Gut: first published as 10.1136/gut.5.5.448 on 1 October 1964. Downloaded from Gut, 1964, 5, 448

Periampullary and duodenal carcinoid tumours

KENNETH W. WARREN, WILLIAM M. McDONALD, AND C. J. HUME LOGAN From the Department of Surgery (Clinic Division), Lahey Clinic Foundation, Boston, Massachusetts, U.S.A.

EDITORIAL SYNOPSIS This is a study of nine patients with this rare tumour involving the . Radical resection is advocated.

The relative rarity of this type of tumour as seen in description of nine patients seen at the Lahey Clinic the collected cases shown in Table I prompts over the years 1954-63. TABLE I PERIAMPULLARY CARCINOID TUMOURS Author Number of Cases Age and Sex Site Barnes and Young (1956) 2 60 M Duodenum, Ist part 56 M Duodenum, Ist part Brentano quoted by van Weel (1962) 1 45 M Ampulla Brunschwig and Childs (1939) 1 41 F Duodenum, 2nd part Cooke (1931) 2 Unspecified Costello and Aitken (1960) 1 46 F Duodenum, 3rd part Ebert et al. (1953) 3 64 F Unspecified 63 M Duodenum, 1st part 60 F Duodenum, Ist part Foreman (1952) 1 42 F Unspecified Gerber and Shields (1960) 1 36 F Unspecified Gerof, Farber, and Lurie (1960) 1 65 F Duodenum, Ist part Hannan, Hazard, and Wise (1951) 3 64 M Duodenum, Ist part 63 M Duodenum, Ist part http://gut.bmj.com/ 70 F Duodenum, 1st part Hasegawa (1923) 1 Unspecified Horsley and Golden (1957) 2 49 F Duodenum, 2nd part 70 F Duodenum, Ist part Kinley and Penner (1962) 3 80 M Duodenum, Ist part 78 M ?Duodenum, 2nd part 60 M Duodenum, 2nd part Laird (1960) 2 72 M Duodenum, Ist part 47 M Duodenum, 1st part

MacDonald (1956) 8 All unspecified on September 26, 2021 by guest. Protected copyright. McRae and Conn (1959) 2 57 M Ampulla 69 M Ampulla Mrazek, Goodwin, and Mohardt (1953) 3 62 M Duodenum, Ist part 61 M Ampulla 57 M Duodenum, 1st part Oberndorfer (1907) 1 Unspecified O'Sullivan and Bowe (1954) 1 63 M ?Duodenum, Ist part Pataky, Nagy, and Popik (1959) 1 38 F Duodenum, 2nd part Pearson and Fitzgerald (1949) 2 63 M Unspecified Unspecified Porter and Whelan (1939) 1 64 F Unspecified Raiford (1932) 1 49 M Duodenum, 1st part Ritchie and Stafford (1944) 1 56 F Unspecified van Weel (1962) 2 49 F Ampulla 70 F Ampulla Warren and Coyle (1951) 1 46 M Ampulla Wolfer (1926) 1 40 M Duodenum, Ist part Review ofLiterature (49 cases) Reported Location of 49 Tumours Sex ratio: 4 males to 3 females Cases Age: Duodenum Average 57 years 1st part 17 Range 36-80 years 2nd part 5 3rd part I Ampulla of Vater 7 Unspecified 19 448 Gut: first published as 10.1136/gut.5.5.448 on 1 October 1964. Downloaded from Periampullary and duodenal carcinoid tumours 449

Table II demonstrates an almost equal sex SIGNS AND SYMPTOMS distribution with an average age of 54 years (range 40-65). It also shows the rather indefinite symptoms Examination of the abdomen revealed no abnormal- which are of a type that would be consistent with ity save in the patient who had a large, palpable many gastrointestinal diseases (Table III). , and, except for this same patient whose urine

TABLE II SUMMARY OF CASES OF PERIAMPULLARY CARCINOID TUMOUR Case Age and Symptoms and Signs Anatomical Site Pathology Surgical Procedure Comment Sex 1 65 Symptomless melaena previously. Duodenum, 1st Invasive, no metas- Resection of 1st Survival 55 months. F Barium meal showed tumour in 1st part; 3 cm. tases part of duodenum Cause of death not part of duodenum. Urine not examined diameter and . Gas- known for indole acetic acid. Preoperative troduodenotomy diagnosis: leiomyoma of duodenum 2 53 Abdominal distress, diarrhoea for 3 Ampulla of Vater; Invasive, lymph Pancreatico- Alive and well M years. Recently, , 6 cm. diameter node metastases duodenectomy 78 months after nausea, vomiting. Lost 29 lb. in surgery 2 years. Barium meal showed constant contracture of mid portion of cap. Preoperative diagnosis, common duct stone 3 47 Abdominal pain, diarrhoea for 6 Duodenum, 1st Invasive, not Liver biopsy Died 5 months M months. Lost 12 lb. History of flushes part; 1 cm. typical. Metas- after diagnosis of head and neck. Heart murmurs in diameter tases to liver, mitral and aortic areas. Barium meal , left showed constriction of duodenal cap; adrenal gland at intravenous cholangiogram, dilated necropsy common . Urine positive for indole acetic acid. Diagnosis: malignant carcinoid tumour 4 40 Anorexia 12 months. Lost 12 lb. Ampulla of Vater Invasive. Metas- Not resectable. Died 17 days after F Jaundice 2 months. Barium meal tases to liver, Gastroenterostomy operation showed duodenal deformity without lymph nodes, choledocho- ulceration. Urine not examined for adrenal gland, jejunostomy

indole acetic acid. Preoperative pituitary gland at http://gut.bmj.com/ diagnosis: periampullary carcinoma necropsy 5 56 Fatigue, anorexia, diarrhoea, ab- Duodenum, 2nd Locally invasive. Not resectable. Died 17 months M dominal distension for 6 months. Lost part; 6 cm. Lymph node Gastroenterostomy after surgery. 50 lb. No mass palpable. Ascites. diameter metastases but no Required numerous Barium meal showed antral gastritis. liver metastases paracenteses Urine not examined for indole acetic acid. Preoperative diagnosis: carcinoma of 6 52 Symptomless. Barium meal showed Duodenum, 2nd Invasive. No meta- Cholecystectomy, Alive and well F duodenal mass. Cholecystogram part; 2 cm. stases choledochotomy, 17 months after showed gall stones. Urine not diameter local removal surgery on September 26, 2021 by guest. Protected copyright. examined for indole acetic acid. after duodenotomy Preoperative diagnosis: duodenal tumour 7 63 Fatigue, fever, excessive perspiration, Duodenum, 1st Invasive. No Local removal by Alive and well F weight loss, jaundice for 2 months; part; 2-2 by 0-8 metastases partial duoden- 18 months after anaemia; pulmonary murmur. Hb. by 0 5 cm. ectomy surgery 9 8 %. Barium meal showed intra- duodenal filling defect. Urine negative for indole acetic acid. Preoperative diagnosis: duodenal tumour 8 56 History of abdominal pain 6 years ago; Duodenum, 2nd Invasive. No Pancreaticoduo- Alive and well M pancreatic cyst drained by internal part metastases denectomy 5 months after anastomosis. Symptoms recurred after surgery 2 years; pancreatic cyst drainage revised. Severe weight loss. Barium meal showed gross distortion of duodenum and delay of gastric emptying. Urine negative for indole acetic acid. Preoperative diagnosis: chronic relapsing pancreatitis 9 56 Right upper quadrant postprandial Cystic duct Invasive, pene- Pancreatico- Alive and well M pain, anorexia for 3 months. Jaundice 4-7 cm. from trating pancreas; duodenectomy 1 month after 1 month later. Urine not examined for papilla of Vater perineural surgery indole acetic acid. Lost 10-15 lb. invasion Preoperative diagnosis: periampullary carcinoma 6 Gut: first published as 10.1136/gut.5.5.448 on 1 October 1964. Downloaded from

450 Kenneth W. Warren, William M. McDonald, and C. J. Hume Logan contained 5-hydroxy-indole acetic acid, the labora- pancreatic ducts has been reported by Peart and tory tests were of little help in evaluation. Radio- colleagues (1963), and the simultaneous develop- logical examination after a barium meal showed a ment of a duodenal carcinoid and a non-beta islet duodenal deformity in six cases and antral gastritis cell tumour of the pancreas was reported by Gerber in another. A correct pre-operative diagnosis was and Shields (1960). made in the one patient whose symptoms suggested Table I illustrates that duodenal carcinoids have a a carcinoid syndrome and whose urine contained maximal incidence in the first portion (57% of the 5-hydroxy-indole acetic acid. The pre-operative 30 cases in which the site was given), less frequently diagnosis in the other cases can be found in Table II. arise from the ampulla of Vater (23 %), and are Table III analyses the symptoms. only rarely found in the third part of the duodenum (3 %). In the present series of nine cases, two arose TABLE III from the ampulla, three from the first part of the ANALYSIS OF SYMPTOMS duodenum, three from the second part of the Symptoms Patients duodenum, and one probably from the cystic duct (Table IV). Weight loss 7 Diarrhoea 3 TABLE IV Pain 5 Fatigue 2 ANALYSIS ACCORDING TO SITE Jaundice 4 Site No. of Cases Melaena Anorexia 4 Duodenum None First part 3 Nausea and vomiting 2 Second part 3 Ampulla of Vater 2 Cystic duct PATHOLOGY HISTORY Ogilvie (1947) stated that the first patho- MACROSCOPIC APPEARANCE These tumours are logical description of carcinoid tumours was made usually reported as being 1 to 2 cm. in diameter; by Langerhans. The low-grade malignancy of these however, three tumours in this series were approxi- tumours prompted Lubarsch (1888) to call them the mately 6 cm in diameter. Careful palpation may fail to demonstrate the smaller tumours which may be

'little carcinomas.' Oberndorfer (1907) coined the http://gut.bmj.com/ term 'carcinoid' tumour. Silver-reducing granules in evident only after a duodenotomy has been per- the cytoplasm of the cells forming carcinoid tumours formed. The tumour is usually rounded or polypoidal were illustrated by Gosset and Masson (1914) and and has a firm consistency. The mucosal surface is because of this it was thought that these tumours usually intact, but, with progression and growth, arose from the Kultschitzky cells. The development ulceration may occur. These tumours are primarily of a typical syndrome of symptoms, the so-called submucosal in location and are yellowish-tan to carcinoid syndrome in association with metastases light orange colour on sectioning. They may from a carcinoid tumour, was first described by penetrate the muscularis layer to the serosa or on September 26, 2021 by guest. Protected copyright. Isler and Hedinger (1953). adjacent organs, for example, the pancreas, but rarely do they perforate into the peritoneal cavity. SITE Formerly, 90% of carcinoid tumours were Mrazek et al. (1953) found that three of the eight thought to arise from the appendix (van Weel, 1962; duodenal tumours which he reported had invasive Kinley and Penner, 1962; Dockerty, 1955). However, characteristics. In our series of nine cases, all had a more recent survey shows this to be closer to 60% this invasive property. Circumferential encroach- (Kinley and Penner, 1962; Ritchie, 1956), the ment of the lumen of the bowel is rare. Lympho- remaining cases arising from other sites in the genous and haematogenous dissemination may be or the bronchus. evident and metastasis may occur in any organ or Duodenal and ampullary carcinoids are rare. tissue (Table V). MacDonald (1956) found eight carcinoid tumours in TABLE V this anatomical location in his review of 149 cases of carcinoid tumour discovered at necropsy. Of the PATHOLOGY OF PERIAMPULLARY CARCINOID TUMOURS 565 cases of carcinoid tumour collected from the Properties of Tumour No. of Cases literature and reported by Dockerty (1955), only 10 Invasive property 9 Metastases to other sites 4 arose in the duodenum. van Weel (1962) stated that Local spread 2 the duodenum is the rarest location for carcinoid Lymph nodes 3 Liver 2 tumours and Ritchie (1956) reported an incidence of Adrenal gland 2 0-2y% at this site. A carcinoid tumour arising in the 1 Gut: first published as 10.1136/gut.5.5.448 on 1 October 1964. Downloaded from

Periampullary and duodenal carcinoid tumours 451 MICROSCOPIC APPEARANCE The microscopic picture Carcinoid tumours without extensive metastases is similar in all of these tumours. Masses or columns were not associated with valvular lesions, but these of polyhedral cells having small round nuclei with were present in all cases of carcinoid with extensive fine granules and vacuoles are demonstrated in metastases. paraffin sections. Columnar-shaped cells, although usually occurring at the periphery of the cell mass, CLINICAL FEATURES may constitute the whole tissue in some instances. Rosettes formed by pyramidal cells may be seen. The AGE 140 cases of cytoplasmic granules are eosinophilic staining and Reviewing carcinoid tumour, Pearson and Fitzgerald (1949) reported an average argentaffin in character. The nuclei rarely show of 25 mitotic figures, but variation in the size of the cells age years for appendiceal carcinoids and 55 and nuclei indicates a more years for the extra-appendiceal sites. These findings aggressive tendency in were substantiated some instances. Mrazek et al. (1953) did not observe by Kinley and Penner (1962) in their review of 52 cases; they found that the average any distinguishable microscopic features in carcin- of with oids from various sites, but found that the degree of age patients appendiceal carcinoids was 34 years and that the average age for other sites was pleomorphism and the presence of mitoses were 66 In the correlated with the clinical The cells years. total series of 10 cases studied at the malignancy. the case may have a trabecular arrangement resembling an Lahey Clinic, including previously reported islet cell tumour of the by Warren and Coyle (1951) in which the tumour pancreas, and histological was situated in the diagnosis of tumours in this region may be very periampullary area, the average difficult. age was 54 years (range of 40 to 65 years). Williams and Sandler (1963) showed that tumours arising from the fore, mid, and hind gut embryonic SEX INCIDENCE This series, and according to divisions have different characteristics. As the Davies (1959), several other series show an approxi- pancreas and the duodenum proximal to the mately equal sex distribution. ampulla of Vater are derived from the foregut, it would be expected that carcinoid tumours in this SYMPTOMS AND SIGNS location would tend to have a wide variety of histo- logical patterns, with argentaffin granules rarely Carcinoid tumours do not have a classical sympto- http://gut.bmj.com/ being present. The association with the carcinoid matology except when the carcinoid syndrome has syndrome would be frequent and the tumour would developed. This lack of specificity of symptoms is have a low 5-hydroxy-tryptamine content and evident by the variety of pre-operative diagnoses. frequently 5-hydroxy-tryptophan would be excreted This feature was also commented upon by Mattingly by the tumour with a high incidence of urinary (1956) and van Weel (1962). van Weel stated that excretion of 5-hydroxy-indole acetic acid. Metastases carcinoid tumours of the duodenum sometimes give to bone and skin would be commonly noted. rise to a dyspeptic syndrome marked by nausea, on September 26, 2021 by guest. Protected copyright. Carcinoid tumours arising in the remainder of the vomiting, epigastric pain, and diarrhoea. He duodenum, which is of mid gut origin, would be remarked that haemorrhage was rare but might be expected to have a characteristic histological structure caused by an accompanying duodenal ulcer. Gerof with demonstrable argentaffin granules. The carcin- et al. (1960) reported a case of massive gastro- oid syndrome would frequently be associated with intestinal bleeding from an eroded carcinoid tumour a high content of 5-hydroxy-tryptamine in the in the first part of the duodenum. Tumours in the tumour and 5-hydroxy-indole acetic acid in the urine. ampullary or periampullary area may produce The tumour would rarely secrete 5-hydroxy- symptoms relevant to obstruction of the common tryptophan and bone and skin metastases would be bile duct (see Mattingly) or to the pancreatic duct unusual. (see Brunschwig and Childs, 1939). Mattingly (1956), MacDonald and Robbins (1957) reported that the Gerber and Shields (1960), and MacDonald (1956) pathological changes in the heart valves of patients have reported a higher incidence of peptic ulceration with the carcinoid syndrome were found to be unlike associated with carcinoid tumour than is found in those in congenital, degenerative, infectious, or the normal population. MacDonald, in a review of collagen diseases. In a review of the reported cases 18,000 necropsies, noted gastric or duodenal ulcers the pulmonary and tricuspid valves were chiefly in 38% of the patients with carcinoid tumours, affected with pearly-gray thickening of the valve whereas the incidence of ulcer for the entire necropsy cusps, binding the edges together and causing a series was only 5.5%. Mattingly found a carcinoid stenotic process occasionally associated with re- tumour of the duodenum producing a high intestinal gurgitation, and right ventricular hypertrophy. obstruction and another which caused a chronic Gut: first published as 10.1136/gut.5.5.448 on 1 October 1964. Downloaded from

452 Kenneth W. Warren, William M. McDonald, and C. J. Hume Logan duodenal obstruction owing to prolapse of the The long-term results in this series are impossible tumour through the pyloric ring. to determine at the present time as two of these Isler and Hedinger (1953) were the first to describe patients were operated on within the past six months the malignant carcinoid syndrome. They reported and two others within the last 18 months. Of the two the occurrence of telangiectasia of the skin and operations most frequently performed, local removal sclerosis of the triscupid and pulmonary valves. was used in three patients and pancreatico-duodenal Since this initial report, other symptoms have been resection in three patients. accepted as manifestations of the syndrome, mainly It is our belief that the rational treatment of a hyper-peristalsis with frequent watery bowel move- resectable tumour of this type in this area should be ments, episodes ofasthma-like broncho-constrictions, pancreatico-duodenal resection. Support for this oedema, and ascites. Flushing is the most character- treatment is shown by the pathological demonstra- istic symptom of the syndrome and usually involves tion of the invasive nature of the tumour in all nine the face, neck, and chest, spreading to the rest of cases reported. The previously forbidding operative the body and lasting for five to 10 minutes. It mortality rate associated with this major operation produces a mottled appearance and with advanced is no longer present, as was shown by Warren et al. disease may become continuous. Palpation of a liver in a review of 218 patients with periampullary containing metastatic carcinoid tumour may initiate carcinoma operated on at the Lahey Clinic over a the syndrome, according to van Weel (1962) and period of 19 years. The operative mortality of 11.9 % Smith and Murphy (1960). in that series, although still high, has been further reduced in recent years by close attention to pre- DIAGNOSIS operative preparation of the patient and to operative details. There was no operative mortality in these The rare occurrence of this type of tumour with its patients. non-specific symptoms makes an accurate pre- operative diagnosis very unlikely unless the carcinoid syndrome has developed. The demonstration by SUMMARY AND CONCLUSION barium meal x-ray examination of the duodenal filling defect may bring the diagnosis to the clinicians' A careful review of the literature has shown that mind, particularly if the tumour has a sessile only 49 patients suffering from periampullary appearance in either the first part or the second part carcinoid tumours have been reported. The small http://gut.bmj.com/ of the duodenum. The only laboratory test that may number of cases signifies the rarity of this condition. be of value is the demonstration of 5-hydroxy-indole We have reported a further nine cases of this unusual acetic acid in the urine; but unless this determination tumour. The non-specificity of the symptoms and is made routinely on all patients, it is unlikely to be physical signs, unless the carcinoid syndrome has of help in making the diagnosis. A positive result developed, makes the pre-operative diagnosis of during the post-operative period may indicate the these tumours impossible. presence of functioning metastases. Although successful treatment has been obtained in many instances by local resection of the tumour, on September 26, 2021 by guest. Protected copyright. in view of the invasive properties of the tumour TREATMENT demonstrated by pathological examination of these The surgical treatment carried out on these nine resected tumours, we favour the radical surgical patients is noted in Table II. The efficacy of a treatment of pancreatico-duodenal resection for all surgical treatment can be assessed only by consider- carcinoid tumours in this area. ing the eventual longevity achieved in each patient. This is shown in Table VI. REFERENCES

Barnes, Z. B., and Young, J. M. (1965). Carcinoid tumors of the TABLE VI duodenum; a review of the literature and a report of two cases, RESULTS OF TREATMENT AT LAHEY CLINIC Surgery, 40, 922-929. Brunschwig, A., and Childs, A. (1939). Resection of carcinoma Treatment No. of Cases Result (carcinoid?) of the infrapapillary portion of the duodenum involving the ampulla of Vater. Reimplantation of the common Pancreatico-duodenectomy 3 1 alive and well (7 years) and pancreatic ducts. Amer. J. Surg., N.S., 45, 320-324. 1 alive and well (6 months) Cooke, H. H. (1931). Carcinoid tumors of the small intestine. 1 alive and well (I month) Arch. Surg., 22, 568-597. Resection of part of 3 1 alive and well (20 months) Costello, C., and Aitken, L. F. (1960). Carcinoid of the duodenum. duodenum I alive and well (19 months) A case report. Missouri Med., 57, 1252-1254. I died (4 years) Davies, A. J. (1959). Carcinoid tumors (argentaffinomata). Ann. roy. Palliative procedures 2 1 died (2 months) coll. Surg. Engl., 25, 277-297. I died (3 weeks) Dockerty, M. B. (1955). Carcinoids of the gastrointestinal tract. No operation 1 patient (An editorial.) Amer. J. clin. Path., 25, 794-795. Gut: first published as 10.1136/gut.5.5.448 on 1 October 1964. Downloaded from Periampullary and duodenal carcinoid tumours 453

Ebert, R. E., Parkhurst, G. F., Melendy, 0. A., and Osborne, M. P. Mrazek, R. G. Jr., Goodwin, M. C., and Mohardt, J. (1953). (1953). Primary tumors of the duodenum. Surg., Gynec. Carcinoid tumors: a clinical and pathologic study of 27 cases. Obstet., 97, 135-139. Surg. Gynec., Obstet., 96, 661-673. Foreman, R. C. (1952). Carcinoid tumors: a report of 38 cases. Oberndorfer, S. (1907). Karzinoide Tumoren des Dunndarms. Ann. Surg., 136, 838-855. Frankfurt. Z. Path., 1, 426-432. Gerber, B. C., and Shields, T. W. (1960). Simultaneous duodenal Ogilvie, R. F. (1947). Pathological Histology, 3rd ed., p. 230. Living- carcinoid and non-beta cell tumors of the pancreas. Two stone, Edinburgh. tumors of high ulcerogenic potential. Arch. Surg., 81, 379-388. O'Sullivan, W. D., and Bowe, J. J. (1954). Carcinoids ofAppendix and Gerof, D. G., Farber, M., and Lurie, A. (1960). Carcinoid tumor of gastrointestinal tract. Arch. Surg., 68, 153-166. duodenum with massive haemorrhage. Amer. J. Gastroent., 34, Pataky, Z., Nagy, L., and Popik, E. (1959). Ober einen vom Pankreas- 532-536. kopf hervorgehenden primaren Argentaffintumorfall. Zbl. allg. Gosset, A., and Masson, P. (1914). Tumeurs endocrines de l'appendice, Path. path. Anat., 99, 442-444. Presse med., 22, 237-240. Pearson, C. M., and Fitzgerald, P. J. (1949). Carcinoid tumors-a Hannan, J. R., Hazard, J. B., and Wise, R. E. (1951). Carcinoid of re-emphasis of their malignant nature; review of 140 cases, the duodenum. Amer. J. Roentgenol., 66, 569-576. Cancer (Philad.), 2, 1005-1026. Hasegawa, T. (1923). (Yber die Carcinoide des Wurmfortsatzes und Peart, W. S., Porter, K. A., Robertson, J. I. S., Sandler, M., and des Dunndarmes. Virchows Arch. path. Anat., 244, 8-37. Baldock. E. (1963). Carcinoid syndrome due to pancreatic- Horsley, G. W., and Golden, B. N. (1957). Carcinoid tumors of the duct neoplasm secreting 5-hydroxytryptophan and 5-hydroxy- duodenum. Int. Abst. Surg., 105, 417-424. tryptamine. Lancet, 1, 239-242. Isler, P., and Hedinger, C. (1953). Metastasierendes Dunndarm- Porter, J. E., and Whelan, C. S. (1939). Argentaffine tumors: report carcinoid mit schweren, vorwiegend das rechte Herz betreffen- of 84 cases: three with metastases. Amer. J. Cancer, 36, 343-358. den Klappenfehlern und Pulmonalstenose-ein eigenartiger Raiford, T. S. (1932). Tumors of the small intestine. Arch. Surg., 25, Symptomenkomplex? Schweiz. med. Wschr., 83, 4-7. 122-127. Kinley, C. E., and Penner, D. W. (1962). Carcinoid tumors: a Ritchie, A. C. (1956). Carcinoid tumors. Amer. J. Med. Sc., 232, review and clinopathological study of 52 cases. Canad. J. Surg., 311-328. 51 138-147. Ritchie, G., and Stafford, W. T. (1944). Argentaffin tumors of the Laird, G. J. (1960). Carcinoid of the duodenum: report of two cases. gastrointestinal tract. Arch. Path., 38, 123-127. J. Amer. med. Ass., 174, 1743-1745. Williams, E. D., and Sandler, M. (1963). The classification ofcarcinoid Lubarsch, 0. (1888). Ueber den primaren Krebs des Ileum nebst tumours. Lancet, 1, 238-239. Bemerkungen uber das gleichzeitige Vorkommen von Krebs Smith, F H., and Murphy, R. (1960). Carcinoid tumors. Med. und Tuberculose. Virchows Arch. path. Anat., 111, 280-317. Clin. N. Amer., 44, 465-474. MacDonald, R. A. (1956). A study of 356 carcinoids of the gastro- Warren, K. W., Cattell, R. B., Blackburn, J. P., and Nora, P. F. (1962). intestinal tract: report of 4 new cases of carcinoid syndrome. A long-term appraisal of pancreaticoduodenal resection for Amer. J. Med., 21, 867-878. peri-ampullary carcinoma. Ann. Surg., 155, 653-662. and, Robbins, S. L. (1957). Pathology of the heart in the carci- -, and Coyle, E. B. (1951). Carcinoid tumors of the gastro- noid syndrome. A comparative study. Arch. Path., 63, 103-112. intestinal tract. Amer. J. Surg., 82, 372-377. Mattingly, T. W. (1956). The functioning carcinoid tumor-a new Weel, M. W. van (1962). Carcinoid tumour of the ampulla of Vater. clinical entity. Med. Ann. D. C., 25, 239-254. Arch. Chir. Neerl., 14, 15-25. McRae, J. M., and Conn, J. H. (1959). Carcinoid of ampulla of Vater. Wolfer, J. A. (1926). Carcinoid tumors of the intestines. Surg. Gynec., Surgery, 46, 902-907. Obstet., 43, 443-449. http://gut.bmj.com/ on September 26, 2021 by guest. Protected copyright.