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Regression of duodenal gastrinomas in a patient with multiple endocrine neoplasia type I after parathyroidectomy
4. Muto T, Bussey HJR, Morson BC. The evolution of cancer of the colon and the rectum. Cancer 1975;36:2251-70. 5. Kosuka S, Nogaki M, Ozaki T, Masumori S. Premalignancy of the mucosal polyp of the large intestine. II. Estimation of the periods required for malignant transformation of mucosal polyps. Dis Colon Rectum 1975;18:494-9. 6. Lane N. The precursor tissue of ordinary large bowel cancer. Cancer Res 1976;36:2669-71. 7. Maskens AP, Dujardin-Loits RM. Experimental adenomas and carcinomas of the large intestine behave as distinct entities: most carcinomas arise de novo in flat mucosa. Cancer 1981;47:81-7. 8. Spratt JS, Ackerman LV. Small primary adenocarcinomas of the colon and the rectum. JAMA 1962;179:337-46. 9. Stearns Maus W. Where are the tiny carcinomas ofthe rectum? Surg Gynecol Obstet 1963;116:625. 10. Samshuddin AM. Microscopic intraepithelial neoplasia in large bowel mucosa. Human PathoI1982;13:51O-12. 11. Jelinek GP, Nava HR, Nime F. Small primary de novo adenocarcinoma of the colon with mesenteric lymphatic metastasis. J Surg OncoI1983;23:185-8. 12. Raclot G, Devalland C, Potet F, Bernard F, Monath C. Colorectal carcinoma arising de novo near a lymphoid follicle. Gastroenterol Clin Bioi 1991;10:775-6. 13. Muto T, Kamiya J, Sawada T, et al. Small "flat adenoma" of the large bowel with special reference to its clinicopathologic features. Dis Colon Rectum 1985;28:847-51. 14. Lynch HT, Smyrk T, Lanspa SJ, et al. Flat adenomas in a colon cancer-prone kindred. J Nat! Cancer Inst 1988;80:27882. 15. Lynch HT, Smyrk T, Lanspa SJ. The colonoscopist and the Lynch syndromes. Gastrointest Endosc 1990;36:156-8. 16. Bradburn DM, Gunn A, Hastings A, Shepherd NA, Chapman PD, Burn J. Histological detection of microadenomas in the
Regression of duodenal gastrinomas in a patient with multiple endocrine neoplasia type I after parathyroidectomy Hugh D. Mai, MD Robert A. Sanowski, MD
About 25% of patients with Zollinger-Ellison syndrome (ZES) have associated neoplasia of other endocrine organs (multiple endocrine neoplasia type I (MEN-I)). The prognosis for this familial form of gastrinoma is much better than that of the sporadic ones because of a lesser potential of becoming malignant. Surgical cure for subjects with gastrinoma and MEN-I, however, is rarely achieved because of the multicentric nature of the tumors, even with the new localization technique of selective venous sampling for gastrin gradient.! Norton et a1. 2 recommended parathyroidectomy as the initial operation for all patients with ZES and concomitant hypercalcemia due to parathyroid adenoma or hyperplasia (MEN-I). As a result of this surgery, it was shown that serum gastrin and From the Department of Gastroenterology, Carl T. Hayden Veterans Affairs Medical Center, Phoenix, Arizona. Reprint requests: Robert Sanowski, MD, Department of Gastroenterology, Hayden Veterans Affairs Medical Center, 650 E. Indian School Road, Phoenix, Arizona 85012. 706
17. 18.
19. 20. 21. 22. 23. 24. 25. 26. 27.
diagnosis of familial adenomatous polyposis. Br J Surg 1991;78:1394-5. Gilbertsen VA, Nelms JM. The prevention of invasive cancer of the rectum. Cancer 1978;41:1137-9. Winawer SJ, Zauber AG, Gerdes H, et al. Reduction in colorectal cancer incidence following colonoscopic polypectomy: report from the National Polyp Study (NPS) [Abstract]. Gastroenterology 1991;100:A41O. Ransohoff DF, Lang CA. Screening for colorectal cancer. N Engl J Med 1991;325:37-41. Friedman GD, Collen MF, Fireman BH. Multiphasic health check-up evaluation: a 16-year follow-up. J Chronic Dis 1986;39:453-63. Nagasako K, lizuka B, Yashiro K, Suzuki S. The diagnosis of superficial type early colorectal cancer [Abstract]. Gastroenterology 1991;100:A389. Tada M, Misaki F, Kawai K. Endoscopic observation of villi with magnifying enterocolonoscopes. Gastrointest Endosc 1982;28:17-9. Bird RP. Observation and quantification of aberrant crypts in the murine colon treated with a colon carcinogen: preliminary findings. Cancer Lett 1987;37:147-51. Pret!ow TP, Barrow BJ, Ashton WS, et al. Aberrant crypts: putative preneoplastic foci in human colonic mucosa. Cancer Res 1991;51:1564-7. Ida K, Tada M. Chromoscopy. In: Sivak MV, ed. Gastroenterologic endoscopy. Philadelphia: WB Saunders, 1987:203-20. Watanabe T, Muto T, Sawada T, et al. Usefulness of oral administration of indigocarmine for colonoscopy [Abstract]. Gastroenterology 1991;100:A21. Ngoi SS, Staino-Coico L, Godwin TA, Wong RJ, DeCosse JJ. Abnormal DNA ploidy and proliferative patterns in superficial colonic epithelium adjacent to colon cancer. Cancer 1990;66:953-9.
basal acid output were significantly reduced and response to H2 antagonists was improved. In this report, we describe a patient with MEN-I and duodenal gastrinomas who not only had a fall in serum gastrin, but also a regression of the tumors, which was documented by endoscopy 6 weeks after parathyroidectomy. This regression has been maintained in 2 years of followup.
CASE REPORT A 39-year-old man was admitted to the hospital after a syncopal episode. He had felt progressively weak and tired for 2 to 3 months prior to the event. He experienced facial flushing, dizziness, then a "black out" incident while working. There was no associated seizure activity, headache, chest pain, palpitation, dyspnea, abdominal pain, or nausea. The patient recovered from the syncope without sequelae. The patient had been treated medically for symptoms of peptic ulcer disease since he was 22 years old. He underwent subtotal gastric resection with Billroth II anastomosis 8 years before because of severe ulcer disease and gastric outlet obstruction. He did not require anti-secretory medication or experience recurrent dyspepsia or heartburn since the operation. Family history was notable for multiple cancers in many of the patient's first-degree relatives: his father died of colon cancer and his mother of pancreatic cancer. One of GASTROINTESTINAL ENDOSCOPY
Figure 3. Biopsy H & E stain of nodules showing APUD tumors (arrows). Obtained at initial endoscopy.
Figure 1. Anastomotic site of gastric remnant showing erythema and multiple superficial ulcerations prior to parathyroidectomy. Figure 2. Afferent loop stump with polypoid lesions (arrow) prior to parathyroidectomy. Figure 4. Gastrinomas reduced in size following parathyroidectomy (arrow). At 2-year follow-up nodules have disappeared.
his brothers had thyroid cancer and his sister was treated for leukemia. Diabetes mellitus and breast cancers were documented on the maternal side of his family. Review of systems was non-contributory including a negVOLUME 38, NO.6, 1992
ative history of weight loss, loss of appetite, or dumping syndrome. He denied any episode of hematemesis, melena, or hematochezia. He was a heavy cigarette smoker and consumed moderate alcohol on weekends. The physical examination was unremarkable except for old surgical scars on the abdomen. There was no sign of orthostatic hypotension, and stool guaiac was negative. Laboratory analysis on admission revealed a microcytic anemia (hemoglobin = 9.2, mean corpuscular volume = 73, reticulocyte count = 4.8, platelet = 607,000, iron = 36, ferritin = 27, and TIEC = 524) and an elevated serum calcium (12.3 mg/dO, phosphorous = 3.9). Because of the iron deficiency anemia and the possibility of hereditary nonpolyposis syndrome (Lynch Type 11), colonoscopy was performed as the initial work-up but no abnormality was found. MEN-I with ZES was also suspected because of the hypercalcemia and the history of complicated ulcer disease at an early age. Hypergastrinemia was demonstrated by a fasting serum level of 2950 pg/ml and parathyroid hormone was also elevated (67 pg/ml), suggesting parathyroid hyperactivity. Upper endoscopy was performed to evaluate the source of probable chronic blood loss and to search for possible gastrinoma in the proximal small bowel. The mucosa of the gastric remnant was irregular and the anastomotic margin was erythematous, friable, and ulcerated (Fig. 1). Multiple, grayish, polypoid lesions were found in the afferent loop stump (Fig. 2). Biopsies of these lesions and that of the stomach revealed nests of small, uniform cells arranged in organoid fashion on hematoxylin and eosin stain, consistent with APUD tumors (Fig. 3). Further evaluation by the Armed Forces Institute of Pathology using immunoperoxidase technique confirmed the diagnosis of gastrinoma in the afferent loop and carcinoid tumor in the gastric remnant. Gastric analysis showed a basal acid output of less than 1 mEq/hr. Secretin-stimulation test was positive with a peak gastrin of 5000 pg/ml at 5 min, compared with 3000 pg/ml at baseline. Urinary 5-HIAA was within the upper limit of normal (15 mg/24 hours). Abdominal CT scan and angiogram failed to reveal pancreatic gastrinoma or metastatic lesions. The patient underwent parathyroidectomy for control of the hypercalcemia. At surgery, all four hyperplastic glands were removed and a partial gland was autografted 707
under the skin of the forearm. The patient remained hypocalcemic for 4 to 5 weeks after surgery. At 6 weeks, he underwent follow-up endoscopy which demonstrated a significant reduction in size of the gastrinomas at the blind end of the afferent loop with smoothening and healing of the gastric mucosa (Fig. 4). Random sampling of the stomach failed to show evidence of gastric carcinoid, whereas target biopsies in the afferent loop were consistent with residual gastrinoma. A repeat fasting serum gastrin showed a lO-fold reduction (340 pg/ml) and the calcium level 7.5 mg/dl. Repeat endoscopy 2 years later demonstrated healing of gastric ulcerations and the absence of nodules in the afferent loop.
ogenetic implications: (1) the parathyroid gland in patients with MEN-I may contain a trophic substance responsible for the growth of APUD tumors including gastrinomas, or (2) hypercalcemia may be an important co-factor for certain mitogenic proteins found in MEN-I8 responsible for inducing growth of involved neoplasia. The regression of the gastric carcinoids follows reduction of the circulating gastrin level, as observed in pernicious anemia with carcinoid following antrectomy. ACKNOWLEDGMENT
DISCUSSION
The authors are grateful for the assistance of Dr. Paul Maton of the National Institute of Health.
We report a patient with MEN-I and multifocal gastrinomas found in the afferent limb of the Billroth II anastomosis as well as concomitant carcinoid tumors in the gastric remnant. Zollinger-Ellison tumors in patients with MEN-I are known to be multicentric and can be found in a duodenallocation. 3- 5 Coexisting gastric carcinoids have been reported with sporadic gastrinomas and in fewer cases with MEN-I. 6 The pathogenesis of the latter is speculated to be from the interaction of genetic factors, hypercalcemia, and the trophic effect of gastrin. 6- 7 Parathyroidectomy is the first line of treatment for gastric acid hypersecretion in patients with MEN-I and ZES. Norton et a1. 2 reported post-parathyroidectomy normalization of gastrin, BAO, and negative provocative tests in two patients with MEN-I as well as reduction of these parameters in seven other patients. We not only detected chemical reduction but also demonstrated by endoscopy for the first time regression of both the gastrinomas and the gastric carcinoid tumors following parathyroidectomy in our patient. This observation may offer two possible path-
1. Sheppard BC, Norton JA, Doppman JL, Maton PN, Gardner JD, Jensen RT. Management of islet cell tumors in patients with multiple endocrine neoplasia: a prospective study. Surgery 1989;106:1108-18. 2. Norton JA, Cornelius MJ, Doppman JL, Maton PN, Gardner JD, Jensen RT. Effect of parathyroidectomy in patients with hyperparathyroidism, Zollinger-Ellison syndrome, and multiple endocrine neoplasia type I: a prospective study. Surgery 1987;102:958-66. 3. Wolfe MM, Jensen RT. Zollinger-Ellison syndrome. Current concepts in diagnosis and management. N Engl J Med 1987;317:1200-9. 4. Andersen DK. Current diagnosis and management of ZollingerEllison syndrome. Ann Surg 1989;210:685-703. 5. Pipeleers-Merichel M, Somers G, Writtens G, et al. Gastrinomas in the duodenums of patients with multiple endocrine neoplasia type I and the Zollinger-Ellison Syndrome. N Engl J Med 1990;322:723-7. 6. Solcia E, Capella C, Dessa F, et al. Gastric carcinoids and related endocrine growths. Digestion 1986;35(suppll):3-22. 7. Carney JA, Go VLW, Fairbanks VF, Moore SB, Alport EC, Nora FE. The syndrome of gastric argyrophil carcinoid tumors and nonantral gastric atrophy. Ann Intern Med 1983;99:761-6. 8. Brandi ML, Aurbach GD, Fitzpatrick LA. Parathyroid mitogenic activity in plasma from patients with familial multiple endocrine neoplasia type I. N Engl J Med 1986;314:1287-93.
708
REFERENCES
GASTROINTESTINAL ENDOSCOPY
Regression of duodenal gastrinomas in a patient with multiple endocrine neoplasia type I after parathyroidectomy Hugh D. Mai, MD Robert A. Sanowski, MD
About 25% of patients with Zollinger-Ellison syndrome (ZES) have associated neoplasia of other endocrine organs (multiple endocrine neoplasia type I (MEN-I)). The prognosis for this familial form of gastrinoma is much better than that of the sporadic ones because of a lesser potential of becoming malignant. Surgical cure for subjects with gastrinoma and MEN-I, however, is rarely achieved because of the multicentric nature of the tumors, even with the new localization technique of selective venous sampling for gastrin gradient.! Norton et a1. 2 recommended parathyroidectomy as the initial operation for all patients with ZES and concomitant hypercalcemia due to parathyroid adenoma or hyperplasia (MEN-I). As a result of this surgery, it was shown that serum gastrin and From the Department of Gastroenterology, Carl T. Hayden Veterans Affairs Medical Center, Phoenix, Arizona. Reprint requests: Robert Sanowski, MD, Department of Gastroenterology, Hayden Veterans Affairs Medical Center, 650 E. Indian School Road, Phoenix, Arizona 85012. 706
17. 18.
19. 20. 21. 22. 23. 24. 25. 26. 27.
diagnosis of familial adenomatous polyposis. Br J Surg 1991;78:1394-5. Gilbertsen VA, Nelms JM. The prevention of invasive cancer of the rectum. Cancer 1978;41:1137-9. Winawer SJ, Zauber AG, Gerdes H, et al. Reduction in colorectal cancer incidence following colonoscopic polypectomy: report from the National Polyp Study (NPS) [Abstract]. Gastroenterology 1991;100:A41O. Ransohoff DF, Lang CA. Screening for colorectal cancer. N Engl J Med 1991;325:37-41. Friedman GD, Collen MF, Fireman BH. Multiphasic health check-up evaluation: a 16-year follow-up. J Chronic Dis 1986;39:453-63. Nagasako K, lizuka B, Yashiro K, Suzuki S. The diagnosis of superficial type early colorectal cancer [Abstract]. Gastroenterology 1991;100:A389. Tada M, Misaki F, Kawai K. Endoscopic observation of villi with magnifying enterocolonoscopes. Gastrointest Endosc 1982;28:17-9. Bird RP. Observation and quantification of aberrant crypts in the murine colon treated with a colon carcinogen: preliminary findings. Cancer Lett 1987;37:147-51. Pret!ow TP, Barrow BJ, Ashton WS, et al. Aberrant crypts: putative preneoplastic foci in human colonic mucosa. Cancer Res 1991;51:1564-7. Ida K, Tada M. Chromoscopy. In: Sivak MV, ed. Gastroenterologic endoscopy. Philadelphia: WB Saunders, 1987:203-20. Watanabe T, Muto T, Sawada T, et al. Usefulness of oral administration of indigocarmine for colonoscopy [Abstract]. Gastroenterology 1991;100:A21. Ngoi SS, Staino-Coico L, Godwin TA, Wong RJ, DeCosse JJ. Abnormal DNA ploidy and proliferative patterns in superficial colonic epithelium adjacent to colon cancer. Cancer 1990;66:953-9.
basal acid output were significantly reduced and response to H2 antagonists was improved. In this report, we describe a patient with MEN-I and duodenal gastrinomas who not only had a fall in serum gastrin, but also a regression of the tumors, which was documented by endoscopy 6 weeks after parathyroidectomy. This regression has been maintained in 2 years of followup.
CASE REPORT A 39-year-old man was admitted to the hospital after a syncopal episode. He had felt progressively weak and tired for 2 to 3 months prior to the event. He experienced facial flushing, dizziness, then a "black out" incident while working. There was no associated seizure activity, headache, chest pain, palpitation, dyspnea, abdominal pain, or nausea. The patient recovered from the syncope without sequelae. The patient had been treated medically for symptoms of peptic ulcer disease since he was 22 years old. He underwent subtotal gastric resection with Billroth II anastomosis 8 years before because of severe ulcer disease and gastric outlet obstruction. He did not require anti-secretory medication or experience recurrent dyspepsia or heartburn since the operation. Family history was notable for multiple cancers in many of the patient's first-degree relatives: his father died of colon cancer and his mother of pancreatic cancer. One of GASTROINTESTINAL ENDOSCOPY
Figure 3. Biopsy H & E stain of nodules showing APUD tumors (arrows). Obtained at initial endoscopy.
Figure 1. Anastomotic site of gastric remnant showing erythema and multiple superficial ulcerations prior to parathyroidectomy. Figure 2. Afferent loop stump with polypoid lesions (arrow) prior to parathyroidectomy. Figure 4. Gastrinomas reduced in size following parathyroidectomy (arrow). At 2-year follow-up nodules have disappeared.
his brothers had thyroid cancer and his sister was treated for leukemia. Diabetes mellitus and breast cancers were documented on the maternal side of his family. Review of systems was non-contributory including a negVOLUME 38, NO.6, 1992
ative history of weight loss, loss of appetite, or dumping syndrome. He denied any episode of hematemesis, melena, or hematochezia. He was a heavy cigarette smoker and consumed moderate alcohol on weekends. The physical examination was unremarkable except for old surgical scars on the abdomen. There was no sign of orthostatic hypotension, and stool guaiac was negative. Laboratory analysis on admission revealed a microcytic anemia (hemoglobin = 9.2, mean corpuscular volume = 73, reticulocyte count = 4.8, platelet = 607,000, iron = 36, ferritin = 27, and TIEC = 524) and an elevated serum calcium (12.3 mg/dO, phosphorous = 3.9). Because of the iron deficiency anemia and the possibility of hereditary nonpolyposis syndrome (Lynch Type 11), colonoscopy was performed as the initial work-up but no abnormality was found. MEN-I with ZES was also suspected because of the hypercalcemia and the history of complicated ulcer disease at an early age. Hypergastrinemia was demonstrated by a fasting serum level of 2950 pg/ml and parathyroid hormone was also elevated (67 pg/ml), suggesting parathyroid hyperactivity. Upper endoscopy was performed to evaluate the source of probable chronic blood loss and to search for possible gastrinoma in the proximal small bowel. The mucosa of the gastric remnant was irregular and the anastomotic margin was erythematous, friable, and ulcerated (Fig. 1). Multiple, grayish, polypoid lesions were found in the afferent loop stump (Fig. 2). Biopsies of these lesions and that of the stomach revealed nests of small, uniform cells arranged in organoid fashion on hematoxylin and eosin stain, consistent with APUD tumors (Fig. 3). Further evaluation by the Armed Forces Institute of Pathology using immunoperoxidase technique confirmed the diagnosis of gastrinoma in the afferent loop and carcinoid tumor in the gastric remnant. Gastric analysis showed a basal acid output of less than 1 mEq/hr. Secretin-stimulation test was positive with a peak gastrin of 5000 pg/ml at 5 min, compared with 3000 pg/ml at baseline. Urinary 5-HIAA was within the upper limit of normal (15 mg/24 hours). Abdominal CT scan and angiogram failed to reveal pancreatic gastrinoma or metastatic lesions. The patient underwent parathyroidectomy for control of the hypercalcemia. At surgery, all four hyperplastic glands were removed and a partial gland was autografted 707
under the skin of the forearm. The patient remained hypocalcemic for 4 to 5 weeks after surgery. At 6 weeks, he underwent follow-up endoscopy which demonstrated a significant reduction in size of the gastrinomas at the blind end of the afferent loop with smoothening and healing of the gastric mucosa (Fig. 4). Random sampling of the stomach failed to show evidence of gastric carcinoid, whereas target biopsies in the afferent loop were consistent with residual gastrinoma. A repeat fasting serum gastrin showed a lO-fold reduction (340 pg/ml) and the calcium level 7.5 mg/dl. Repeat endoscopy 2 years later demonstrated healing of gastric ulcerations and the absence of nodules in the afferent loop.
ogenetic implications: (1) the parathyroid gland in patients with MEN-I may contain a trophic substance responsible for the growth of APUD tumors including gastrinomas, or (2) hypercalcemia may be an important co-factor for certain mitogenic proteins found in MEN-I8 responsible for inducing growth of involved neoplasia. The regression of the gastric carcinoids follows reduction of the circulating gastrin level, as observed in pernicious anemia with carcinoid following antrectomy. ACKNOWLEDGMENT
DISCUSSION
The authors are grateful for the assistance of Dr. Paul Maton of the National Institute of Health.
We report a patient with MEN-I and multifocal gastrinomas found in the afferent limb of the Billroth II anastomosis as well as concomitant carcinoid tumors in the gastric remnant. Zollinger-Ellison tumors in patients with MEN-I are known to be multicentric and can be found in a duodenallocation. 3- 5 Coexisting gastric carcinoids have been reported with sporadic gastrinomas and in fewer cases with MEN-I. 6 The pathogenesis of the latter is speculated to be from the interaction of genetic factors, hypercalcemia, and the trophic effect of gastrin. 6- 7 Parathyroidectomy is the first line of treatment for gastric acid hypersecretion in patients with MEN-I and ZES. Norton et a1. 2 reported post-parathyroidectomy normalization of gastrin, BAO, and negative provocative tests in two patients with MEN-I as well as reduction of these parameters in seven other patients. We not only detected chemical reduction but also demonstrated by endoscopy for the first time regression of both the gastrinomas and the gastric carcinoid tumors following parathyroidectomy in our patient. This observation may offer two possible path-
1. Sheppard BC, Norton JA, Doppman JL, Maton PN, Gardner JD, Jensen RT. Management of islet cell tumors in patients with multiple endocrine neoplasia: a prospective study. Surgery 1989;106:1108-18. 2. Norton JA, Cornelius MJ, Doppman JL, Maton PN, Gardner JD, Jensen RT. Effect of parathyroidectomy in patients with hyperparathyroidism, Zollinger-Ellison syndrome, and multiple endocrine neoplasia type I: a prospective study. Surgery 1987;102:958-66. 3. Wolfe MM, Jensen RT. Zollinger-Ellison syndrome. Current concepts in diagnosis and management. N Engl J Med 1987;317:1200-9. 4. Andersen DK. Current diagnosis and management of ZollingerEllison syndrome. Ann Surg 1989;210:685-703. 5. Pipeleers-Merichel M, Somers G, Writtens G, et al. Gastrinomas in the duodenums of patients with multiple endocrine neoplasia type I and the Zollinger-Ellison Syndrome. N Engl J Med 1990;322:723-7. 6. Solcia E, Capella C, Dessa F, et al. Gastric carcinoids and related endocrine growths. Digestion 1986;35(suppll):3-22. 7. Carney JA, Go VLW, Fairbanks VF, Moore SB, Alport EC, Nora FE. The syndrome of gastric argyrophil carcinoid tumors and nonantral gastric atrophy. Ann Intern Med 1983;99:761-6. 8. Brandi ML, Aurbach GD, Fitzpatrick LA. Parathyroid mitogenic activity in plasma from patients with familial multiple endocrine neoplasia type I. N Engl J Med 1986;314:1287-93.
708
REFERENCES
GASTROINTESTINAL ENDOSCOPY