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Digestive Diseases and Sciences, Vol. 50, No. 3 (March 2005), pp. 509–513 ( C 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, In an international consensus report, it was suggested that the stomach is the seventh most common location for the level of hypergastrinemia induced by long-term treat- the formation of carcinoid tumor (1). In a study from the ment with a H,K-ATPase inhibitor would not be sufficient Mayo Clinic in Rochester, Minnesota, published prior to to increase the risk of developing gastric carcinoid tumor the widespread availability of endoscopy, gastric carcinoid tumor comprised 6% of all gastrointestinal carcinoid tu- There has been one case reported of an individual in mors (2). In a study of 8305 carcinoid tumors (1), 3.2% of whom a gastric carcinoid tumor was detected during long- carcinoids were identified in the stomach. Of these cases term anti-ulcer therapy which included lansoprazole (7).
of gastric carcinoid tumor, 79% were Caucasian in origin In that single report, the patient had recurrent gastric and and 64% were females. The average age at diagnosis of duodenal ulcers, but no information was provided about gastric carcinoid tumor ranged from 62 to 69 years. The 5- the patient's gastric acid secretion or serum gastrin level year survival with gastric carcinoid tumor was 64% with or imaging of the pancreas.
localized disease, 40% with regional disease, and 10% Interest in the potential relationship between the chronic with distant disease.
use of H,K-ATPase inhibitors and gastric carcinoid tumors Hypergastrinemia is a known risk factor for the develop- has returned following a recent report showing that, since ment of gastric carcinoid tumor. Prior workers suggested 1950, the percentage of gastric carcinoids among all stom- major relationships between gastric atrophy that induces ach malignancies has increased from 0.3 to 1.8% (8). In achlorhydria, resulting in hypergastrinemia, with subse- addition, since 1969, the percentage of gastric carcinoids quent development of gastric carcinoid tumor (3, 4). In among all gut carcinoid tumors has increased from 2.4 to some patients with Zollinger–Ellison syndrome, hyper- 8.7% (8). Factors that may be important in this increase gastrinemia is also associated with the development of in the incidence of gastric carcinoid tumor are therefore gastric carcinoid tumor (4).
of high interest.
Prior to the introduction of H,K-ATPase inhibitors, studies in rats revealed a risk of development of small CASE REPORT
intramucosal gastric carcinoid tumors originating fromenterochromaffin-like cell origin (5). Hypergastrinemia in A 52-year-old Caucasian female was seen by her physician patients receiving chronic (mean of 13 months) omepra- for postprandial nausea and diarrhea. The patient denied the use zole therapy has been shown to induce hyperplasia of gas- of alcohol or tobacco products. She had had no weight loss, chestpain, palpitations, malaise, vertigo, syncope, or melena. She had tric endocrine cells in 11–19% of the patients, but with been diagnosed with type I diabetes mellitus 12 years prior to no dysplastic or neoplastic lesions of endocrine cells (6).
this visit. The patient had been diagnosed 9 years previously withbipolar illness, she had been diagnosed with hypothyroidism23 years before, and she had a long-standing diagnosis of hyper- Manuscript received July 19, 2004; accepted August 27, 2004.
tension. The patient was started on lansoprazole, 30 mg daily, From the *Division of Gastroenterology & Hepatology, Department
and upper endoscopy was arranged for the patient at a 2-month of Medicine, †Department of Surgery, and ‡Department of Pathology,
follow-up. Her nausea remained at 2 months and had been only Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.
Address for reprint requests: Timothy R. Koch, MD, Division minimally improved with a bland diet.
of Gastroenterology & Hepatology, Medical College of Wisconsin, The patient underwent upper endoscopy in December 2003.
9200 West Wisconsin Avenue, Milwaukee, Wisconsin 53226, USA; 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)
2005 Springer Science+Business Media, Inc.

ATTILA ET AL.
of lansoprazole and a 2-week follow-up upper endoscopy wasscheduled.
Fasting serum gastrin was repeated at 2 weeks and it had decreased to 483 pg/ml. At repeat upper endoscopy off of lanso-prazole, gastric fluid was aspirated from the antrum and sent tothe laboratory for pH-metry. The pH of gastric fluid was found tobe 2.0. Due to the location of the patient's gastric cardia nodules,it was thought that endomucosal resection at upper endoscopywould create a high risk for the patient. Each of the gastric fundicand cardia nodules was individually biopsied, and each biopsywas identified as a carcinoid tumor.
The patient underwent an [In-111]-octreotide scan in nu- clear medicine, and only a normal distribution of tracer activ-ity was identified. A helical computerized tomography scan ofthe abdomen using a 2.5-mm scan thickness was performed,with the administration of gas granules to distend the stom-ach; a 2-mm hepatic cyst was identified but there was no bil-iary ductal dilation; the spleen, pancreas, adrenal glands, and Fig 1. At upper endoscopy, in a view of the stomach obtained during
kidneys were normal; there was no nodule or mass identi- retroflexion, multiple nodules are seen adjacent to the gastroesophageal fied within the stomach, and no retroperitoneal or mesenteric adenopathy; and the mesentery was normal and no ascites waspresent.
that was within 1–2 cm of the gastro-esophageal junction, and The patient was referred to gastrointestinal surgery for an three fundic nodules ranging in size from 5 to 10 mm (see opinion regarding therapy for multifocal gastric carcinoid tu- Figure 1). The patient was also noted to have three tiny nod- mor. Therapeutic options including (a) endoscopic surveillance, ules in the distal second portion of the duodenum. The remain- (b) combined endoscopic surveillance and/or resection with open ing examination was unremarkable. Biopsies were separately or laparoscopic antrectomy, and (c) total gastrectomy with re- obtained from the antrum, from the upper gastric nodules, and section of all carcinoid bearing mucosa were discussed and in- from the distal duodenal nodules. Duodenal and antral biop- formed consent was obtained. The patient agreed to undergo sies revealed no pathological diagnosis; there was intact villous a potentially curative total gastrectomy with an approximately architecture of the duodenal mucosa with no increase in intraep- 45-cm Roux-en-y esophagojejunostomy and D2 lymphadenec- ithelial lymphocytes; gastric mucosa revealed normal glandu- tomy. This resection included removal of all lymph node-bearing lar architecture, and a Warthin–Starry stain did not reveal any tissue located peripheral and parallel to the lesser and greater Helicobacter pylori organisms. Biopsies of the fundic and cor- curves and around the celiac axis. Due to the presence of pus nodules revealed groups and nests of cells with monomor- cholelithiasis, cholecystectomy was also performed. The patient phic round nuclei, inconspicuous nucleoli and eosinophilic, and tolerated the procedure well; there were no intraoperative or a slightly granular cytoplasm. Due to these findings of gastric postoperative complications and the patient was discharged on carcinoid tumor, special staining was performed. Immunohisto- postoperative day 8 while tolerating a postgastrectomy diet.
chemical stain for gastrin revealed no immunoreactive material.
At pathology, multiple cardiac and fundic polyps were identi- However, immunohistochemical stains for synaptophysin and fied after opening the stomach. Sections taken from these polyps chromogranin A revealed immunoreactive material within tumor revealed gastric carcinoid tumors. These tumors at immunos- taining were strongly immunoreactive for chromogranin A (see The patient was then seen in follow-up at the gastrointe- Figure 2) and weakly immunoreactive for synaptophysin. Im- stinal clinic. Several years prior to this visit, the patient had munohistochemical staining for gastrin revealed no immunore- described alternating periods of diarrhea and constipation pre- active material. Multiple areas of the stomach revealed prominent viously diagnosed as due to irritable bowel syndrome. There intestinal metaplasia of the complete type, with scattered goblet was no family history of peptic ulcer disease or gastrointesti- cells and increased Paneth cells within the affected glands. There nal cancer. The patient had no prior history of treatment with a was no metastatic tumor present in five compartment 1 (lymph H,K-ATPase inhibitor, and she denied use of any nonsteroidal node stations 1–6) representative lymph nodes. Similarly five anti-inflammatory drug. She denied flushing or parasthesias, and compartment II (lymph node stations 6–11) lymph nodes were she had no history of diabetic retinopathy. At this time, her med- negative for metastatic disease.
ications included celecoxib, lansoprazole, 30 mg daily, levothy- At transmission electron microscopy, multiple sections were roxine sodium, lamotrigine, quetiapine fumarate, insulin, ator- examined and the findings were homogeneous. The find- vastatin calcium, zolpidem tartrate, and ramipril. In addition, ings revealed granule-filled neuroendocrine secretory cells (see she was using a daily combination supplement containing folacin Figure 3). There were very dense granules showing a size and (2.5 mg), cyanocobalamin (1 mg), and pyridoxine · HCl (25 mg).
shape pleomorphism characteristic of carcinoid tumor cells.
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 weredetected at a titer of 1:320. Intrinsic factor antibodies were not There has been one previous case report of a gastric detected. It was requested that the patient discontinue the use carcinoid tumor in a patient receiving lansoprazole (7). In Digestive Diseases and Sciences, Vol. 50, No. 3 (March 2005)

GASTRIC CARCINOID TUMOR WITH ANEMIA Fig 2. Histology of a gastric nodule demonstrates that the lamina pro-
pria mucosa contains groups and nests of cells with monomorphic round
nuclei, inconspicuous nucleoli, and granular cytoplasm. Immunohisto-
chemical staining reveals chromogranin A-like immunoreactivity within
tumor cells. (Original magnification, ×10.)
that case, however, information that should be importantin understanding the case included a lack of knowledge Fig 3. Examination of the gastric tumor by transmission electron mi-
about the patient's gastric acid secretion, serum gastrin croscopy. There are granule-filled neuroendocrine secretory cells. Mul- level, and imaging of the pancreas (to exclude a Zollinger– tiple nuclei are present, with very dense granules showing size and shapepleomorphism characteristic of carcinoid tumor cells. (Original magni- Ellison tumor). In the present case, only while receiving fication, ×4000.) lansoprazole did the patient clearly have a serum gastrinlevel above 1000 pg/ml, a level previously suggested to condition that would exacerbate the risk of chronic treat- be associated with the development of multicentric gastric ment with a H,K-ATPase inhibitor.
carcinoids in pernicious anemia (9). In the present case, the Screening of patients with pernicious anemia has been patient had a gastric pH of 2.0 while off of lansoprazole, previously considered. It has been reported that 15 to 20% and computerized tomography of the abdomen revealed of patients with type 1 diabetes mellitus have parietal cell a normal pancreas. Since this patient had only received antibodies (12). In a study of 88 patients with type 1 dia- lansoprazole for a relatively short period of time prior betes mellitus, 57% of individuals with parietal cell anti- to the diagnosis of gastric carcinoid tumor, this suggests bodies had autoimmune gastritis (12). In 26% of patients that achlorhydria is not a prerequisite for hypergastrinemia with parietal cell antibodies, premalignant lesions were and subsequent formation of multifocal gastric carcinoid identified with enterochromaffin-cell hyperplasia; one pa- tient had gastric carcinoid tumor, with corpus intestinal In this case, the patient did have an elevation of her metaplasia in 11 patients, including 1 with linitis plas- serum chromogranin A level. A previous study of patients with gastrinomas suggested a correlation between serum In addition to this screening of high-risk type 1 diabetic chromogranin A level and the presence of gastric carci- patients by using serum gastrin and parietal cell antibody noids (10). By contrast, serum histamine or serotonin, or levels, screening by performance of upper endoscopy has urinary 5-hydroxyindoleacetic acid, did not correlate with been examined recently. In a study of 71 patients with the presence of gastric carcinoids (10).
pernicious anemia, upper endoscopy was performed at 3- In early studies of omeprazole, about 3% of patients year intervals, but only for a mean time of 5.8 years (13).
had plasma gastrin levels above 400 pg/ml (11). It was During the follow-up period, two gastric cancers and eight suggested that it was not cost effective to screen all pa- gastric carcinoids were detected. Patients who developed tients to detect such a small percentage (11), and it was gastric carcinoid tumors were younger and had a longer suggested that there was a paucity of treatment options in duration of pernicious anemia.
these patients. We are suggesting from the present case In a second endoscopic study, 128 patients with perni- report that the presence of pernicious anemia would be a cious anemia underwent upper endoscopy, and 68 patients Digestive Diseases and Sciences, Vol. 50, No. 3 (March 2005) ATTILA ET AL.
then underwent biannual follow-up upper endoscopy, for ing gastric carcinoid tumor by facilitating hypergastrine- a mean of 4.33 endoscopies per patient (14). Among the mia. In select patients such as those patients with Type 1 128 patients, 2 individuals were found to have gastric diabetes mellitus and parietal cell antibodies, considera- carcinoid tumor. During the endoscopic follow-up, three tion should be given to obtaining a fasting serum gastrin cases of gastric dysplasia but no gastric carcinoma or gas- level prior to initiation of treatment with a H,K-ATPase tric carcinoid tumor were identified (14). The authors con- cluded that routine follow-up upper endoscopy was notuseful for screening individuals with pernicious anemia.
The optimal resectional therapy for gastric carcinoid 1. Modlin IM, Sandor A: An analysis of 8305 cases of carcinoid tumors.
tumors remains controversial. Many centers advocate pri- Cancer 79(4):813–829, 1997 mary resection for small and/or localized tumors. Often 2. Thompson GB, van Heerden JA, Martin JK Jr, Schutt AJ, Ilstrup Type I gastric carcinoids can be removed endoscopically DM, Carney JA: Carcinoid tumors of the gastrointestinal tract: with antrectomy added, to remove the source of gastrin, if a presentation, management, and prognosis. Surgery 98:1054–1063, carcinoid tumor recurs. This therapeutic strategy, however, 3. Carney JA, Go VLW, Fairbanks VF, Moore SB, Alport EC, Nora requires long-term endoscopic surveillance. Total gastrec- FE: The syndrome of gastric carcinoid tumors and nonantral gastric tomy may be necessary for multiple or diffuse tumors, as atrophy. Ann Intern Med 99:761–766, 1983 was the case in the present patient (15).
4. Freston JW, Borch K, Brand SJ, Carlsson E, Creutzfeldt W, A recent review (8) of 562 gastric carcinoid tumors over Hakanson R, Olbe L, Solcia E, Walsh JH, Wolfe MM: Effects 50 years has raised concern over the use of more conser- of hypochlorhydria and hypergastrinemia on structure and func-tion of gastrointestinal cells. A review and analysis. Dig Dis Sci vative management strategies. Despite the fact that most 40(Suppl 2):50S–62S, 1995 gastric carcinoids are diagnosed at an early stage, a 63% 5. Havu N: Enterochromaffin-like cell carcinoids of gastric mucosa overall 5-year survival rate indicates that many of these in rats after life-long inhibition of gastric secretion. Digestion tumors demonstrate a more "malignant" biology than pre- 35(Suppl 1):42–55, 1986 viously believed. Cumulative analysis indicated that 10 to 6. Solcia E, Rindi G, Havu N, Elm G: Qualitative studies of gastric endocrine cells in patients treated long-term with omeprazole. Scand 30% of gastric carcinoid cases exhibited regional lymph J Gastroenterol Suppl 166:129–137, 1989 node or distant metastasis at diagnosis (8). Similar recent 7. Haga Y, Nakatsura T, Shibata Y, Sameshima H, Nakamura Y, reports of other gastrointestinal carcinoids have noted ma- Tanimur M, Ogawa M: Human gastric carcinoid detected during lignant potential even in small lesions (16).
long-term antiulcer therapy of H2 receptor antagonist and proton The patient currently described required total gastrec- pump inhibitor. Dig Dis Sci 43:253–257, 1998 8. Modlin IM, Lye KD, Kidd M: A 50-year analysis of 562 gastric carci- tomy due to the multifocal and widely dispersed nature of noids: small tumor or larger problem? Am J Gastroenterol 99:23–32, the carcinoid tumors. The addition of a D2 lymphadenec- tomy is also controversial. However, the decision to per- 9. Hirschowitz BI, Griffith J, Pellegrin D, Cummings OV: Rapid re- form an extended lymphadenectomy was based on the gression of enterochromaffin-like cell gastric carcinoids in perni- small additional risk of morbidity in this patient and, as cious anemia after antrectomy. Gastroenterology 102:1409–1418,1992 recent data would indicate, that currently we are unable to 10. Bashir S, Gibril F, Ojeaburu JV, Asgharian B, Entsuah LK, Ferraro precisely identify the malignant potential of these tumors.
G, Crafa P, Bordi C, Jensen RT: Prospective study of the ability of The mechanisms for development of gastric carcinoid histamine, serotonin, or serum chromogranin A levels to identify tumor remain unclear. In a previous study, loss of het- gastric carcinoids in patients with gastrinomas. Aliment Pharmacol erozygosity in the MEN-1 gene was identified in 75% of Ther 16:1367–1382, 2002 11. Freston JW: Clinical significance of hypergastrinaemia: rele- 20 patients with Zollinger–Ellison syndrome and gastric vance to gastrin monitoring during omeprazole therapy. Digestion carcinoids (17). Since loss of heterozygosity was not seen 51(Suppl 1):102–114, 1992 in all patients, a cause-and-effect relationship could not be 12. De Block CE, De Leeuw IH, Bogers JJ, Pelckmans PA, Ieven proven. However, hypergastrinemia has been suggested to MM, Van Marck EA, Van Acker KL, Van Gaal LF: Autoimmune be the major identified factor in patients with gastric car- gastropathy in type 1 diabetic patients with parietal cell antibod-ies: histological and clinical findings. Diabetes Care 26:82–88, cinoids of enterochromaffin-like cell origin (18). These tumors have been identified in patients with achlorhydria, 13. Kokkola A, Sjoblom SM, Haapiainen R, Sipponen P, Puolakkainen normochlorhydria, and hyperchlorhydria, thus minimiz- P, Jarvinen H: The risk of gastric carcinoma and carcinoid tumours ing the potential importance of gastric acid secretion (18).
in patients with pernicious anemia. A prospective follow-up study.
The mechanism by which hypergastrinemia induces gas- Scand J Gastroenterol 33:88–92, 1998 14. Bresky G, Mata A, Llach J, Ginis MA, Pellisi M, Soria MT, tric carcinoid formation, however, remains unknown.
Fernandez-Esparrach G, Mondelo F, Bordas JM: Endoscopic find- In summary, treatment of nonspecific symptoms with a ings in a biennial follow-up program in patients with pernicious H,K-ATPase inhibitor could increase the risk of develop- anemia. Hepatogastroenterology 50:2264–2266, 2003 Digestive Diseases and Sciences, Vol. 50, No. 3 (March 2005) GASTRIC CARCINOID TUMOR WITH ANEMIA 15. Modlin IM, Lye KD, Kidd M: Carcinoid tumors of the stomach.
17. Debelenko LV, Emmert-Buck MR, Zhuang Z, et al.: The multiple Surg Oncol 12:153–172, 2003 endocrine neoplasia type I gene locus is involved in the pathogenesis 16. Heah SM, Eu KW, Ooi BS, et al.: Tumor size is irrelevant in pre- of type H gastric carcinoids. Gastroenterology 113:773–781, 1997 dicting malignant potential of carcinoid tumors of the rectum. Tech 18. Waldum HL, Sandvik AK, Idle JR: Gastrin is the most important fac- Coloproctology 5:73–77, 2001 tor in ECL tumorigenesis. Gastroenterology 114:1113–1114, 1998 Digestive Diseases and Sciences, Vol. 50, No. 3 (March 2005)

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