vol. 50, No. 3 (March 2005), pp ( C 2005) DOI: /s CASE REPORT Multifocal Gastric Carcinoid Tumor in a Patient with Pernicious Anemia Receiving Lansoprazole TAN ATTILA, MD,* RAJ SANTHARAM, MD,* DENNIS BLOM, MD, RICHARD KOMOROWSKI, MD, and TIMOTHY R. KOCH, MD* KEY WORDS: carcinoid tumor; stomach; proton pump inhibitor; gastrin. Gastric carcinoid tumors remain rare. Among all sites, the stomach is the seventh most common location for the formation of carcinoid tumor (1). In a study from the Mayo Clinic in Rochester, Minnesota, published prior to the widespread availability of endoscopy, gastric carcinoid tumor comprised 6% of all gastrointestinal carcinoid tumors (2). In a study of 8305 carcinoid tumors (1), 3.2% of carcinoids were identified in the stomach. Of these cases of gastric carcinoid tumor, 79% were Caucasian in origin and 64% were females. The average age at diagnosis of gastric carcinoid tumor ranged from 62 to 69 years. The 5- year survival with gastric carcinoid tumor was 64% with localized disease, 40% with regional disease, and 10% with distant disease. Hypergastrinemia is a known risk factor for the development of gastric carcinoid tumor. Prior workers suggested major relationships between gastric atrophy that induces achlorhydria, resulting in hypergastrinemia, with subsequent development of gastric carcinoid tumor (3, 4). In some patients with Zollinger Ellison syndrome, hypergastrinemia is also associated with the development of gastric carcinoid tumor (4). Prior to the introduction of H,K-ATPase inhibitors, studies in rats revealed a risk of development of small intramucosal gastric carcinoid tumors originating from enterochromaffin-like cell origin (5). Hypergastrinemia in patients receiving chronic (mean of 13 months) omeprazole therapy has been shown to induce hyperplasia of gastric endocrine cells in 11 19% of the patients, but with no dysplastic or neoplastic lesions of endocrine cells (6). Manuscript received July 19, 2004; accepted August 27, From the *Division of Gastroenterology & Hepatology, Department of Medicine, Department of Surgery, and Department of Pathology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA. Address for reprint requests: Timothy R. Koch, MD, Division of Gastroenterology & Hepatology, Medical College of Wisconsin, 9200 West Wisconsin Avenue, Milwaukee, Wisconsin 53226, USA; TimKoch@worldnet.att.net. In an international consensus report, it was suggested that the level of hypergastrinemia induced by long-term treatment with a H,K-ATPase inhibitor would not be sufficient to increase the risk of developing gastric carcinoid tumor (4). There has been one case reported of an individual in whom a gastric carcinoid tumor was detected during longterm anti-ulcer therapy which included lansoprazole (7). In that single report, the patient had recurrent gastric and duodenal ulcers, but no information was provided about the patient s gastric acid secretion or serum gastrin level or imaging of the pancreas. Interest in the potential relationship between the chronic use of H,K-ATPase inhibitors and gastric carcinoid tumors has returned following a recent report showing that, since 1950, the percentage of gastric carcinoids among all stomach malignancies has increased from 0.3 to 1.8% (8). In addition, since 1969, the percentage of gastric carcinoids among all gut carcinoid tumors has increased from 2.4 to 8.7% (8). Factors that may be important in this increase in the incidence of gastric carcinoid tumor are therefore of high interest. CASE REPORT A 52-year-old Caucasian female was seen by her physician for postprandial nausea and diarrhea. The patient denied the use of alcohol or tobacco products. She had had no weight loss, chest pain, palpitations, malaise, vertigo, syncope, or melena. She had been diagnosed with type I diabetes mellitus 12 years prior to this visit. The patient had been diagnosed 9 years previously with bipolar illness, she had been diagnosed with hypothyroidism 23 years before, and she had a long-standing diagnosis of hypertension. The patient was started on lansoprazole, 30 mg daily, and upper endoscopy was arranged for the patient at a 2-month follow-up. Her nausea remained at 2 months and had been only minimally improved with a bland diet. The patient underwent upper endoscopy in December At endoscopy, the patient had evidence for antral gastritis. Upon retroflexion, the patient was noted to have a 5-mm cardia nodule Digestive Diseases and Sciences, Vol. 50, No. 3 (March 2005) /05/ /0 C 2005 Springer Science+Business Media, Inc.

2 ATTILA ET AL. Fig 1. At upper endoscopy, in a view of the stomach obtained during retroflexion, multiple nodules are seen adjacent to the gastroesophageal junction. that was within 1 2 cm of the gastro-esophageal junction, and three fundic nodules ranging in size from 5 to 10 mm (see Figure 1). The patient was also noted to have three tiny nodules in the distal second portion of the duodenum. The remaining examination was unremarkable. Biopsies were separately obtained from the antrum, from the upper gastric nodules, and from the distal duodenal nodules. Duodenal and antral biopsies revealed no pathological diagnosis; there was intact villous architecture of the duodenal mucosa with no increase in intraepithelial lymphocytes; gastric mucosa revealed normal glandular architecture, and a Warthin Starry stain did not reveal any Helicobacter pylori organisms. Biopsies of the fundic and corpus nodules revealed groups and nests of cells with monomorphic round nuclei, inconspicuous nucleoli and eosinophilic, and a slightly granular cytoplasm. Due to these findings of gastric carcinoid tumor, special staining was performed. Immunohistochemical stain for gastrin revealed no immunoreactive material. However, immunohistochemical stains for synaptophysin and chromogranin A revealed immunoreactive material within tumor cells. The patient was then seen in follow-up at the gastrointestinal clinic. Several years prior to this visit, the patient had described alternating periods of diarrhea and constipation previously diagnosed as due to irritable bowel syndrome. There was no family history of peptic ulcer disease or gastrointestinal cancer. The patient had no prior history of treatment with a H,K-ATPase inhibitor, and she denied use of any nonsteroidal anti-inflammatory drug. She denied flushing or parasthesias, and she had no history of diabetic retinopathy. At this time, her medications included celecoxib, lansoprazole, 30 mg daily, levothyroxine sodium, lamotrigine, quetiapine fumarate, insulin, atorvastatin calcium, zolpidem tartrate, and ramipril. In addition, she was using a daily combination supplement containing folacin (2.5 mg), cyanocobalamin (1 mg), and pyridoxine HCl (25 mg). Physical examination of the abdomen was unremarkable. Fasting serum gastrin at that time was elevated, at 1111 (range, 0 100) pg/ml. Serum chromogranin A level was elevated at 54 (range, 6 to 39) ng/ml, and anti-parietal cell antibodies were detected at a titer of 1:320. Intrinsic factor antibodies were not detected. It was requested that the patient discontinue the use of lansoprazole and a 2-week follow-up upper endoscopy was scheduled. Fasting serum gastrin was repeated at 2 weeks and it had decreased to 483 pg/ml. At repeat upper endoscopy off of lansoprazole, gastric fluid was aspirated from the antrum and sent to the laboratory for ph-metry. The ph of gastric fluid was found to be 2.0. Due to the location of the patient s gastric cardia nodules, it was thought that endomucosal resection at upper endoscopy would create a high risk for the patient. Each of the gastric fundic and cardia nodules was individually biopsied, and each biopsy was identified as a carcinoid tumor. The patient underwent an [In-111]-octreotide scan in nuclear medicine, and only a normal distribution of tracer activity was identified. A helical computerized tomography scan of the abdomen using a 2.5-mm scan thickness was performed, with the administration of gas granules to distend the stomach; a 2-mm hepatic cyst was identified but there was no biliary ductal dilation; the spleen, pancreas, adrenal glands, and kidneys were normal; there was no nodule or mass identified within the stomach, and no retroperitoneal or mesenteric adenopathy; and the mesentery was normal and no ascites was present. The patient was referred to gastrointestinal surgery for an opinion regarding therapy for multifocal gastric carcinoid tumor. Therapeutic options including (a) endoscopic surveillance, (b) combined endoscopic surveillance and/or resection with open or laparoscopic antrectomy, and (c) total gastrectomy with resection of all carcinoid bearing mucosa were discussed and informed consent was obtained. The patient agreed to undergo a potentially curative total gastrectomy with an approximately 45-cm Roux-en-y esophagojejunostomy and D2 lymphadenectomy. This resection included removal of all lymph node-bearing tissue located peripheral and parallel to the lesser and greater curves and around the celiac axis. Due to the presence of cholelithiasis, cholecystectomy was also performed. The patient tolerated the procedure well; there were no intraoperative or postoperative complications and the patient was discharged on postoperative day 8 while tolerating a postgastrectomy diet. At pathology, multiple cardiac and fundic polyps were identified after opening the stomach. Sections taken from these polyps revealed gastric carcinoid tumors. These tumors at immunostaining were strongly immunoreactive for chromogranin A (see Figure 2) and weakly immunoreactive for synaptophysin. Immunohistochemical staining for gastrin revealed no immunoreactive material. Multiple areas of the stomach revealed prominent intestinal metaplasia of the complete type, with scattered goblet cells and increased Paneth cells within the affected glands. There was no metastatic tumor present in five compartment 1 (lymph node stations 1 6) representative lymph nodes. Similarly five compartment II (lymph node stations 6 11) lymph nodes were negative for metastatic disease. At transmission electron microscopy, multiple sections were examined and the findings were homogeneous. The findings revealed granule-filled neuroendocrine secretory cells (see Figure 3). There were very dense granules showing a size and shape pleomorphism characteristic of carcinoid tumor cells. DISCUSSION There has been one previous case report of a gastric carcinoid tumor in a patient receiving lansoprazole (7). In 510 Digestive Diseases and Sciences, Vol. 50, No. 3 (March 2005)

3 GASTRIC CARCINOID TUMOR WITH ANEMIA Fig 2. Histology of a gastric nodule demonstrates that the lamina propria mucosa contains groups and nests of cells with monomorphic round nuclei, inconspicuous nucleoli, and granular cytoplasm. Immunohistochemical staining reveals chromogranin A-like immunoreactivity within tumor cells. (Original magnification, 10.) that case, however, information that should be important in understanding the case included a lack of knowledge about the patient s gastric acid secretion, serum gastrin level, and imaging of the pancreas (to exclude a Zollinger Ellison tumor). In the present case, only while receiving lansoprazole did the patient clearly have a serum gastrin level above 1000 pg/ml, a level previously suggested to be associated with the development of multicentric gastric carcinoids in pernicious anemia (9). In the present case, the patient had a gastric ph of 2.0 while off of lansoprazole, and computerized tomography of the abdomen revealed a normal pancreas. Since this patient had only received lansoprazole for a relatively short period of time prior to the diagnosis of gastric carcinoid tumor, this suggests that achlorhydria is not a prerequisite for hypergastrinemia and subsequent formation of multifocal gastric carcinoid tumor. In this case, the patient did have an elevation of her serum chromogranin A level. A previous study of patients with gastrinomas suggested a correlation between serum chromogranin A level and the presence of gastric carcinoids (10). By contrast, serum histamine or serotonin, or urinary 5-hydroxyindoleacetic acid, did not correlate with the presence of gastric carcinoids (10). In early studies of omeprazole, about 3% of patients had plasma gastrin levels above 400 pg/ml (11). It was suggested that it was not cost effective to screen all patients to detect such a small percentage (11), and it was suggested that there was a paucity of treatment options in these patients. We are suggesting from the present case report that the presence of pernicious anemia would be a Fig 3. Examination of the gastric tumor by transmission electron microscopy. There are granule-filled neuroendocrine secretory cells. Multiple nuclei are present, with very dense granules showing size and shape pleomorphism characteristic of carcinoid tumor cells. (Original magnification, 4000.) condition that would exacerbate the risk of chronic treatment with a H,K-ATPase inhibitor. Screening of patients with pernicious anemia has been previously considered. It has been reported that 15 to 20% of patients with type 1 diabetes mellitus have parietal cell antibodies (12). In a study of 88 patients with type 1 diabetes mellitus, 57% of individuals with parietal cell antibodies had autoimmune gastritis (12). In 26% of patients with parietal cell antibodies, premalignant lesions were identified with enterochromaffin-cell hyperplasia; one patient had gastric carcinoid tumor, with corpus intestinal metaplasia in 11 patients, including 1 with linitis plastica (12). In addition to this screening of high-risk type 1 diabetic patients by using serum gastrin and parietal cell antibody levels, screening by performance of upper endoscopy has been examined recently. In a study of 71 patients with pernicious anemia, upper endoscopy was performed at 3- year intervals, but only for a mean time of 5.8 years (13). During the follow-up period, two gastric cancers and eight gastric carcinoids were detected. Patients who developed gastric carcinoid tumors were younger and had a longer duration of pernicious anemia. In a second endoscopic study, 128 patients with pernicious anemia underwent upper endoscopy, and 68 patients Digestive Diseases and Sciences, Vol. 50, No. 3 (March 2005) 511

4 ATTILA ET AL. then underwent biannual follow-up upper endoscopy, for a mean of 4.33 endoscopies per patient (14). Among the 128 patients, 2 individuals were found to have gastric carcinoid tumor. During the endoscopic follow-up, three cases of gastric dysplasia but no gastric carcinoma or gastric carcinoid tumor were identified (14). The authors concluded that routine follow-up upper endoscopy was not useful for screening individuals with pernicious anemia. The optimal resectional therapy for gastric carcinoid tumors remains controversial. Many centers advocate primary resection for small and/or localized tumors. Often Type I gastric carcinoids can be removed endoscopically with antrectomy added, to remove the source of gastrin, if a carcinoid tumor recurs. This therapeutic strategy, however, requires long-term endoscopic surveillance. Total gastrectomy may be necessary for multiple or diffuse tumors, as was the case in the present patient (15). A recent review (8) of 562 gastric carcinoid tumors over 50 years has raised concern over the use of more conservative management strategies. Despite the fact that most gastric carcinoids are diagnosed at an early stage, a 63% overall 5-year survival rate indicates that many of these tumors demonstrate a more malignant biology than previously believed. Cumulative analysis indicated that 10 to 30% of gastric carcinoid cases exhibited regional lymph node or distant metastasis at diagnosis (8). Similar recent reports of other gastrointestinal carcinoids have noted malignant potential even in small lesions (16). The patient currently described required total gastrectomy due to the multifocal and widely dispersed nature of the carcinoid tumors. The addition of a D2 lymphadenectomy is also controversial. However, the decision to perform an extended lymphadenectomy was based on the small additional risk of morbidity in this patient and, as recent data would indicate, that currently we are unable to precisely identify the malignant potential of these tumors. The mechanisms for development of gastric carcinoid tumor remain unclear. In a previous study, loss of heterozygosity in the MEN-1 gene was identified in 75% of 20 patients with Zollinger Ellison syndrome and gastric carcinoids (17). Since loss of heterozygosity was not seen in all patients, a cause-and-effect relationship could not be proven. However, hypergastrinemia has been suggested to be the major identified factor in patients with gastric carcinoids of enterochromaffin-like cell origin (18). These tumors have been identified in patients with achlorhydria, normochlorhydria, and hyperchlorhydria, thus minimizing the potential importance of gastric acid secretion (18). The mechanism by which hypergastrinemia induces gastric carcinoid formation, however, remains unknown. In summary, treatment of nonspecific symptoms with a H,K-ATPase inhibitor could increase the risk of developing gastric carcinoid tumor by facilitating hypergastrinemia. In select patients such as those patients with Type 1 diabetes mellitus and parietal cell antibodies, consideration should be given to obtaining a fasting serum gastrin level prior to initiation of treatment with a H,K-ATPase inhibitor. REFERENCES 1. Modlin IM, Sandor A: An analysis of 8305 cases of carcinoid tumors. Cancer 79(4): , Thompson GB, van Heerden JA, Martin JK Jr, Schutt AJ, Ilstrup DM, Carney JA: Carcinoid tumors of the gastrointestinal tract: presentation, management, and prognosis. Surgery 98: , Carney JA, Go VLW, Fairbanks VF, Moore SB, Alport EC, Nora FE: The syndrome of gastric carcinoid tumors and nonantral gastric atrophy. 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