Endocrine Tumors of the Small and Large Intestine

Path. Res. Pract. 191,366-372 (1995)

Endocrine Tumors of the Small and Large Intestine E. Solcia, R. Fiocca, G. Rindi, L. Villani, O. Luinetti, M. Burrell, F. Bosi and E. Silini Department of Human Pathology and Genetics, University of Pavia

SUMMARY Among endocrine tumors arising in the intestinal tract, midgut argentaffin EC cell carcinoids, duodenal gastrin cell tumors and rectal trabecular L cell carcinoids, in order of decreasing frequency, are those better represented. Together they account for more than 80% of such tumors. Duodenal somatostatin cell tumors, gangliocytic paragangliomas and poorly differentiated neuroendocrine carcinomas, are also well defined tumor entities. The carcinoid syndrome with intermittent flushing, hypotension and diarrhea, and the Zollinger-Ellison syndrome with severe peptic ulcer disease, are the only hyperfunctional syndromes consistently found in association with these tumors. The carcinoid syndrome arises in about 10% of intestinal carcinoids, usually in their advanced metastatic stage. The Zollinger-Ellison syndrome occurs in association with about 40% of gastrin cell tumors, including small intramural growths. Tumor prognosis depends on mode and site of presentation, histology, cell type(s), size, level of invasion, metastases (especially distant metastases) and associated clinical syndrome or background disease.

Endocrine peptides and monoamines are the most specific markers of gut endocrine tumors and represent useful tools for their characterization and classification. The immunohistochemical detection of hormones and related prohormones, in conjunction with cell characterization at ultrastructural level, allow precise correlation of tumor cell differentiation and function with tumor-associated hyperfunctional syndromes 9, 43. Problems may arise in classifying endocrine tumors based on these grounds, because of the frequent occurrence in the same tumor of multiple cell types producing different hormones. Thus, it seems appropriate to restrict the use of functionallabellings like 'gastrinoma' or 'somatostatinoma' to those tumors which, besides showing the appropriate hormone in tumor cells, are associated with hyperfunctional syndrome. Tumors which do not present a hyperfunctional syndrome may be classified on the grounds of their prevalent tumor cell type (e.g. 'gastrin cell tumor', 'somatostatin cell tumor' or 'ECL cell tumor'), or even on the basis of more conventional morpholo-

gic criteria like histological pattern, reactivity to silver techniques, site of origin, etc. (e.g. 'gastric argyrophil carcinoid' or 'rectal trabecular carcinoid'). The classification of gastrointestinal endocrine tumors reported in Table 1, based on personal investigation of 204 cases, is useful for careful clinico-pathologic correlation. Gastrin (G) Cell Growths Gastrin cell tumors, i.e. tumors showing an overwhelming population of gastrin cells or tumors with any proportion of gastrin cells associated with the Zollinger-Ellison syndrome, represent the largest group in reported series of endocrine tumors arising in the upper small intestine 7, 9, 50. In our series of 32 cases, they showed strong preference for males (71 %) and proximal duodenum, where 83 % of the cases were located. A similar predilection for the proximal duodenum can also be noted in some previous studies 35, 50.

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Intestinal Endocrine Tumors· 367 Table 1. Cytologic and clinicopathologic characterization of gut endocrine tumors Cases Site No.

Prevalent cell type

Main hormonal products

Associated syndrome or pathologic condition

Gastric argyrophil carcinoid

48

Bodylfundus

ECL

Histamine, 5HT/5HTP

Atypical carcinoid sy. CAGIG cell hyperplasia ZES/MEN-1.

Gastrin cell tumor

34

Duodenum, antrum, jejunum

G

Gastrin

ZES,ECL cell growth

Somatostatin cell tumor

8

Duodenum, antrum, JeJunum

D

Somatostatin

N eurofi bromatosis

PP cell tumor

2

Duodenum

PP

Pancreatic peptide

Gangliocytic 'paraganglioma'

4

Duodenum

D, PP

Somatostatin, PP

Argentaffin carcinoid

55

Appendix, small and large intestine, stomach

EC

5HT, subst.P

Hindgut trabecular carcinoid

33

Rectum, colon, appendix

L

Enteroglucagones, PP, ppy

Inappropriate tumors

2

Stomach, jejunum

Mixed endocrine-exocrine

3

Stomach, rectum

Undefined tumors

2

Duodenum, stomach

13

Stomach, rectum

Tumor types Well differentiated

Carcinoid sy.

ACTHIMSH, VIP

Cushing or VIPoma sy.

Variable

Variable

Poorly differentiated Neuroendocrine carcmoma

Protoendocrine

CAG, Chronic atrophic gastritis; ZES, Zollinger-Ellison syndrome; MEN-1, multiple endocrine neoplasia, type 1; sy. syndrome; 5HT, 5-hydoxytryptamine.

The Zollinger-Ellison syndrome (ZE5) with hypergastrinemia, gastric hypersecretion and refractory peptic ulcer disease, is the only syndrome of endocrine hyperfunction consistently obvserved in association with endocrine tumors of the duodenum and upper jejunum9, 50, 52. It was found in 12 cases (24% of our 50 patients with duodeno-jejunal tumors, or 37.5% of those with gastrin cell tumors), three of whom had type 1 multiple endocrine neoplasia (MEN-i) syndrome. In the past, duodenal gastrinomas have been reported in 13 -15 % of all patients with ZES, located in the pancreas or regional lymph nodes 23 • More recent studies show an higher incidence of duodenal tumors, possibly due to improved diagnostic procedures 9. In fact, duodeno-jejunal gastrinomas are frequently small in size; only three of our 12 cases were larger than 1 cm and none exceeded 1.5 cm. Therefore, they are often missed unless carefully searched for at endoscopy or surgery, and may cause paraduodenal metastases of apparently missing primaries ll ,52. The latter may well have been occult microgastrinomas located in a ring of duodenal mucosa removed during previous gastric surgery, as

suggested by the frequent occurrence of such tumors in juxtapyloric duodenal mucosa. 50 far, all appropriately investigated cases of duodenal tumors associated with MEN/ZES revealed gastrin producing tumor cells, whereas many pancreatic tumors associated with this syndrome lacked histochemical evidence of gastrin productionS, 25, 35, 46. Eighteen of our 34 cases (53 %) of gastrointestinal (2 pyloric, 29 duodenal and 3 jejunal) gastrin cell tumors were apparently 'nonfunctioning'. They were all located in the duodenal bulb. No systematic preoperative measurements of serum gastrin and gastric acid secretion had been performed in such patients, five of whom presented ordinary peptic ulcer disease and one with diarrhea cured by tumor surgery. Diagnosis and functional characterization of these tumors at the clinical level is particularly difficult because the small, very well differentiated gastrin cell tumors arising in the duodenal bulb may cause milder peptic ulcer disease than the usual ZES caused by pancreatic gastrinomas. Tumors associated with overt ZES differ from their apparently nonfunctioning counterparts in arising ear-

368 . E. Solcia et al.

lier in life (median age at diagnosis of 36 years, as opposed to 66) and having a higher incidence of metastatic (three cases, as against none), deeply infiltrative (seven out of 12, as against three of 18) and non-bulbar cases (five, as opposed to none). All these findings suggest a different natural history of the tumor disease in the two conditions. Nonfunctioning, clinically silent tumors represent a particularly benign disease, while ZES tumors have low grade malignant potential, especially when arising at sites where gastrin cells are not normally present, such as the jejunum or pancreas9, 44. Metastases in regional lymph nodes have been reported in four of eight duodenal gastrinomas with ZE/MEN syndrome 35 , in 25% of 103 duodenal tumors with ZES, 24% of which also had MEN-l syndrome23, and in five out of six jejunal gastrinomas 9. Interestingly, local lymph node metastases seem to have little influence on the survival of patients with ZESll,49. From a revision of the literature, the frequency of local lymph nodes metastases resulted to be only slightly higher in pancreatic (39%) versus duodenal (28 %) gastrinomas, whereas liver metastases were up to nine times more frequent (27 to 3%) among pancreatic cases. An overall malignancy rate of 38% has been reported in ZES cases with duodenal tumor23 as against 70% in pancreatic gastrinomas 13 • Peptides detected in tumor cell subpopulations are cholecystokinin, pancreatic polypeptide (PP), neurotensin, somatostatin, insulin and the alpha chain of human chorionic gonadotrophin. Interestingly, somatostatin, which is known to inhibit gastrin release from gastrinomas, has been detected in only two of 12 ZES tumors in our series, while it was present in eight of 14 nonfunctioning tumors. Multifocal, intraepithelial growths forming chains or micro nodules of endocrine cells, sometimes with mild atypia and in direct continuity with tumor growth, have been found in the deep crypts of intestinal mucosa adjacent to gastrin cell tumors. These findings, which are especially prominent in MEN/ZES cases, strongly support the concept that such tumors originate from differentiated intra epithelial endocrine cells28 ,37. Gastrin cell tumors arise infrequently in the antropyloric mucosa and are partly associated with hypergastrinemia and peptic ulcer disease 3, 27, 48. Some cases were multifocal and coupled with gastrin cell hyperplasia. Of our two pyloric cases, one was a solitary 2 em large tumor associated with peptic ulcer and the other a silent microgastrinoma. Somatostatin Cell Tumors A moderate number of duodenal tumors composed of well differentiated somatostatin D cells has been reported in the literature 9,1O. None of these cases developed the full blown 'somatostatinoma' syndrome (diabetes mellitus, diarrhea, steatorrhea, hypo- or achlorhydria, anemia and gallstones), which has been reported in association with some pancreatic D cell tu-

mors 26 , although association with diabetes and/or gallstones has been noted in some cases 10, 51. Eight of our 47 duodenal tumors showed numerous somatostatin cells with few or no other endocrine cells. Seven of the eight tumors arose in the ampullary region, which had already been reported as a preferential location for such tumors 7, 9, 10, 19, 36, 50, 51. This explains their frequent association with obstructive biliary disease. A significant proportion of ampullary somatostatin cell tumors were discovered in patients with cutaneous neurofibromatosis 10, 19, 50, including two of our seven cases. Infiltration of the duodenal wall or Oddi's sphincter was detected in our 6 ampullary cases with type C glandular structure and in most similar cases in the literature. Paraduodenallymph node metastases were observed in the majority of cases. The unusually high (though low grade) malignancy rate of these tumors is at variance with the relatively benign behavior of other types of duodenal endocrine tumors. Somatostatin tumors also differ in showing tubuloacinar structure, intestinal type microvilli, binding of WGA and PNA lectins 36 , epithelial membrane antigen (EMA) expression and some evidence of luminal secretion possibly contributing to psammoma body formation. Ganglioneuromatous Paragangliomas The ganglioneuromatous paraganglioma is a rare tumor resulting from an admixture of 1) polygonal, cuboidal or columnar epithelial endocrine cells arranged in solid nests and ribbons or forming small tubulo-acini, resembling more nonargantaffin carcinoids than non-chromaffin paragangliomas, 2) mature ganglion cells and 3) Schwann-like spindle cells enveloping nerve cells, axons and epithelial cells or forming small fascicles9, 34. Most tumors develop in the submucosa (with or without a mucosal component and infiltration of the muscularis propria) of the duodenum, especially in the periampullary region. Benign behavior distinguishes ganglioneuromatous paraganglioma from purely endocrine tumors, such as gastrin and somatostatin cell tumors and rare argentaffin carcinoids or PP cell tumors which arise in the same area and are known to have some malignant potential. However, a single case with local lymph node metastasis, due to its carcinoid-like component, has been reported. Somatostatin cells were present in the epithelial endocrine component of our four tumors, as well as in the 10 tumors investigated by Hamid and coworkers22. In addition, PP cells and rare glucagon or insulin cells have been detected in ganglioneuroma to us paragangliomas, suggesting that they may be a hamartia of the pancreatic anlage22, 34. However, somatostatin and PP cells are normally present in human adult ampullary glands and in fetal duodenal mucosa. Moreover, scattered insulin and PP cells have been detected in 5 % to 25 % of the duodenal endocrine

Intestinal Endocrine Tumors . 369

tumors investigated 9,50, none of which showed neuromatous component or inpancreatic heterotopia. These findings suggest that a potential for pancreatic hormone expression is, to some extent, inherent to duodenal endocrine tumors, independent of type and origin. The 'endodermal-neuroectodermal' complexes described by van Cam penh out in fetal duodenum and reputed to be homologous with the 'neuroinsular' complexes reported in the pancreas 53 may offer an alternative explanation for the histogenesis of paragangliomas. In fact, abundant endocrine cells, probably originating from endodermal epithelium, have been found to colonize the stroma between human intestinal epithelium and muscularis propria during early fetal life 45 . Such neuroendocrine complexes, like those described in the appendix 39 , may well represent the starting point for an endocrine tumor with associated neuromatous growth. Argentaffin (EC Cell) Carcinoids EC carcinoids account for nearly all endocrine tumors arising in the ileum, appendix and Merkel's diverticulum, for the majority of those arising in the jejunum and cecum, and for a restricted minority of those occurring in the duodenum, stomach, distal colon and rectum. Carcinoid tumors of the small intestine were found in 0.65% of all autopsies at the Mayo Clinic, most of which (133 out of 137 cases) were incidental findings, and only 9% showed metastases. On the other hand, 52 of the 72 surgical cases were clinically symptomatic and nearly all were metastatic. Intermittent intestinal obstruction was present in 57% of the symptomatic patients. The well known 'carcinoid syndrome' with flushing, diarrhea, valvular involvement, etc., was found in only 14 patients (7% of the whole series of 209 cases), all of whom had metastases, mostly of the liver3l. The primary tumor, multiple in about one fourth of the cases, usually appears as a deep mucosal-submucosal nodule with apparently intact or slightly eroded overlying mucosa. Deep infiltration of the muscular wall and peritoneum is a frequent finding. Extensive involvement of the mesentery stimulates considerable fibroblastic reaction with resulting contraction, kinking of the bowel and obstruction of the lumen. Thus obstruction, the most frequent and significant among presenting symptoms, is only shown by an invasive and relatively advanced disease. A close relationship was found between size of the primary lesion and incidence of metastases; where lesions measured less than 1 cm in diameter, 1 to 2 cm and 2 cm or more, metastases were found in 2 %, 50% and 80% of the cases respectively3l. The invasiveness of the tumor is also significant in this respect, as no metastases were found in 17 'superficially invasive' tumors, as opposed to 'deeply invasive' cases where 23 out of 26 had metastases 2l . Solid nests or islets of tumor cells, often with peripheral palisading, represent the typical, highly diagnostic

(type A) histological pattern in most argentaffin EC cell tumors of the midgut4l . In some cases, rosette type, gland-like structures can be seen within the solid nests. This variant of the fundamental structure has been designated as mixed insular + glandular (A + C) structure and seems more prognostic ally favorable than the pure type A structure24 . In areas of deep invasion with abundant sclerosis, the cell nests may be compressed into cords and trabeculae. Practically all tumor cells are intensely argyrophilic, lead-hematoxylin-positive and reactive with chromogranin A and B antibodies. The characterization of tumor cells as EC cells can be achieved with a variety of histochemical methods for serotonin, including argentaffin, diazonium, formaldehyde-induced fluorescence and immunohistochemical tests. As serotonin occurs in some non-EC cells and related tumors 44, 45, electron microscopical examination of serotonin immunoreactive tumors (especially those failing to react with the argentaffin test) is necessary to confirm their EC cell nature by detecting characteristic pleomorphic, intensely osmiophilic granules 42,47. Substance P and other tachykinins such as eledoisin, physalemin, kassinin, and substance K, have been found to be reliable markers of a fraction (EC l cells) of intestinal EC cells as well as of midgut EC cell carcinoids4,29, while foregut EC cells and related tumors remained mostly unreactive. Minority populations of enkephalin, somatostatin, gastrin, ACTH, calcitonin, motilin, neurotensin, glucagon/glicentin and PP/pYY immunoreactive cells, unassocciated with pertinent hyperfunctional signs, have been reported in some ileal and jejunal tumors mostly composed of argentaffin cells 29 , 55. However, in many cases of ileal argentaffin carcinoids, no other hormone apart from serotonin and substance P or related tachykinins can be detected 29 . Most carcinoids of the appendix have been shown to be EC cell argentaffin tumors of type A or A + C structure 41 , arising, at least in part, from subepithelial endocrine cells scattered in the deep lamina propria. The intimate relationship of such subepithelial endocrine cells and related carcinoids with nerves of Meissner's plexus, which has been confirmed by ultrastructural investigations, could be due to in vivo release of a neurotrophic factor from hyperplastic or neoplastic EC cells. Interestingly, insulin-like growth factor (IGF-I) has been detected in midgut agentaffin carcinoids and found to be released by tumor EC cells in vitr0 33 . Nearly all appendiceal carcinoids are small (usually less than 1 cm) tumors, either discovered by chance at operation, incidentally at pelvic or gallbladder surgery30, or found in patients undergoing surgery because of symptoms of acute appendicitis40. They account for about half of the entire group of benign and malignant tumors of the appendix and show prediction (71 %) for the tip of the organ. Most carcinoids display muscular and lymphatic invasion or perineural involvement; two thirds of the cases in Moertel's series also showed invasion of the peritoneum, possibly through endolymphatic growth 30 . Despite these signs of apparent aggressiveness

370 . E. Solcia et al.

and histological malignancy, and in contrast with ileal carcinoids, lymph node or distant metastases were an exception (1,4% of Moertel's series; 35 cases until 1968 in the world literature) as were associated 'carcinoid'syndromes (5 cases)30. Most cases were cured by appendectomy without recurrence 40 . Metastatic cases were usually from tumors larger than 2 em. No relevant histological, cytological or cytochemical differences have been detected between most ileal and appendiceal carcinoids, despite their very different clinical behavior. At both sites, argentaffin EC cells of EC I subtype producing both serotonin and substance P have been observed. They were usually arranged in solid nests with some peripheral palisading (type A structure), occasionally with microlumina (type A + C). Very small (usually 2 to 3 mm) nonargentaffin microcarcinoids with prevalence of type B or B + C structure have also been observed in the appendix 12 . We have investigated a few such cases and found glicentin and PP immunoreactive cells ultrastructurally resembling L cells, thus reproducing some patterns of rectal L cell carcinoids. L cells, together with EC and somatostatin cells, are a regular component of the crypt epithelium of normal appendix. Hindgut Trabecular (L Cell) Carcinoids These carcinoids arise mostly in the rectum; a few have been reported in the colon, the pelvic soft tissue posterior to the rectum (from rectal duplication, occasionally) or the ileum. They are characterized by a predominance of a type B ribbon pattern, often admixed with type C (tubulo-acini or broad, irregular trabeculae with rosettes) and occasionally with areas of type A solid nests structure. Rectal carcinoids account for 12 to 27% (16% of our 204 cases, Table 1) of all gastrointestinal carcinoids 17, 56. They usually appear as submucosal nodules, often with apparently intact overlying epithelium and sometimes with polypoid appearance 8. The majority of these tumors are usually diagnosed during investigation for other gastrointestinal diseases, when asymptomatic and measuring 1 em or less in diameter. In a 1962 review of the literature, Bates found 234 cases which measured less than 1 em, 77 between 1 and 2 em, and 45 more than 2 em in diameter, whose malignancy rates were 1,7%, 10% and 82%, respectively2. An overall malignancy rate of 11 % to 15% has been calculated in some studies 14, 17. As malignancy criteria, a size greater than 2 em, ulceration, infiltration of the muscularis propria and presence of more than 2 mitoses in 10 high power (x 400) microscopic fields have been recognized. Amongst 62 rectal carcinoids from surgical pathology files which have been investigated immunohistochemically, 48 (77%) have been found to display more or less abundant glucagonlglicentin and/or PP/ PYY immunoreactivities typical of intestinal L cells, while only 21 (32%) showed 5 HT immunoreactivity and 12 (18 %) somatostatin immunoreactivity, usually

in only a few tumor cells1, 15, 16,33,54,55. Glucagon-29, glucagon-37, glicentin, proglucagon cryptic fragments, PYY, PP and pro-PP-icosapeptide, all proved useful immunochemical markers of rectal carcinoids l6 . Minority populations of substance P, insulin, enkephalin, B-endorphin, neurotensin and motilin immunoreactive cells have been observed in occasional tumors 1, 55. Eighty two of 85 colorectal carcinoids tested showed immunoreactivity for prostatic acid phosphatase, a finding relatively unusual in other gut endocrine tumors and possibly related to the common origin of rectum and prostate from cloacal hindgut 14 . Thus, L cells seem to represent the dominant tumor cell component in rectal carcinoids and to be positively related to type B or B + C structure. A relationship between type A solid nest areas of both rectal and colonic tumors and serotonin-producing EC cells has also been noted 16 . A similar correlation of histological patterns, tumor cell types and hormones produced has been observed in the appendix, small bowel and ovary where L cell trabecular carcinoids with glicentinlPP-related immunoreactivities rarely occur43 , as in addition to the prevalent type A, serotonin-producing EC cell tumor 38 . No definite hyperfunctional syndrome has been identified in association with L cell tumors producing 'enteroglucagon' (glucagon-37, glicentin, GLP1, GLP2) and PP/PYY-reiated hormonal peptides. Constipation is one of the main complaints of patients bearing trabecular rectal carcinoids. The classical carcinoid syndrome has been reported only exceptionally in association with rectal carcinoids, which proved to be of 5HT-producing argentaffin type 20 . Neuroendocrine Carcinomas (NECs) Small cell carcinomas with poor endocrine differentiation have been reported in the colon 18. These frankly malignant tumors should be separated from ordinary, well-differentiated endocrine tumors of benign nature or low-grade malignancy. We have observed 4 cases in the colon-rectum, all of which were single large tumors, 2 to 7 cm in size, and metastatic. Under conventional light microscopy, poorly differentiated endocrine carcinomas are characterized by small to medium size, round to spindle-shaped cells with indistinct nucleoli and scanty cytoplasma arranged in poorly defined, solid nests and sheets, often with necrotic centres. Scattered argyrophilic cells or cell processes were observed in the majority of cases when stained with Grimelius' silver. Serotonin and appropriate or inappropriate hormonal peptides (calcitonin, ACTH, etc.) have been more rarely detected. Ultrastructurally, a few small (100 to 200 nm in diameter) secretory granules resembling those of immature 'protoendocrine' cells of early fetal development have been observed, often concentrated in thin cell processes not seen on conventional light microscopy. None of the tumors so far reported were associated with an overt endocrine syndrome, even when hor-

Intestinal Endocrine Tumors· 371

mone-like immunoreactivities were detected in tumor tissue, possibly because of the low concentration of hormones produced or because inactive prohormones rather than active molecular species were produced. Acknowledgements This work was supported in part by grants from the Italian Health Ministry to IRCCS Policlinico San Matteo.

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Key words: Endocrine tumors - Carcinoids - Gastrinoma - Intestine Prof. Enrico Solcia, Dipartimento di Patologia Umana, ed Ereditaria, Via Forlanini, 16, 1-27100 Pavia, Italy