- Email: [email protected]
Familial endocrine adenomatosis with associated zollinger-ellison syndrome
Familial Endocrine Associated
Zollinger-Ellison Wermer’s
Il. J.
LULU,
Adenomatosis
M.D., T. E. CORCORAN, M.D., AND
WI. ANDRE,
1954 Wermer documented the familial occurrence of intractable peptic ulcer with coexisting adenomatosis of the pancreatic islet cells, anterior pituitary gland, and parathyroid glands [I]. In 1955 Zollinger and Ellison presented their classic paper on severe peptic ulceration in patients with pancreatic islet cell tumors [Z]. Since that time increasing numbers of cases of the Zollinger-Ellison syndrome have been reported with cases of multiple endocrine adenomas which exhibit a propensity to familial distribution [3-61. The original characteristics as outlined by Wermer [1] included benign tumor of the anterior pituitary gland, adenomatous hyperplasia of the parathyroids, multiple benign or malignant pancreatic islet cell tumors, and peptic ulceration. This was later broadened by Wermer [5] to include adenomatous goiter, multiple benign or malignant cortical adrenal tumors, carcinoid bronchial adenomas, and multiple lipomatosis. This paper presents a case of Wermer’s syndrome with a familial propensity and reviews some of the diagnostic and therapeutic problems encountered. REPORTS
The patient, a forty-one year old white man, was admitted to the Des Moines Veterans CASE I.
* PRESENT ADDRESS: 62nd Med. Det., 3rd Field Hospital, Vol. 115, May 1968
M.D.,*
Des Moines, Iowa
Administration Hospital on July 8,1965 for treatment of severe epigastric pain. Past history revealed repeated attacks of renal calculi for which he was hospitalized elsewhere in January 1964. A resection of three of four parathyroid glands was performed at that time. The histologic report on one of the glands removed showed a parathyroid adenoma. (Fig. 1.) A diagnosis of Zollinger-Ellison syndrome was made at that time but since improvement in the patient’s ulcer symptoms occurred, he was allowed to return home on medical management, The ulcer symptoms recurred and he was admitted to the Veterans Administration Hospital on July 8, 1965. Physical examination revealed an emaciated, acutely ill, forty-one year old white man, 69 inches in height and weighing 118 pounds. There was tenderness to palpation in the epigastrium and scars were found from the previous surgical procedures, but the examination was otherwise unremarkable. Twelve hour nocturnal fasting gastric analysis yielded a total volume of 4,500 cc. with 472 mEq./L. of free hydrochloric acid. Routine laboratory studies gave normal results except for revealing a hemoconcentration. Serum calcium and phosphorus studies gave results within normal limits, as did quantitative calcium urine determinations. Serum electrolyte values were as follows: carbon dioxide combining power 31.1 volumes per cent, chlorides 83 mEq./L., sodium 139 mEq./L., and potassium 3.0 mEq./L. An upper gastrointestinal series revealed the rugae to be quite coarse and irregular. The duodenal bulb was irritable and filled poorly and the appearance of the gastric mucosa was suggestive of gastritis. Despite the history of duodenal ulcer, no ulceration was noted. (Fig. 2.) After nineteen days of strict medical treatment the patient was seen by the surgical service because of
N
CASE
Syndrome
Syndrome
From the Department of Surgery and Pathology, Veterans Administration Hospital, Des Moines, Iowa. Send reprint request to Dr. Louis T. Palumbo, Department of Surgery, Veterans ddministration Center, Des Moines, Iowa 50308.
I
with
695
A.P.O. 307, San Francisco,
California 96307.
Lulu, Corcoran, and Andre
696
4
3 FIG. 3. Left adrenal gland with cortical adenoma.
FIG.4. Distal two thirds of the pancreas with three islet cell adenomas (arrows). severe abdominal pain. A diagnosis of perforated peptic ulcer was made. At surgery, in July 1965, a perforation of the jejunum 10 cm. from the ligament of Treitz was found and this was closed with an omental patch graft. There was minimal contamination of the peritoneal cavity, but the stomach and small intestine were markedly thickened and edematous. A small 8 mm. nodule was felt in the body of the pancreas and a large mass measuring about 6 by 8 by 4 cm. was palpated in the region of the left adrenal gland. Since the patient’s condition was satisfactory, the distal two thirds of the pancreas, with the spleen, was resected and a left adrenalectomy performed. (Fig. 3 and 4.) Postoperatively the patient did well except for persistent epigastric pain which did not respond to treatment.
The pathology report on the removed tissue revealed the following: (1) multiple islet cell adenomas of the pancreas (Fig. 5), (2) cortical adenoma of the left adrenal gland weighing 155 gm., and (3) spleen. Results of serial postoperative twelve hour fasting nocturnal gastric analyses ranged from 700 to 3,650 ml. in total volume and from 58 to 409 mEq./L. of free hydrochloric acid. Fasting blood sugar levels ranged from 100 to 132 mg. per cent. Since it was obvious that the ulcer diathesis was uncontrolled, the patient was operated on again on August 13, seventeen days after the initial abdominal surgery. At this time total gastrectomy was performed with esophagojejunostomy, jejunojejunostomy, and resection of the previous jejunal perforation. Biopsies of two suspicious areas in the uncinate process of the pancreas were also carried out. A shallow duodenal ulcer was left in situ. American
Journal of Suvgevy
Adenomatosis with Zollinger-Ellison Syndrome
697
FIG. 5. Microsconic armearance of uancreatic islet cell adenoma. Original mag__ nification X 90.-
The pathology report on the removed tissue showed the following: (1) peripancreatic lymph node containing islet cell adenocarcinoma, (2) islet cell adenocarcinoma of the pancreas (Fig. 6), (3) portion of duodenum, (4) portion of stomach showing mucosal hypertrophy (Fig. 7), (5) portion of jejunum, and (G) jejunal ulcer. All material was submitted to the Armed Forces Institute of Pathology in Washington, D. C. ; and their pathologists concurred in our diagnoses. Postoperatively the patient did well and was discharged from the hospital on September 3, 1965. Since discharge the patient has been seen at periodic intervals. LVhen last seen in April 1967, he had gained 35 pounds. He had passed further urinary calculi which were analyzed and found to consist of ammonium and calcium phosphates. Repeat studies of calcium, phosphorus, and tubular resorption of phosphorus gave results within normal limits, and an intravenous pyelogram and skull films taken with particular reference to the sella turcica showed nothing abnormal, CASE II. The patient, a forty-two year old merchant seaman and brother of the patient reported in case I, was admitted to the Veterans Administration Center in Des Moines in August 1964 for a terminal malignant disease and died six days after admission. On admission he complained of severe intermittent epigastric pain which was burrowing in character and radiating into the back and which was of Vol. 115. May 1968
eighteen months’ duration. He denied having alcoholism. Past history revealed treatment over a ten month period in several hospitals in the United States for a “ruptured pancreatic cyst” and for diabetes mellitus. Two months prior to admission he underwent biopsy of the left scalene node, which was reportedly “malignant.” He had repeatedly passed renal calculi and in 1954 had undergone a right nephrotomy for calculi. In 195i a right thoracotomy had been performed for “carcinoma of the thymus” at another hospital, Physical examination revealed well healed scars from the aforementioned operations and a large, firm, and tender epigastric mass. The patient was extremely dehydrated and progressed into acute renal failure. Intravenous pyelograms revealed no visualization and retrograde pyelograms showed a normal collecting system with no evidence of obstruction. Results of laboratory studies were as follows: hemoglobin was 11.8 gm. per cent and hematocrit 41.0 per cent. Urinalysis revealed 3 plus albumin, 15 to 18 white blood cells per high power field, 0 to 2 red blood cells per high power field, and 0 to 2 white blood cell casts per high power field. White blood cell count was 13, 900 per mma., with 64 per cent neutrophils, 35 per cent band neutrophils, and 1 per cent lymphocytes. Serum electrolytes were as follows: sodium 128 mEq./L., chlorides 85 mEq./L., potassium 3.2 mEq./L., calcium 2.5 mEq./L., phosphorus 3.2 mEq./L. Carbon dioxide combining
Lulu, Corcoran, and Andre
698
Fro. 6. Microscopic appearance inal magnification X 45.
of pancreatic
power was 20.7 volumes per cent, total protein 4.1 gm. per cent, albumin 2.6 per cent, globulin 1.5 gm. per cent, blood urea nitrogen 30 to 92 mg. per cent, alkaline phosphatase 6.3 Bodansky units, fasting blood sugar 110 mg. per cent, serum amylase 556 S units. Blood volume was 3.4 L. with a predicted normal of 5.6 L. Despite therapy the patient died. Postmortem examination revealed lobar pneumonia, bilateral pleural effusion and ascites, islet cell adenocarcinoma
FIG. 7. Total gastrectomy
FIG. 8. Pancreatic
islet cell adenocarcinoma.
of the pancreas with mediastinal lymph node metastasis, adrenal abscesses, and bilateral sandlike nephrolithiasis. No comment was made about the parathyroid glands, although the thyroid was described as being normal. (Fig. 8 and 9.) The patient’s mother died of “carcinoma of the after a diagnostic liver biopsy had been pancreas” performed. (Fig. 10.) No autopsy had been performed. There are two other male siblings alive and well.
specimen showing hypertrophy
islet cell adenocarcinoma.
Orig-
of rugae. Arrow points to esophagus.
Original magnification
X 90. American Journal of Surgery
Adenomatosis
with Zollinger-Ellison
FIG. 9. Mediastinal lymph node containing inal magnification X 90. COMMENTS
This striking familial incidence of malignant pancre, atic lesions, all of which were islet cell adenoc ,arcinomas, would tend to conform to WermCx’s syndrome and should suggest diligent search for multiple endocrine adenomas in pa-
FIG. 10. Liver metastasis containing nikation X 160. Vol. 115, May 1968
Syndrome
islet cell adenocarcinoma.
699
Orig-
tients presenting with Zollingcx-Ellison. syndrome [5,6]. The incidence of multiple en docrine a.denopathies ranges from 20 to 30 per cent diag nosed clinically to 50 per cent diagno sed at aultopsy [3, 7-101.
islet cell adenocarcinoma.
Original mag-
700
Lulu, Corcoran, and Andre
More than eighty cases of polyendocrine adenomatosis had been reported by 1966 with most of the more recent reports showing the disease to be associated with peptic ulceration. The presenting symptoms of Zollinger-Ellison syndrome in order of frequency were epigastric or ulcer-like pain, vomiting, weight loss, diarrhea, melena, hematemesis, and abdominal cramps [9,10]. The sex incidence was reported as varying from equal [9] to 3 to 2 in favor of male patients [lo]. The age of patients at onset of symptoms ranged from the third to the fifth decade. The ulcer was most commonly located in the duodenum, but in approximately 25 per cent of the patients the ulcer was found in such atypical locations as the distal duodenum or jejunum [lo]. In a review of 260 registered cases of Zollinger-Ellison syndrome Mlison and Wilson [lo] found only 3 per cent with polyendocrine adenomatosis. Solitary nodules were more often located in the pancreatic head (22 per cent), with 7 per cent in the body, and 19 per cent in the tail; 50 to 60 per cent were malignant [lo]. Distinct nodules were noted in 78 per cent of the cases and 40 per cent of the cases involved multiple nodules [9]. Extrapancreatic tumor without evidence of pancreatic tumor occurred in 15 per cent of the cases. The diagnosis of islet cell hyperplasia was made when the islet exceeded 250 p in diameter [a], but the eagerness of the pathologist to support the clinical diagnosis in reported cases without recognizable adenomas must cause one to accept such diagnosis with caution, particularly when the body and tail of the pancreas are resected where islets are normally more numerous 1111. Radiologic criteria which have been cited as diagnostic of polyendocrine adenomatosis include [IZ]: (1) giant hypertropy of the gastric rugae (Menetrier’s disease) ; (2) peptic ulceration, frequently multiple, enormous in size, and atypical in location; (3) widening of the duodenum distal to the bulb, with markedly enlarged and coarsened mucosal folds with rigidity of the duodenal wall; (4) jejunal changes similar to those described in the duodenum; and (5) adherence of contrast material to the large mucosal folds after the bolus has passed, which was described as a striking finding. Twelve hour nocturnal fasting gastric secretions reported in large series [9,10] ranged from less than 26 mEq. of free hydrochloric acid to 700 mEq. and from 250 ml. to over 6,900 ml. in
total volume. The average amount of free hydrochloric acid was 165 mEq. TREATMENT
Treatment has now been standardized fairly well by most authorities on the subject [4,921,131. Medical therapy is universally agreed to be unsuccessful and results in death. Surgical therapy, in most cases, must include total gastrectomy with or without pancreatic resection. Total pancreatectomy is not believed to be warranted but subtotal pancreatectomy in conjunction with total gastrectomy is advisable even in the absence of obvious pancreatic tumor nodules since more than half of the adenomas are malignant. SUMMARY
A case of Wermer’s syndrome with a familial background of islet cell adenocarcinoma is presented. The need for a diligent search for such multiple endocrine adenomas is stressed. A brief review of the literature is followed by a discussion of surgical treatment. Acknowledgment: Drs. R. Tidrick and E. Mason of the Department of Surgery of the University of Iowa Hospitals aided in procuring the patients’ past records. Dr. J. Davis of the Department of Pathology of the University of Iowa and Dr. R. Dunn of Fort Dodge, Iowa supplied microscopic sections. REFERENCES 1. CLAUDE, H. and BOUDOUIN,A. Cited by Wermer, P.
2.
3.
4,
5.
6.
7. 8.
Genetic aspects of adenomatosis of endocrine glands. Am. J. Med., 16: 363, 1954. ZOLLINGER, R. M. and ELLISON, E. H. Primary peptic ulcerations of jejunum associated with islet cell tumors of the pancreas. Ann. Surg., 142: 709, 1955. MIEHER, W. C., JR., HARTSOCK, R. T., GEOKAS, M. C., BALLARDS, H. S., and FRAME, B. Peptic ulcer as a manifestation of familial polyendocrine disease. J.A.M.A., 179: 854, 1962. MOLDAWER, M. Multiple endocrine tumors and Zollinger-Ellison syndrome in families: one or two syndromes?. Metabolism, 11: 153, 1962. WERMER, P. Endocrine adenomatosis and peptic ulcer in a large kindred. Inherited multiple tumors and mosaic pleiotropism in man. Am. J. Surg., 105: 205, 1963. ZOLLINGER, R. M. and CRAIG, T. V. Endocrine tumors and peptic ulcer. Am. J. Med., 29: 761, 1960. DEMUTH, W. E., JR. Zollinger-Ellison syndrome. Arch. Surg., 88: 244, 1964. GIBSON, J. B. and WELBOURN, R. B. Islet-cell American Jouvnal of Surgery
Adenomatosis with Zollinger-Ellison Syndrome tumors and peptic ulceration. Postgrad. M. J., 36: 154, 1960. 9. CHRISTLIEB, A. R. and SCHUSTER,M. M. ZollingerEllison syndrome. Arch. Int. Med., 114:381, 1964. 10. ELLISON, E. H. and WILSON, S. D. The ZollingerEllison syndrome: reappraisal and evaluation of 260 registered cases. Am. Surg., 160: 512, 1964. 11. FRANTZ, V. F. Tumors of the pancreas. Armed
Vol.
115, May
1968
701
Forces Institute of Pathology, fast. 27, sect. VII. Washington, 1959. 12. SCHLAEGER, R., LE MAY, M., and WERMER, P. Upper gastro-intestinal tract alternations in adenomatosis of the endocrine glands. &diology, 75: 517, 1960. 13. PRIEST, W. M. and ALEXANDER, M. K. Islet-cell tumor pancreas with peptic ulceration, diarrhoea and hypokalaemia. Lanret, 2: 1145, 1957.
Zollinger-Ellison Wermer’s
Il. J.
LULU,
Adenomatosis
M.D., T. E. CORCORAN, M.D., AND
WI. ANDRE,
1954 Wermer documented the familial occurrence of intractable peptic ulcer with coexisting adenomatosis of the pancreatic islet cells, anterior pituitary gland, and parathyroid glands [I]. In 1955 Zollinger and Ellison presented their classic paper on severe peptic ulceration in patients with pancreatic islet cell tumors [Z]. Since that time increasing numbers of cases of the Zollinger-Ellison syndrome have been reported with cases of multiple endocrine adenomas which exhibit a propensity to familial distribution [3-61. The original characteristics as outlined by Wermer [1] included benign tumor of the anterior pituitary gland, adenomatous hyperplasia of the parathyroids, multiple benign or malignant pancreatic islet cell tumors, and peptic ulceration. This was later broadened by Wermer [5] to include adenomatous goiter, multiple benign or malignant cortical adrenal tumors, carcinoid bronchial adenomas, and multiple lipomatosis. This paper presents a case of Wermer’s syndrome with a familial propensity and reviews some of the diagnostic and therapeutic problems encountered. REPORTS
The patient, a forty-one year old white man, was admitted to the Des Moines Veterans CASE I.
* PRESENT ADDRESS: 62nd Med. Det., 3rd Field Hospital, Vol. 115, May 1968
M.D.,*
Des Moines, Iowa
Administration Hospital on July 8,1965 for treatment of severe epigastric pain. Past history revealed repeated attacks of renal calculi for which he was hospitalized elsewhere in January 1964. A resection of three of four parathyroid glands was performed at that time. The histologic report on one of the glands removed showed a parathyroid adenoma. (Fig. 1.) A diagnosis of Zollinger-Ellison syndrome was made at that time but since improvement in the patient’s ulcer symptoms occurred, he was allowed to return home on medical management, The ulcer symptoms recurred and he was admitted to the Veterans Administration Hospital on July 8, 1965. Physical examination revealed an emaciated, acutely ill, forty-one year old white man, 69 inches in height and weighing 118 pounds. There was tenderness to palpation in the epigastrium and scars were found from the previous surgical procedures, but the examination was otherwise unremarkable. Twelve hour nocturnal fasting gastric analysis yielded a total volume of 4,500 cc. with 472 mEq./L. of free hydrochloric acid. Routine laboratory studies gave normal results except for revealing a hemoconcentration. Serum calcium and phosphorus studies gave results within normal limits, as did quantitative calcium urine determinations. Serum electrolyte values were as follows: carbon dioxide combining power 31.1 volumes per cent, chlorides 83 mEq./L., sodium 139 mEq./L., and potassium 3.0 mEq./L. An upper gastrointestinal series revealed the rugae to be quite coarse and irregular. The duodenal bulb was irritable and filled poorly and the appearance of the gastric mucosa was suggestive of gastritis. Despite the history of duodenal ulcer, no ulceration was noted. (Fig. 2.) After nineteen days of strict medical treatment the patient was seen by the surgical service because of
N
CASE
Syndrome
Syndrome
From the Department of Surgery and Pathology, Veterans Administration Hospital, Des Moines, Iowa. Send reprint request to Dr. Louis T. Palumbo, Department of Surgery, Veterans ddministration Center, Des Moines, Iowa 50308.
I
with
695
A.P.O. 307, San Francisco,
California 96307.
Lulu, Corcoran, and Andre
696
4
3 FIG. 3. Left adrenal gland with cortical adenoma.
FIG.4. Distal two thirds of the pancreas with three islet cell adenomas (arrows). severe abdominal pain. A diagnosis of perforated peptic ulcer was made. At surgery, in July 1965, a perforation of the jejunum 10 cm. from the ligament of Treitz was found and this was closed with an omental patch graft. There was minimal contamination of the peritoneal cavity, but the stomach and small intestine were markedly thickened and edematous. A small 8 mm. nodule was felt in the body of the pancreas and a large mass measuring about 6 by 8 by 4 cm. was palpated in the region of the left adrenal gland. Since the patient’s condition was satisfactory, the distal two thirds of the pancreas, with the spleen, was resected and a left adrenalectomy performed. (Fig. 3 and 4.) Postoperatively the patient did well except for persistent epigastric pain which did not respond to treatment.
The pathology report on the removed tissue revealed the following: (1) multiple islet cell adenomas of the pancreas (Fig. 5), (2) cortical adenoma of the left adrenal gland weighing 155 gm., and (3) spleen. Results of serial postoperative twelve hour fasting nocturnal gastric analyses ranged from 700 to 3,650 ml. in total volume and from 58 to 409 mEq./L. of free hydrochloric acid. Fasting blood sugar levels ranged from 100 to 132 mg. per cent. Since it was obvious that the ulcer diathesis was uncontrolled, the patient was operated on again on August 13, seventeen days after the initial abdominal surgery. At this time total gastrectomy was performed with esophagojejunostomy, jejunojejunostomy, and resection of the previous jejunal perforation. Biopsies of two suspicious areas in the uncinate process of the pancreas were also carried out. A shallow duodenal ulcer was left in situ. American
Journal of Suvgevy
Adenomatosis with Zollinger-Ellison Syndrome
697
FIG. 5. Microsconic armearance of uancreatic islet cell adenoma. Original mag__ nification X 90.-
The pathology report on the removed tissue showed the following: (1) peripancreatic lymph node containing islet cell adenocarcinoma, (2) islet cell adenocarcinoma of the pancreas (Fig. 6), (3) portion of duodenum, (4) portion of stomach showing mucosal hypertrophy (Fig. 7), (5) portion of jejunum, and (G) jejunal ulcer. All material was submitted to the Armed Forces Institute of Pathology in Washington, D. C. ; and their pathologists concurred in our diagnoses. Postoperatively the patient did well and was discharged from the hospital on September 3, 1965. Since discharge the patient has been seen at periodic intervals. LVhen last seen in April 1967, he had gained 35 pounds. He had passed further urinary calculi which were analyzed and found to consist of ammonium and calcium phosphates. Repeat studies of calcium, phosphorus, and tubular resorption of phosphorus gave results within normal limits, and an intravenous pyelogram and skull films taken with particular reference to the sella turcica showed nothing abnormal, CASE II. The patient, a forty-two year old merchant seaman and brother of the patient reported in case I, was admitted to the Veterans Administration Center in Des Moines in August 1964 for a terminal malignant disease and died six days after admission. On admission he complained of severe intermittent epigastric pain which was burrowing in character and radiating into the back and which was of Vol. 115. May 1968
eighteen months’ duration. He denied having alcoholism. Past history revealed treatment over a ten month period in several hospitals in the United States for a “ruptured pancreatic cyst” and for diabetes mellitus. Two months prior to admission he underwent biopsy of the left scalene node, which was reportedly “malignant.” He had repeatedly passed renal calculi and in 1954 had undergone a right nephrotomy for calculi. In 195i a right thoracotomy had been performed for “carcinoma of the thymus” at another hospital, Physical examination revealed well healed scars from the aforementioned operations and a large, firm, and tender epigastric mass. The patient was extremely dehydrated and progressed into acute renal failure. Intravenous pyelograms revealed no visualization and retrograde pyelograms showed a normal collecting system with no evidence of obstruction. Results of laboratory studies were as follows: hemoglobin was 11.8 gm. per cent and hematocrit 41.0 per cent. Urinalysis revealed 3 plus albumin, 15 to 18 white blood cells per high power field, 0 to 2 red blood cells per high power field, and 0 to 2 white blood cell casts per high power field. White blood cell count was 13, 900 per mma., with 64 per cent neutrophils, 35 per cent band neutrophils, and 1 per cent lymphocytes. Serum electrolytes were as follows: sodium 128 mEq./L., chlorides 85 mEq./L., potassium 3.2 mEq./L., calcium 2.5 mEq./L., phosphorus 3.2 mEq./L. Carbon dioxide combining
Lulu, Corcoran, and Andre
698
Fro. 6. Microscopic appearance inal magnification X 45.
of pancreatic
power was 20.7 volumes per cent, total protein 4.1 gm. per cent, albumin 2.6 per cent, globulin 1.5 gm. per cent, blood urea nitrogen 30 to 92 mg. per cent, alkaline phosphatase 6.3 Bodansky units, fasting blood sugar 110 mg. per cent, serum amylase 556 S units. Blood volume was 3.4 L. with a predicted normal of 5.6 L. Despite therapy the patient died. Postmortem examination revealed lobar pneumonia, bilateral pleural effusion and ascites, islet cell adenocarcinoma
FIG. 7. Total gastrectomy
FIG. 8. Pancreatic
islet cell adenocarcinoma.
of the pancreas with mediastinal lymph node metastasis, adrenal abscesses, and bilateral sandlike nephrolithiasis. No comment was made about the parathyroid glands, although the thyroid was described as being normal. (Fig. 8 and 9.) The patient’s mother died of “carcinoma of the after a diagnostic liver biopsy had been pancreas” performed. (Fig. 10.) No autopsy had been performed. There are two other male siblings alive and well.
specimen showing hypertrophy
islet cell adenocarcinoma.
Orig-
of rugae. Arrow points to esophagus.
Original magnification
X 90. American Journal of Surgery
Adenomatosis
with Zollinger-Ellison
FIG. 9. Mediastinal lymph node containing inal magnification X 90. COMMENTS
This striking familial incidence of malignant pancre, atic lesions, all of which were islet cell adenoc ,arcinomas, would tend to conform to WermCx’s syndrome and should suggest diligent search for multiple endocrine adenomas in pa-
FIG. 10. Liver metastasis containing nikation X 160. Vol. 115, May 1968
Syndrome
islet cell adenocarcinoma.
699
Orig-
tients presenting with Zollingcx-Ellison. syndrome [5,6]. The incidence of multiple en docrine a.denopathies ranges from 20 to 30 per cent diag nosed clinically to 50 per cent diagno sed at aultopsy [3, 7-101.
islet cell adenocarcinoma.
Original mag-
700
Lulu, Corcoran, and Andre
More than eighty cases of polyendocrine adenomatosis had been reported by 1966 with most of the more recent reports showing the disease to be associated with peptic ulceration. The presenting symptoms of Zollinger-Ellison syndrome in order of frequency were epigastric or ulcer-like pain, vomiting, weight loss, diarrhea, melena, hematemesis, and abdominal cramps [9,10]. The sex incidence was reported as varying from equal [9] to 3 to 2 in favor of male patients [lo]. The age of patients at onset of symptoms ranged from the third to the fifth decade. The ulcer was most commonly located in the duodenum, but in approximately 25 per cent of the patients the ulcer was found in such atypical locations as the distal duodenum or jejunum [lo]. In a review of 260 registered cases of Zollinger-Ellison syndrome Mlison and Wilson [lo] found only 3 per cent with polyendocrine adenomatosis. Solitary nodules were more often located in the pancreatic head (22 per cent), with 7 per cent in the body, and 19 per cent in the tail; 50 to 60 per cent were malignant [lo]. Distinct nodules were noted in 78 per cent of the cases and 40 per cent of the cases involved multiple nodules [9]. Extrapancreatic tumor without evidence of pancreatic tumor occurred in 15 per cent of the cases. The diagnosis of islet cell hyperplasia was made when the islet exceeded 250 p in diameter [a], but the eagerness of the pathologist to support the clinical diagnosis in reported cases without recognizable adenomas must cause one to accept such diagnosis with caution, particularly when the body and tail of the pancreas are resected where islets are normally more numerous 1111. Radiologic criteria which have been cited as diagnostic of polyendocrine adenomatosis include [IZ]: (1) giant hypertropy of the gastric rugae (Menetrier’s disease) ; (2) peptic ulceration, frequently multiple, enormous in size, and atypical in location; (3) widening of the duodenum distal to the bulb, with markedly enlarged and coarsened mucosal folds with rigidity of the duodenal wall; (4) jejunal changes similar to those described in the duodenum; and (5) adherence of contrast material to the large mucosal folds after the bolus has passed, which was described as a striking finding. Twelve hour nocturnal fasting gastric secretions reported in large series [9,10] ranged from less than 26 mEq. of free hydrochloric acid to 700 mEq. and from 250 ml. to over 6,900 ml. in
total volume. The average amount of free hydrochloric acid was 165 mEq. TREATMENT
Treatment has now been standardized fairly well by most authorities on the subject [4,921,131. Medical therapy is universally agreed to be unsuccessful and results in death. Surgical therapy, in most cases, must include total gastrectomy with or without pancreatic resection. Total pancreatectomy is not believed to be warranted but subtotal pancreatectomy in conjunction with total gastrectomy is advisable even in the absence of obvious pancreatic tumor nodules since more than half of the adenomas are malignant. SUMMARY
A case of Wermer’s syndrome with a familial background of islet cell adenocarcinoma is presented. The need for a diligent search for such multiple endocrine adenomas is stressed. A brief review of the literature is followed by a discussion of surgical treatment. Acknowledgment: Drs. R. Tidrick and E. Mason of the Department of Surgery of the University of Iowa Hospitals aided in procuring the patients’ past records. Dr. J. Davis of the Department of Pathology of the University of Iowa and Dr. R. Dunn of Fort Dodge, Iowa supplied microscopic sections. REFERENCES 1. CLAUDE, H. and BOUDOUIN,A. Cited by Wermer, P.
2.
3.
4,
5.
6.
7. 8.
Genetic aspects of adenomatosis of endocrine glands. Am. J. Med., 16: 363, 1954. ZOLLINGER, R. M. and ELLISON, E. H. Primary peptic ulcerations of jejunum associated with islet cell tumors of the pancreas. Ann. Surg., 142: 709, 1955. MIEHER, W. C., JR., HARTSOCK, R. T., GEOKAS, M. C., BALLARDS, H. S., and FRAME, B. Peptic ulcer as a manifestation of familial polyendocrine disease. J.A.M.A., 179: 854, 1962. MOLDAWER, M. Multiple endocrine tumors and Zollinger-Ellison syndrome in families: one or two syndromes?. Metabolism, 11: 153, 1962. WERMER, P. Endocrine adenomatosis and peptic ulcer in a large kindred. Inherited multiple tumors and mosaic pleiotropism in man. Am. J. Surg., 105: 205, 1963. ZOLLINGER, R. M. and CRAIG, T. V. Endocrine tumors and peptic ulcer. Am. J. Med., 29: 761, 1960. DEMUTH, W. E., JR. Zollinger-Ellison syndrome. Arch. Surg., 88: 244, 1964. GIBSON, J. B. and WELBOURN, R. B. Islet-cell American Jouvnal of Surgery
Adenomatosis with Zollinger-Ellison Syndrome tumors and peptic ulceration. Postgrad. M. J., 36: 154, 1960. 9. CHRISTLIEB, A. R. and SCHUSTER,M. M. ZollingerEllison syndrome. Arch. Int. Med., 114:381, 1964. 10. ELLISON, E. H. and WILSON, S. D. The ZollingerEllison syndrome: reappraisal and evaluation of 260 registered cases. Am. Surg., 160: 512, 1964. 11. FRANTZ, V. F. Tumors of the pancreas. Armed
Vol.
115, May
1968
701
Forces Institute of Pathology, fast. 27, sect. VII. Washington, 1959. 12. SCHLAEGER, R., LE MAY, M., and WERMER, P. Upper gastro-intestinal tract alternations in adenomatosis of the endocrine glands. &diology, 75: 517, 1960. 13. PRIEST, W. M. and ALEXANDER, M. K. Islet-cell tumor pancreas with peptic ulceration, diarrhoea and hypokalaemia. Lanret, 2: 1145, 1957.