Act8 Path. Jap. 26(2): 161-177, 1976
THE RELATIONSHIP OF GASTROINTESTINAL ENDOCRINE CELLS TO GASTRIC EPITHELIAL CHANGES WITH SPECIAL REFERENCE TO GASTRIC CANCER
Eiichi TAHARA, Shojiro &zu~cll, Teturo KODAMA and Akira YAMADA Department of Pathology, Hiroehima University 19chool of Medicine, Hiroehima (Received on August 12, 1974)
Using advanced gastric adenocarcinoma and carcinoid as human material and gastric adenocarcinoma in rats induced by MNNG and in mice by localized X-irradiation of the stomach a s experimental material, a pathological study was made on the relationship of gastric endocrine cells to gastric cancer. The results of the present study suggest that most of the endocrine cells in the cancer tissue are derived from the didterentiation of cancer cells. Therefore, the following three may be given as the aformentioned relationship, that is, 1) carcinoid of endocrine cell origin, 2) endocrine cell carcinoma showing undifferentiated adenocarcinoma, and 3) endocrine cell cloning developed from the differentiation of cancer cell of adenocarcinoma. There is the possibility that most of 2) are of 3) origin and thus 2) and 3) should be discriminated from 1), having a functioning tumor in rare cases. The significance of reactive hyperplasia of endocrine cells in the non-metaplastic mucosa of the stomach around cancer and atypical epithelium is not yet determined, but that of EC cell seems at least to be related with the development of intestinal metaplasia in the gastric mucosa. ACTA PATH. JAP. 25: 161-177.1975.
It is well known from the past that special cells such enterochromafi cells or basal granulated cells exist in the gastrointestinal tract. Recent ultrastructural and immunochemical studies1 have demonstrated that 6 9 types of endocrine cells in the muoosa of the mammalian alimentary tract are morphologically and functionally independent cells and produce different gastrointestinal hormones which have been discovered from the beginning of this century. PEARSEet al.a have assumed that these cells belong to APUD (amine and precursor uptake and decarboxylation) series and more recently FUJITA et aL3 have classified endocrine cells of the gastrointestinal tract and pancreas under one category, and suggested that
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they will be called the gastro-entero-pancreatic (GEP) endocrine system. These recent investigations and new concepts presented by anatomists have exercised a great influence on oncology, especially on the histogenesis and classification of tumors of endocrine cell origin and on the analysis of heterotopic hornione producing tumors and furthermore introduced a good number of new problems. The authors have previously reported that at least 4-5 types of gastric endocrine cells exist in the gastric mucosa4. The present paper deals with the morphological study made on the relationship of endocrine cells to gastric epithelial changes with special reference to neoplastic changes.
Material and Method 1) Human Material (159 cases of gastric cancer and 5 cases of csrcinoid)
Gastric cancer cases: A total of 159 cases of advanced cmcer were used as mPterial, that is, 54 operative czses of papillary-tubular adenocarcinoma, 51 caaes of poorly differentiated adenocarcinoma, and 54 cases of signet-ring cell carcinoma. These tissues were stretchfixed in 10% formalin solution and for each 2-10 tissue specimens were prepared by cutting dong the long axis involving the focus. According to the prescribed procedure, these specimens were embedded in paraffin and then stained with hematoxylin-eosin stain, MassonFontana’s stain for argentaffin reaction and Bodian’s or Grimelius’s stain for argyrophil reaction. The unstained specimens were exmained under the fluorescence microscope for the presence of auto-fluorescence of cancer cells. The fresh cancer tissue of 33 cases (12 cases of papillary-tubular adenocarcinoma, 10 cases of poorly differentiated adenocarcinoma and 11 cases of signet-ring cell carcinoma) were fixed in 3% glutaraldehyde solution, post-fixed in 1% osmium acid, and embedded in epoxy resin. The ultra-thin specimens were double stained in uranyl lead acetate. Carcinoid cases: The tissues of 5 cases of primary gastric carcinoid were stained with the foregoing stains and subjected to histological observation. Using the paraffin block of the tumor tissue of the 3 cases responding negative to silver reaction, electron microscopic examination was made for the presence or absence of special secretory granules within the tumor cells. 2 ) Experimental Material
M ” G rat gastric cancer: Drinking water containing 80 pg/ml of N-methyl-”-nitroN-nitosoguanidine (hereinafter abbreviated as MNNG) was administered to Wistar rats (6 weeks after birth) for 7 months and tissues of the gastric cancers in the glandular stomach ohtained during the 60-week period following commencement of this experiment were used. Mouse gastric adenocarcinoma induced by localized X-irradation of the stomach : Localized X-irradation of the stomach (8000 rads) of ICR/JCR strain mice (8 weeks after birth) was made and some of the results8 obtained within 20 weeks were used. As in the human material these two types of experimental material were subjected to the forcgoing light microscopic, fluorescence microscopic and electron microscopic observations.
Results Human Gastric Cancer Cases Of the 159 cases of advanced cancer, cancer cells having argyrophil positive
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Fig. 1. Poorly Werentiated adenoaarcinoma. 54-year-old male. Note endocrine cell clone (E cells) within cancer cells in the subeerosa. ~4,800.
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granules were observed in 11 cases or 6.9% and furthermore, argentaffin cells responding positive to Masson-Fontana’s reaction were noted in 4 cases or 2.5%. Thus, non-argentaffi argyrophil cells were seen in 7 cases or 4.4%. The criterion for evaluating cancer cell positive for silver reaction was applied to cancer tissue showing infiltration of adenocarcinoma extending from the submucosa to the deep region. The frequency and distribution of silver positive granules and special secreting cells within the cancer cells varied considerably and they were often observed in several scattered cell colonies (Fig. 1, 2) and rarely contained both secretory granules of mucous and endocrine granules (Fig. 3). I n one case of signet-ring cell carcinoma, argentaffin cells appeared diffusely and extensively from the submucosa to the serosa (Fig. 4 a and 4 b). This case corresponds to the case of “diffuse argentaffioma” reported by KUBOet al. (1971)‘. The relation between these silver positive cells and histological type of cancer is shown in Table 1. Argentaffi cells were observed in 3 cases (5.5%) among the 54 cases of papillarytubular adenocarcinoma, argyrophil cells in 5 cases (9.8%) among the 51 cases of poorly differentiated adenocarcinoma, argyrophil cells in 2
Fig. 2. High magnification of E cell. Note special secretory granules (200-300 mp in diameter) and numerous filaments. x 12,000.
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Fig. 3. Poorly differentiated adenocarcinoma. 65-year-old male. Cancer cell c o n t a b mucous (arrow) and endocrine granules. x 12,000.
Table 1. Incidence of Endocrine Cells in Histological Typea of amtric Carcinoma in Man Histological type
Total No.
Argyrophil cell
Argentaffin cell
Papillary-tubular Poorly differentiated Signet-ring cell
* Diffuse type cases (3.7%) and argentafin cell in the aformentioned case (2.5%) among the 54 cases of signet-ring cell carcinoma. These findings suggest a tendency for silver positive cells especially argyrophil cells within cancer cells to appear more frequently in undifferentiated adenocarcinomas. Proliferation of argentafk cells (EC cell) is often observed in the intestinal metaplastic epithelium frequently developing around the cancer, but hardly any
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Fig. 4a. Signet-ring cell czrcinomu. 58-year-old male. Note numerous argentaffin cells in cancer cells. Maseon-Fontana’s stain.
Fig. 4b. These argentaffin cells in same focus of Fig. 4a exhibit autofluorescence under the fluorescence microscope.
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Fig. 5. Reactive hyperplasia of argentaffin cells in the human pyloric gland mound the cancer. MaesonFontana’s stain.
Fig. 6. Reactive hyperplasia of ~lrggrophi1 cells in the human pyloric gland around the cancer. Grimelius’s stein.
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G cells could be seen in the region of the pyloric gland replaced by extensive metaplasia. Reactive proliferation of argentaffin or argyrophil cells could be frequently found in the non-metaplastic epithelium not only around the cancer but also the atypical epithelium of benign and malignant border-line lesion (Figs. 5 and 6).
Human Carcinoid Cases Table 2 gives the age, sex, site, and histological classification of the 5 cases of gastric carcinoid. Histological classification is based on that of SOGA(1973)8. Combination of the histological type with silver reaction showed 1 cases of mixed type argyrophil cell type, 1 case of B type argyrophil cell type, and 3 cases of nonreactive cell type (one A type and two mixed type). Electon microscopic examination was made on the non-reactive cell type using paraffin blocks and in all cases special secretory granules 150-3OOmp in size were observed. In case No. 5, the primary focus showed non-reactive cell type, but a portion of metastatic foci of the regional lymph nodes was composed of argyrophil cells (Fig. 7). Case No. 5 is an interesting case with a primary focus showing ulcer formation 4 x 5 cm in size. The superficial layer occupying about 1/3 of the the tumor is composed of tubular adenocarcinoma and the margin between it and the noncancerous mucosa of the intestinal metaplasia is made up of well differentiated adenocarcinoma. The zone from the mid-layer to the deep tissue (from the submucosa to the serosa) which occupied more than 213 of the tumor was composed of mixed type carcinoid (Fig. 8). A d e h i t e transition was observed between this adenocarcinoma and carcinoid. None of these five cases of gastric carcinoid presented clinical symptoms of endocrine abnormality. Table 2. Caaee of Uastric Carcinoida
No. case
*
Age Sex
Site
Histological type*
62, M. 66, M. 47, F. 42, F. 72, M.
Antrum-body Antrum Antrum Antrum-body Antrum
Mixed A B Mixed Mixed
Silver reaction Argyrophil Non-reactive Argyrophil Non-reactive Non-reactive**
Soga’s classfication10,
** Argyrophil positive in metastatic foci of gclstric lymphnodes. Cases of Experimental Gastric Cancer
1) Experimental odenocarcinoma of the glandular stomach in rats: The process of gastric cancer development in rats induced by the oral administration of MNNG
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Fig. 7. Human carcinoid. 72-year-old male. Note argyrophil positive granules in tumor oells of metastatic carcinoid in the lymph nodes. Grimelius’s stain.
Fig. 8. Primary tumor of Fig. 7. Tumor is composed of tubular edenocercinoma and typical wcinoid. H-E. shin.
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Fig. 9a. Adenocarcinoma of the glandular stomach in rat induced by MNNG. Cancer cells in the subseross contain large number of argyrophil cell. Bodian shin.
Fig. 9b. Fine structure of Fig. 9a. Note numerous endocrine granules. x14,OOO.
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Fig. 10a. Adenocarcinoma of the glandular stomach in mouse by X-irradiation. H-E. stain.
Fig. lob. Note few secretory granules (arrows, 200-300 mp in diameter).
x 12,000.
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was followed. After 20 weeks from the day when the experiment was commenced, in the pyloric mucosa down adenomatous hyperplasia was found to be invading from the ulcer margin into the submucosa or upward adenomatous hyperplasia presenting a protuberant lesion was observed to be growing into the gastric cavity. Glandular hyperplasia does not generally exhibit atypical cells but often has acid mucus. Furthermore, hyperplasia of silver positive cell especially argentaffin cells was observed in the polypoid lesions. After 30 weeks adenocarcinoma developed and as in the case of human gastric cancer silver positive cells were scatteringly seen within the cancer tissue. In one case of tubular adenocarcinoma numerous endocrine cells appeared on the 47th week. I n some region of this cancer which had invaded into the muscle layer, there was proliferation of many non-argentaffin argyrophil cells (Fig. 9a, b), which under the fluorescence microscope released autofluorescence of golden color. Electron microscopically, large number of special secretory granules (200-300 mp in size) were found within these cancer cells and in rare instances there were cancer cells which contained both mucous and endocrine granules.
2)Experimental adenocarcinoma of the glandular stomach in mice induced by Xirradiation: The development of experimental gastric cancer in mice induced by localized X-irradiation of the stomach was followed. From about the 10th week following X-irradiation there was a development of atypical glandular hyperplasia with invasion of regenerative epithelium from the ulcer margin into the muck layer. Many of these epithelial cells possessed acid mucus. On the 20th week after X-irradiation, adenocarcinoma developed and infiltrated from the serosa into the pancreas (Big. 10a). The frequency of siver positive cells was less in precancerous and cancerous lesion induced by X-irradiation in comparison with that in gastric lesion by the aformentioned MNNG. A small number of argentaffin cells could be seen between the cancer cells showing differentiation into intestinal metaplasia. Cancer cells containing endocrine secretory granules were observed electron microscopically (Big. lob).
Discussion Since the f i s t report made by €€AMPERL (1927)8that silver positive cells appear in the carcinoma of the gastrointestinal tract, many related investigations have been made to date. The frequency of argyrophil cells in the 159 cases of human gastric cancer in this study was 4.4% and that of argentafb cells was 25%, but AZZOPARDI et a2.10 reported that of argyrophil cells in 100 cases of gastric cancer to be 13% and that of argentaffin cells to be 8%. Among 382 cases of gastric cancer studies by KUBOet al.1 the frequency of argentaffin cells was found to be 3.1%.
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With regard to the relationship between histological type of gastric cancer and the frequency of such cells, the results of the present study are in agreement with studies by other authors.7110 These cells are more abundant in undifferentiated adenocarcinoma including signet-ring cell carcinoma and poorly differentiated adenocarcinoma than in differentiated adenocarcinoma. Argyrophil cells in particular appear at a frequency of 13.6% in undifferentiated adenocarcinoma. In one case in which argentah cells were diffusely and extensively observed in signet-ring cell carcinoma, there is a possibility of functioning tumor of the serotonin producing tumor. In fact, KUBOet al.7 have reported a case presenting not only a morphological feature identical to this case but also carcinoid syndrome. They have proposed to call such cases as these “diffuse argentahoma.” As to the origin of such endocrine cells appearing in these adenocarcinomas, first, as the concomitant change of cancer there is the possibility that cell focus of reactive hyperplastic and non-neoplastic change around the cancer ir;l involved within the cancer tissue. This possibility, however, appears small in view of the criterion used in the present study on human cancer to determine whether cells are silver postive cells or not. The authors wish to endorse the opinion taken by AZZOPARDor KUBO et a1.7. The appearance of endocrine cell within the cancer tissue, such as Paneth‘s cells, parietal cells and chief cells in the gastric cancer, seems to be attributable to differentiation of tumor cells for the following reason. Though various theories have been postulated on the histogenesis of gastrointestinal endocrine cells, the authors have made an assumption that most of the gastric endocrine cells develop from entodermal indifferent cells in view of the fact that differentiation of endocrine cells is observed during the regeneration of experimental gastric ulcer4 and that cells having two secretory granules, that is endocrine garnules and mucous granules,ll are observed in the normal mucosa of the stomach as acinar islet cells of the pancreas. Thus, gastric cancer which may be considered to arise from indifferent cell with multipotency seems to exhibt various histological types and differentiation of cancer such as from adenocarcinoma to typical pattern of carcinoid and to have rare possibilty of functioning tumor. In fact, there have been cases10 in which gastrointestinal adenocarcinoma caused metastasis to the lymph nodes to present a histological picture of carcinoid or carcinoid syndrome. Some cases of mixed carcinoid and mucug intestinal tumor reported by HERNANDEZ et al.1a and cases10 of microcarcinoid in the signet ring cell carcinoma of the stomach should not be assumed to be both proliferation of tumor originating from endocrine cells and adenocarcinoma but to be neoplastic cells which have differentiated into endocrine cells. The relationship between carcinoid and endocrine c e h of the gastrointestinal tract has been studied from various aspects, and a number of new problems have
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been presented. Since OBERND0FERl3 first presented the name of carcinoid in 1907, many studies have been made on tumors belonging to this category, such as histochemical studies on argentaffinity or argyrophilia and electron microscopic studies, clinical biochemical analyses14,l5ll6on the relationship of special syndromes to serotonin, 5-HTP, histamine and bradykinin, classification17 of carcinoid based on embryological development site and experimental studies18~1Qon Mastomys gastric tumors. Thus the concept of carcinoid has been making a vast change. On the other hand, a t almost the same time as the foregoing studiesit has been elucidated by anatomists that 5-9 types of endocrine cells which are different morphologically and functionally are scattered in the gastrointestinal tract of various types of mammals. Furthemore, FUJITAet ~ 1 . 1 1in~ view of similarity between endocrine cells and hormones of the gastrointestinal tract and those of the pancreas have classified these under the nomenclature of GPE endocrine system. Recently S O G Ahas ~ taken the position that carcinoids should be placed under the category of “foregut endocrine cell tumor” arising from the foregut endocrine cells which are scattered within the GEP endocrine system, the lung and other organs. If carcinoids were not restricted to tumors of EC cell (enterochromaffin cell, Kultschitzky cell) origin (classical carcinoid) and were to be derived from many endocrine cells of the foregut, SOGAhas reported that it would be possible to explain the various morphological and functional characteristics of carcinoid as heretofore reported in the literature.8 Indeed, his hypothesis and histological classification of carcinoid are unique and are considered to be logical in explaining many types of carcinoids. However, type C and type D of carcinoid according to his classification present a number of problems. These are typical cases of tubular adenocarcinoma and poorly differentiated adenocarcinoma containing many special secretory granules though silver positive or negative. Is it proper to classify these as carinoids? Two cases of human and experimental gastric cancer cases in this study, the cases of diffuse carcinoma reported by KUBOet al.7, the gastric cancer reported by SOGAet al. (1971)20to be a r g e n t a h cell adenocarcinoma, and the cases of adenocarcinoma the appendix reported by ROSAI( 1968)21 and KLEIN (174)22to be of endocrine cell origin, cannot be ruled out to have the possibility that they are developed from differentiation of tumor cells. The authors wish to emphasize that carcinoid should be considered to be an endocrine cell tumor developing from endocrine cells of the foregut and that though no disagreement is given to the theory that most of their biological characteristics are malignant, their diagnosis should be made comprehensively based on the heretofore characteristic histological picture together with histochemical and electron microscopic findings. Generally, classification of tumors is made according to histonomical classification and among the wide categories of tumors there are some which are not
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necessarily consistent with the histonomical criteria. If the classification based on the morphology of the tumor including metaplasia, differentiation and disdifferentiation were confused with the histonomical classification in referring to a name of a certain tumor, the scope of that tumor would of consequence become large. With regard to type C and D of carcinoid of Soga's classification,lg further review should be made with respect to their histogenesis as in the case of oat cell carcinoma of the lung. The case of carcinoid in this report as Case 6, is almost identical to the case of mixed carcinoid and mucus secreting tumor reported by HERNANDEZ et aZ.11, but for the origin cells of these cases not only endocrine cells but also indifferent cells may be given. Therefore, the following three may be given as the relationship of gastric epithelial tumor to gastric endocrine cells, that is, (1) carcinoid of endocrine cell origin, (2) endocrine cell carcinoma with a predominant picture of poorly differentiated adenocarcinoma, and (3) endocrine cell cloning due to differentiation of cancer cells of adenocarcinoma. LThe mutual relationship is summarized in Table 3. There is a strong possibilty that a part of (2) is due to (3) origin and therefore (2) and (3) should be discriminated from (1) and in rare cases there is the possibilty of functioning tumor. Table 3. The. Re.la.ti0nahi.p of Endoorine C d b to Qaatric Canoer Endocrine cells
f 1 Carcinoma cell
Indifferent cell
/ Carcinoid Endocrine cell carcinoma
-
t
Endocrine cell clone
More interesting i A the relationship of non-cancerous changes of the gastric mucosa to the endocrine ,cells of GEP endocrine system. First, intestinal metaplasia which frequently develops in the pyloric region, G cells evidently decrease or disappear as reported by RUBIN(1969)aS and OUATA (1971),B4but EC cells exhibit a remarkable proliferation. This indicates that when metaplasia is severe and extensive, the distribution of endocrine cells make a remarkable change. In general this intestinal metaplasia frequently develops around gastric cancer or ulcer, but it is interesting that when argentafi cells (EC cells) reactively proliferate about the cancer and atypical epithelium, these are observed in the gastric mucosa which has yet to show intestinal metaplasia. Reactive hyperplasia of argyrophil cells can be observed also in human cancers,B6 carcinoid,Bo and polypoid lesions in rats induced by MNNG regardless of intestinal metaplasia. The sigdcance of such reactive proliferation of endocrine cells around the tumor is
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yet not determined, but it is speculated that the reactive proliferation of EC cells is a t least involved in the development of intestinal metaplasia. A recent investigation27 has been reported on the change of endocrine cells especially G cells in gastrointestinal ulcers, that is, hyperplasia of G cells is often observed in cases showing hyperacidity. The authors in their e ~ p e r i m e n t ~in ,'~ which artificial acute ulcer was induced in the gastric body of the glandular stomach in mice observed the development of gastric endocrine cells. There was no increase in G cells, but ECL cells were found from the early period in the regenerative ~ r ~ been ~ presented on Zollinger-Ellison's syndrome epithelium. A few r e p ~ r t s have and pernicious anemia, but there are many unresolved problems requiring further study with regard to the role of GEP endocrine system in gastrointestinal diseases. In the authors' experimental studyso on the effects of GEP hormones on gastric cancer in rats induced by MNNG, a very interesting finding has been observed that scirrhous cancer develops in the group given gastrointestinal hormones such as gastrin for a given period. The effects of GEP endocrine cells in chronic gastritis and peptic ulcer on the ability to secrete gastric juice is an important problem to be resolved in the future together with the question of what types of cells or hormones among GEP endocrine cells participate in the histogenesis and differentiation of gastric tumor. References 1. SOLCIA,E., VASSALLO, G. and CAPELLA,C.: Cytology and cytochemistry of hormone producing cells of the upper gastrointestinal tract. I n ; (ed. by) W. Creutzfelt: Origin, chemistry, physiology and pathophysiology of the gastrointestinal hormones. p 3-29, Stuttgart and New York, F.K. Schattauer Verlag, 1970. 2. CARVALHEIRA, A.F., WELSCH,U. and PEARSE, A.G.E.: Cytochemical and ultrastructural observation on the argentaffin and aryrophil cells of the gastro-intestinal tract in mammals, and their place in the APUD series of polypeptide-secretory cells. Histochemie 14: 33-46, 1968. 3. FUJITA, T. and KOBAYASHI, S.: The cell and hormones of the GEP endocrine system - The current of studies. In; (ed. by) T. Fujita: Gastro-entero-pancreatic endocrine system. A cell-biological approach. p 1-16. Igaku Shoin Ltd. Tokyo, 1973. 4. TAHARA,E: Fine structure of several types of endocrine cells in mouse gastric mucosa with special reference to the histologenesis. Hiroshima J.M. Sci. 20: 255-268, 1971. 5. TAW, E. and YAWA, A.: Experimental study on the histogenesis and differentiation of gastric cancer- ultrastructural observation on the gastric adenocarcinoma in rat induced by N-methyl-N'-nitro-N-nitorsouganidine. Tr.SOC. Path. Jap. LXI. 122, 1972 (in Japanwe). 6. TAEARA, E. and HIROSE, F.: Induction of gastric adenocarcinoma in mice by Xirradiation. 111) Elctron microscopic observetion on the development of gastric carcinoma in ICR strain. Proceedings of the Japanese Cancer Association. The 30nd Annual Meeting. 35, 1971 (in Japaneae). 7. KUBO, T. and WATANABE, H.: Neoplastic argentaffin cells in gastric and intestinal carcinoma. Cancer 27: 447-454, 1971. 8. SOQA,J.: Carcinoids: their changing concepts and a new histological classification.
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In: (ed. by) T. Fujita: Gastro-enteropancreatic endocrine system. A cell-biological approach. p 101-119, Igaku Shoin Ltd. Tokyo 1973. HAKCPERL,H.: Uber die ,,gelben (chromaffinen)" Zellen im gesunden und kranken Magendarmschlauch. Virchow. Arch. Path. Anat. 266 : 609-648, 1927. AZZOPARDI, J.G. and POLLOCK, D.L.: Argentaffin and argyrophil cells in gastric carcinoma. J. Path. Bact. 86: 443461, 1963. TAHARA,E.: Regeneration of gastric epithelia in mice. An electron microscopic study. Hiroshima J.M. Sci. 20: 66-99, 1971. HERNANDEZ, F.J. and P m , L.D.: Mixed carcinoid and mucus secreting inteatinel tumors. Arch. Path. 88: 489496, 1969. OBERNDBOPER, S.: Karzinoide Tumoren des Diinndarme. Frmkfurt. Z. Path. 1: 426-
432, 1907. I.H., Corcorna, A.C., Udenfreind, S., Szoedsma, A. and Weiasbach. H.: Argent14. PAQE, affinoma as endocrine tumor. Lancet 1: 198-199, 1966. A.H., PLATT, D.S. and SNOW,P.J.D.: A 6-hydroxy16. CUPBELL, A.C.P., GOWENCLO~K, tryptophan-secreting carcinoid tumor. Gut. 4 : 61-67, 1963. W.A. and DOUTER, R.B.: Evidence for the release of brady16. OATES,J.A., PETTINQER, kinii in carcinoid syndrome. J. Clin. Invest. 45: 173-178, 1966. E.D. and SANDLER, M.: The classification of carcinoid tumors. Lancet 1: 17. WILLIAMS, 238-239, 1963. K., UAHARA, H. and HIRAIDE, K.: Some characteristic features 18. SOQA,J., TAZAWA,
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20. 61. 22. 23. 24. 26. 26.
of spontaneous argyrophil cell carcinoids in glandular stomach of Praomys ( h t o m y s ) natalensis. In experimental carcinoma of the glandular stomach. G A " Monogr. No. 8. 16-38. Maruzen Co., Ltd. Tokyo. 1969. HOSODA, S., NAKAMURA, W., SHELL,K.C. and STERWART, H.L.: Histamine production by transplatanable argyrophil gastric wcinoid of Praomys ( h t o m y s ) natalensis. Sicence. 170: 464-456, 1970. SOQA,J., TAZAWA, K., AIZAWA,O., WADA, K. and MUTO, T.: Argentaffi cell adenocarcinoma of the stomach: An atypical carcinoid ? Cancer 28: 999-1003, 1971. ROSAI,J. and RODBINQUEZ, H.A.: Application of electron microscopy to the differential diganosis of tumors. Amer. J. Clin. Path. 50: 666662, 1968. ~ E I N H.Z.: , Mucinous carcinoid of the appendix. Cancer 33: 770-777, 1974, RUBIN, W.: Prolfieration of endocrine like (enterochromaffi) cells in atrophic gastric mucosa. Gastroenterol. 57: 641-648, 1969. NABEYU, A. and OQATA,T.: Cytological studies on the enterochromaffi cells in the intestinal metaplaaia. Tohoku J. exp. Med. 105: 366-363, 1971. SOGA,J. and HANATO, T.: Argymphil cell: Hyperplastic, preneoplastic and neoplastic proliferations. - A preminary observation -. Acta Medic et Biologjca. 18: 1-6, 1970. BLACK,W.C. and H m m , H.E.: Diffuse hyperplasia of gastric argyrophil cells and multiple carcinoid tumors. A histological and ultraetructmal study. Cancer 21: 1080-
1099, 1968. 0.: Endocrine cell of the stomach and pancreae 27. S o w , E., CAPELLA,C. and VASSALLO, in statea of gastric hypersecretion. Rendic. R. Gastroenterol. 2: 147-168, 1970. J.M., STAQQ,B. and F'EARSE,A.G.E.: The G cells in pernicious anemia. Gut. 28. POLAK, 12: 319-323, 1971. J.M., COULLINQ, L., DOE, W. and PEARSE, A.G.E.: T w o typea of Zollinger29. POLAK,
Ellison syndrome; immunoluorescent, cytochemical and ultrastructural studiea of the antral and pancreatic gastric cells in different clinical ahtea. Gut. 13: 601612, 1972. E., HAIZWKA,8. and YAMADA, A.: The effects of GEP endocrine hormones 30. TAHARA, on the development of experimental carcinoma of the glanduler stomach in rat induced by MNNG. Proceedings of the Japanese Cancer Association. The 33nd Annual Meeting. 1974.
THE RELATIONSHIP OF GASTROINTESTINAL ENDOCRINE CELLS TO GASTRIC EPITHELIAL CHANGES WITH SPECIAL REFERENCE TO GASTRIC CANCER
Eiichi TAHARA, Shojiro &zu~cll, Teturo KODAMA and Akira YAMADA Department of Pathology, Hiroehima University 19chool of Medicine, Hiroehima (Received on August 12, 1974)
Using advanced gastric adenocarcinoma and carcinoid as human material and gastric adenocarcinoma in rats induced by MNNG and in mice by localized X-irradiation of the stomach a s experimental material, a pathological study was made on the relationship of gastric endocrine cells to gastric cancer. The results of the present study suggest that most of the endocrine cells in the cancer tissue are derived from the didterentiation of cancer cells. Therefore, the following three may be given as the aformentioned relationship, that is, 1) carcinoid of endocrine cell origin, 2) endocrine cell carcinoma showing undifferentiated adenocarcinoma, and 3) endocrine cell cloning developed from the differentiation of cancer cell of adenocarcinoma. There is the possibility that most of 2) are of 3) origin and thus 2) and 3) should be discriminated from 1), having a functioning tumor in rare cases. The significance of reactive hyperplasia of endocrine cells in the non-metaplastic mucosa of the stomach around cancer and atypical epithelium is not yet determined, but that of EC cell seems at least to be related with the development of intestinal metaplasia in the gastric mucosa. ACTA PATH. JAP. 25: 161-177.1975.
It is well known from the past that special cells such enterochromafi cells or basal granulated cells exist in the gastrointestinal tract. Recent ultrastructural and immunochemical studies1 have demonstrated that 6 9 types of endocrine cells in the muoosa of the mammalian alimentary tract are morphologically and functionally independent cells and produce different gastrointestinal hormones which have been discovered from the beginning of this century. PEARSEet al.a have assumed that these cells belong to APUD (amine and precursor uptake and decarboxylation) series and more recently FUJITA et aL3 have classified endocrine cells of the gastrointestinal tract and pancreas under one category, and suggested that
%.fa
€Elm %-, E% P-BL !J?Z 11183 sa This study was premnted at the 62th General Meeting of the Japanem Pathological Society, Chibs, 1973. A part of this study was supported by a Grant-in-Aid for Scientific Research of the Japanese Ministry of Education. 161
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they will be called the gastro-entero-pancreatic (GEP) endocrine system. These recent investigations and new concepts presented by anatomists have exercised a great influence on oncology, especially on the histogenesis and classification of tumors of endocrine cell origin and on the analysis of heterotopic hornione producing tumors and furthermore introduced a good number of new problems. The authors have previously reported that at least 4-5 types of gastric endocrine cells exist in the gastric mucosa4. The present paper deals with the morphological study made on the relationship of endocrine cells to gastric epithelial changes with special reference to neoplastic changes.
Material and Method 1) Human Material (159 cases of gastric cancer and 5 cases of csrcinoid)
Gastric cancer cases: A total of 159 cases of advanced cmcer were used as mPterial, that is, 54 operative czses of papillary-tubular adenocarcinoma, 51 caaes of poorly differentiated adenocarcinoma, and 54 cases of signet-ring cell carcinoma. These tissues were stretchfixed in 10% formalin solution and for each 2-10 tissue specimens were prepared by cutting dong the long axis involving the focus. According to the prescribed procedure, these specimens were embedded in paraffin and then stained with hematoxylin-eosin stain, MassonFontana’s stain for argentaffin reaction and Bodian’s or Grimelius’s stain for argyrophil reaction. The unstained specimens were exmained under the fluorescence microscope for the presence of auto-fluorescence of cancer cells. The fresh cancer tissue of 33 cases (12 cases of papillary-tubular adenocarcinoma, 10 cases of poorly differentiated adenocarcinoma and 11 cases of signet-ring cell carcinoma) were fixed in 3% glutaraldehyde solution, post-fixed in 1% osmium acid, and embedded in epoxy resin. The ultra-thin specimens were double stained in uranyl lead acetate. Carcinoid cases: The tissues of 5 cases of primary gastric carcinoid were stained with the foregoing stains and subjected to histological observation. Using the paraffin block of the tumor tissue of the 3 cases responding negative to silver reaction, electron microscopic examination was made for the presence or absence of special secretory granules within the tumor cells. 2 ) Experimental Material
M ” G rat gastric cancer: Drinking water containing 80 pg/ml of N-methyl-”-nitroN-nitosoguanidine (hereinafter abbreviated as MNNG) was administered to Wistar rats (6 weeks after birth) for 7 months and tissues of the gastric cancers in the glandular stomach ohtained during the 60-week period following commencement of this experiment were used. Mouse gastric adenocarcinoma induced by localized X-irradation of the stomach : Localized X-irradation of the stomach (8000 rads) of ICR/JCR strain mice (8 weeks after birth) was made and some of the results8 obtained within 20 weeks were used. As in the human material these two types of experimental material were subjected to the forcgoing light microscopic, fluorescence microscopic and electron microscopic observations.
Results Human Gastric Cancer Cases Of the 159 cases of advanced cancer, cancer cells having argyrophil positive
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Fig. 1. Poorly Werentiated adenoaarcinoma. 54-year-old male. Note endocrine cell clone (E cells) within cancer cells in the subeerosa. ~4,800.
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granules were observed in 11 cases or 6.9% and furthermore, argentaffin cells responding positive to Masson-Fontana’s reaction were noted in 4 cases or 2.5%. Thus, non-argentaffi argyrophil cells were seen in 7 cases or 4.4%. The criterion for evaluating cancer cell positive for silver reaction was applied to cancer tissue showing infiltration of adenocarcinoma extending from the submucosa to the deep region. The frequency and distribution of silver positive granules and special secreting cells within the cancer cells varied considerably and they were often observed in several scattered cell colonies (Fig. 1, 2) and rarely contained both secretory granules of mucous and endocrine granules (Fig. 3). I n one case of signet-ring cell carcinoma, argentaffin cells appeared diffusely and extensively from the submucosa to the serosa (Fig. 4 a and 4 b). This case corresponds to the case of “diffuse argentaffioma” reported by KUBOet al. (1971)‘. The relation between these silver positive cells and histological type of cancer is shown in Table 1. Argentaffi cells were observed in 3 cases (5.5%) among the 54 cases of papillarytubular adenocarcinoma, argyrophil cells in 5 cases (9.8%) among the 51 cases of poorly differentiated adenocarcinoma, argyrophil cells in 2
Fig. 2. High magnification of E cell. Note special secretory granules (200-300 mp in diameter) and numerous filaments. x 12,000.
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Fig. 3. Poorly differentiated adenocarcinoma. 65-year-old male. Cancer cell c o n t a b mucous (arrow) and endocrine granules. x 12,000.
Table 1. Incidence of Endocrine Cells in Histological Typea of amtric Carcinoma in Man Histological type
Total No.
Argyrophil cell
Argentaffin cell
Papillary-tubular Poorly differentiated Signet-ring cell
* Diffuse type cases (3.7%) and argentafin cell in the aformentioned case (2.5%) among the 54 cases of signet-ring cell carcinoma. These findings suggest a tendency for silver positive cells especially argyrophil cells within cancer cells to appear more frequently in undifferentiated adenocarcinomas. Proliferation of argentafk cells (EC cell) is often observed in the intestinal metaplastic epithelium frequently developing around the cancer, but hardly any
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Fig. 4a. Signet-ring cell czrcinomu. 58-year-old male. Note numerous argentaffin cells in cancer cells. Maseon-Fontana’s stain.
Fig. 4b. These argentaffin cells in same focus of Fig. 4a exhibit autofluorescence under the fluorescence microscope.
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Fig. 5. Reactive hyperplasia of argentaffin cells in the human pyloric gland mound the cancer. MaesonFontana’s stain.
Fig. 6. Reactive hyperplasia of ~lrggrophi1 cells in the human pyloric gland around the cancer. Grimelius’s stein.
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G cells could be seen in the region of the pyloric gland replaced by extensive metaplasia. Reactive proliferation of argentaffin or argyrophil cells could be frequently found in the non-metaplastic epithelium not only around the cancer but also the atypical epithelium of benign and malignant border-line lesion (Figs. 5 and 6).
Human Carcinoid Cases Table 2 gives the age, sex, site, and histological classification of the 5 cases of gastric carcinoid. Histological classification is based on that of SOGA(1973)8. Combination of the histological type with silver reaction showed 1 cases of mixed type argyrophil cell type, 1 case of B type argyrophil cell type, and 3 cases of nonreactive cell type (one A type and two mixed type). Electon microscopic examination was made on the non-reactive cell type using paraffin blocks and in all cases special secretory granules 150-3OOmp in size were observed. In case No. 5, the primary focus showed non-reactive cell type, but a portion of metastatic foci of the regional lymph nodes was composed of argyrophil cells (Fig. 7). Case No. 5 is an interesting case with a primary focus showing ulcer formation 4 x 5 cm in size. The superficial layer occupying about 1/3 of the the tumor is composed of tubular adenocarcinoma and the margin between it and the noncancerous mucosa of the intestinal metaplasia is made up of well differentiated adenocarcinoma. The zone from the mid-layer to the deep tissue (from the submucosa to the serosa) which occupied more than 213 of the tumor was composed of mixed type carcinoid (Fig. 8). A d e h i t e transition was observed between this adenocarcinoma and carcinoid. None of these five cases of gastric carcinoid presented clinical symptoms of endocrine abnormality. Table 2. Caaee of Uastric Carcinoida
No. case
*
Age Sex
Site
Histological type*
62, M. 66, M. 47, F. 42, F. 72, M.
Antrum-body Antrum Antrum Antrum-body Antrum
Mixed A B Mixed Mixed
Silver reaction Argyrophil Non-reactive Argyrophil Non-reactive Non-reactive**
Soga’s classfication10,
** Argyrophil positive in metastatic foci of gclstric lymphnodes. Cases of Experimental Gastric Cancer
1) Experimental odenocarcinoma of the glandular stomach in rats: The process of gastric cancer development in rats induced by the oral administration of MNNG
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Fig. 7. Human carcinoid. 72-year-old male. Note argyrophil positive granules in tumor oells of metastatic carcinoid in the lymph nodes. Grimelius’s stain.
Fig. 8. Primary tumor of Fig. 7. Tumor is composed of tubular edenocercinoma and typical wcinoid. H-E. shin.
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Fig. 9a. Adenocarcinoma of the glandular stomach in rat induced by MNNG. Cancer cells in the subseross contain large number of argyrophil cell. Bodian shin.
Fig. 9b. Fine structure of Fig. 9a. Note numerous endocrine granules. x14,OOO.
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Fig. 10a. Adenocarcinoma of the glandular stomach in mouse by X-irradiation. H-E. stain.
Fig. lob. Note few secretory granules (arrows, 200-300 mp in diameter).
x 12,000.
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was followed. After 20 weeks from the day when the experiment was commenced, in the pyloric mucosa down adenomatous hyperplasia was found to be invading from the ulcer margin into the submucosa or upward adenomatous hyperplasia presenting a protuberant lesion was observed to be growing into the gastric cavity. Glandular hyperplasia does not generally exhibit atypical cells but often has acid mucus. Furthermore, hyperplasia of silver positive cell especially argentaffin cells was observed in the polypoid lesions. After 30 weeks adenocarcinoma developed and as in the case of human gastric cancer silver positive cells were scatteringly seen within the cancer tissue. In one case of tubular adenocarcinoma numerous endocrine cells appeared on the 47th week. I n some region of this cancer which had invaded into the muscle layer, there was proliferation of many non-argentaffin argyrophil cells (Fig. 9a, b), which under the fluorescence microscope released autofluorescence of golden color. Electron microscopically, large number of special secretory granules (200-300 mp in size) were found within these cancer cells and in rare instances there were cancer cells which contained both mucous and endocrine granules.
2)Experimental adenocarcinoma of the glandular stomach in mice induced by Xirradiation: The development of experimental gastric cancer in mice induced by localized X-irradiation of the stomach was followed. From about the 10th week following X-irradiation there was a development of atypical glandular hyperplasia with invasion of regenerative epithelium from the ulcer margin into the muck layer. Many of these epithelial cells possessed acid mucus. On the 20th week after X-irradiation, adenocarcinoma developed and infiltrated from the serosa into the pancreas (Big. 10a). The frequency of siver positive cells was less in precancerous and cancerous lesion induced by X-irradiation in comparison with that in gastric lesion by the aformentioned MNNG. A small number of argentaffin cells could be seen between the cancer cells showing differentiation into intestinal metaplasia. Cancer cells containing endocrine secretory granules were observed electron microscopically (Big. lob).
Discussion Since the f i s t report made by €€AMPERL (1927)8that silver positive cells appear in the carcinoma of the gastrointestinal tract, many related investigations have been made to date. The frequency of argyrophil cells in the 159 cases of human gastric cancer in this study was 4.4% and that of argentafb cells was 25%, but AZZOPARDI et a2.10 reported that of argyrophil cells in 100 cases of gastric cancer to be 13% and that of argentaffin cells to be 8%. Among 382 cases of gastric cancer studies by KUBOet al.1 the frequency of argentaffin cells was found to be 3.1%.
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With regard to the relationship between histological type of gastric cancer and the frequency of such cells, the results of the present study are in agreement with studies by other authors.7110 These cells are more abundant in undifferentiated adenocarcinoma including signet-ring cell carcinoma and poorly differentiated adenocarcinoma than in differentiated adenocarcinoma. Argyrophil cells in particular appear at a frequency of 13.6% in undifferentiated adenocarcinoma. In one case in which argentah cells were diffusely and extensively observed in signet-ring cell carcinoma, there is a possibility of functioning tumor of the serotonin producing tumor. In fact, KUBOet al.7 have reported a case presenting not only a morphological feature identical to this case but also carcinoid syndrome. They have proposed to call such cases as these “diffuse argentahoma.” As to the origin of such endocrine cells appearing in these adenocarcinomas, first, as the concomitant change of cancer there is the possibility that cell focus of reactive hyperplastic and non-neoplastic change around the cancer ir;l involved within the cancer tissue. This possibility, however, appears small in view of the criterion used in the present study on human cancer to determine whether cells are silver postive cells or not. The authors wish to endorse the opinion taken by AZZOPARDor KUBO et a1.7. The appearance of endocrine cell within the cancer tissue, such as Paneth‘s cells, parietal cells and chief cells in the gastric cancer, seems to be attributable to differentiation of tumor cells for the following reason. Though various theories have been postulated on the histogenesis of gastrointestinal endocrine cells, the authors have made an assumption that most of the gastric endocrine cells develop from entodermal indifferent cells in view of the fact that differentiation of endocrine cells is observed during the regeneration of experimental gastric ulcer4 and that cells having two secretory granules, that is endocrine garnules and mucous granules,ll are observed in the normal mucosa of the stomach as acinar islet cells of the pancreas. Thus, gastric cancer which may be considered to arise from indifferent cell with multipotency seems to exhibt various histological types and differentiation of cancer such as from adenocarcinoma to typical pattern of carcinoid and to have rare possibilty of functioning tumor. In fact, there have been cases10 in which gastrointestinal adenocarcinoma caused metastasis to the lymph nodes to present a histological picture of carcinoid or carcinoid syndrome. Some cases of mixed carcinoid and mucug intestinal tumor reported by HERNANDEZ et al.1a and cases10 of microcarcinoid in the signet ring cell carcinoma of the stomach should not be assumed to be both proliferation of tumor originating from endocrine cells and adenocarcinoma but to be neoplastic cells which have differentiated into endocrine cells. The relationship between carcinoid and endocrine c e h of the gastrointestinal tract has been studied from various aspects, and a number of new problems have
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been presented. Since OBERND0FERl3 first presented the name of carcinoid in 1907, many studies have been made on tumors belonging to this category, such as histochemical studies on argentaffinity or argyrophilia and electron microscopic studies, clinical biochemical analyses14,l5ll6on the relationship of special syndromes to serotonin, 5-HTP, histamine and bradykinin, classification17 of carcinoid based on embryological development site and experimental studies18~1Qon Mastomys gastric tumors. Thus the concept of carcinoid has been making a vast change. On the other hand, a t almost the same time as the foregoing studiesit has been elucidated by anatomists that 5-9 types of endocrine cells which are different morphologically and functionally are scattered in the gastrointestinal tract of various types of mammals. Furthemore, FUJITAet ~ 1 . 1 1in~ view of similarity between endocrine cells and hormones of the gastrointestinal tract and those of the pancreas have classified these under the nomenclature of GPE endocrine system. Recently S O G Ahas ~ taken the position that carcinoids should be placed under the category of “foregut endocrine cell tumor” arising from the foregut endocrine cells which are scattered within the GEP endocrine system, the lung and other organs. If carcinoids were not restricted to tumors of EC cell (enterochromaffin cell, Kultschitzky cell) origin (classical carcinoid) and were to be derived from many endocrine cells of the foregut, SOGAhas reported that it would be possible to explain the various morphological and functional characteristics of carcinoid as heretofore reported in the literature.8 Indeed, his hypothesis and histological classification of carcinoid are unique and are considered to be logical in explaining many types of carcinoids. However, type C and type D of carcinoid according to his classification present a number of problems. These are typical cases of tubular adenocarcinoma and poorly differentiated adenocarcinoma containing many special secretory granules though silver positive or negative. Is it proper to classify these as carinoids? Two cases of human and experimental gastric cancer cases in this study, the cases of diffuse carcinoma reported by KUBOet al.7, the gastric cancer reported by SOGAet al. (1971)20to be a r g e n t a h cell adenocarcinoma, and the cases of adenocarcinoma the appendix reported by ROSAI( 1968)21 and KLEIN (174)22to be of endocrine cell origin, cannot be ruled out to have the possibility that they are developed from differentiation of tumor cells. The authors wish to emphasize that carcinoid should be considered to be an endocrine cell tumor developing from endocrine cells of the foregut and that though no disagreement is given to the theory that most of their biological characteristics are malignant, their diagnosis should be made comprehensively based on the heretofore characteristic histological picture together with histochemical and electron microscopic findings. Generally, classification of tumors is made according to histonomical classification and among the wide categories of tumors there are some which are not
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necessarily consistent with the histonomical criteria. If the classification based on the morphology of the tumor including metaplasia, differentiation and disdifferentiation were confused with the histonomical classification in referring to a name of a certain tumor, the scope of that tumor would of consequence become large. With regard to type C and D of carcinoid of Soga's classification,lg further review should be made with respect to their histogenesis as in the case of oat cell carcinoma of the lung. The case of carcinoid in this report as Case 6, is almost identical to the case of mixed carcinoid and mucus secreting tumor reported by HERNANDEZ et aZ.11, but for the origin cells of these cases not only endocrine cells but also indifferent cells may be given. Therefore, the following three may be given as the relationship of gastric epithelial tumor to gastric endocrine cells, that is, (1) carcinoid of endocrine cell origin, (2) endocrine cell carcinoma with a predominant picture of poorly differentiated adenocarcinoma, and (3) endocrine cell cloning due to differentiation of cancer cells of adenocarcinoma. LThe mutual relationship is summarized in Table 3. There is a strong possibilty that a part of (2) is due to (3) origin and therefore (2) and (3) should be discriminated from (1) and in rare cases there is the possibilty of functioning tumor. Table 3. The. Re.la.ti0nahi.p of Endoorine C d b to Qaatric Canoer Endocrine cells
f 1 Carcinoma cell
Indifferent cell
/ Carcinoid Endocrine cell carcinoma
-
t
Endocrine cell clone
More interesting i A the relationship of non-cancerous changes of the gastric mucosa to the endocrine ,cells of GEP endocrine system. First, intestinal metaplasia which frequently develops in the pyloric region, G cells evidently decrease or disappear as reported by RUBIN(1969)aS and OUATA (1971),B4but EC cells exhibit a remarkable proliferation. This indicates that when metaplasia is severe and extensive, the distribution of endocrine cells make a remarkable change. In general this intestinal metaplasia frequently develops around gastric cancer or ulcer, but it is interesting that when argentafi cells (EC cells) reactively proliferate about the cancer and atypical epithelium, these are observed in the gastric mucosa which has yet to show intestinal metaplasia. Reactive hyperplasia of argyrophil cells can be observed also in human cancers,B6 carcinoid,Bo and polypoid lesions in rats induced by MNNG regardless of intestinal metaplasia. The sigdcance of such reactive proliferation of endocrine cells around the tumor is
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yet not determined, but it is speculated that the reactive proliferation of EC cells is a t least involved in the development of intestinal metaplasia. A recent investigation27 has been reported on the change of endocrine cells especially G cells in gastrointestinal ulcers, that is, hyperplasia of G cells is often observed in cases showing hyperacidity. The authors in their e ~ p e r i m e n t ~in ,'~ which artificial acute ulcer was induced in the gastric body of the glandular stomach in mice observed the development of gastric endocrine cells. There was no increase in G cells, but ECL cells were found from the early period in the regenerative ~ r ~ been ~ presented on Zollinger-Ellison's syndrome epithelium. A few r e p ~ r t s have and pernicious anemia, but there are many unresolved problems requiring further study with regard to the role of GEP endocrine system in gastrointestinal diseases. In the authors' experimental studyso on the effects of GEP hormones on gastric cancer in rats induced by MNNG, a very interesting finding has been observed that scirrhous cancer develops in the group given gastrointestinal hormones such as gastrin for a given period. The effects of GEP endocrine cells in chronic gastritis and peptic ulcer on the ability to secrete gastric juice is an important problem to be resolved in the future together with the question of what types of cells or hormones among GEP endocrine cells participate in the histogenesis and differentiation of gastric tumor. References 1. SOLCIA,E., VASSALLO, G. and CAPELLA,C.: Cytology and cytochemistry of hormone producing cells of the upper gastrointestinal tract. I n ; (ed. by) W. Creutzfelt: Origin, chemistry, physiology and pathophysiology of the gastrointestinal hormones. p 3-29, Stuttgart and New York, F.K. Schattauer Verlag, 1970. 2. CARVALHEIRA, A.F., WELSCH,U. and PEARSE, A.G.E.: Cytochemical and ultrastructural observation on the argentaffin and aryrophil cells of the gastro-intestinal tract in mammals, and their place in the APUD series of polypeptide-secretory cells. Histochemie 14: 33-46, 1968. 3. FUJITA, T. and KOBAYASHI, S.: The cell and hormones of the GEP endocrine system - The current of studies. In; (ed. by) T. Fujita: Gastro-entero-pancreatic endocrine system. A cell-biological approach. p 1-16. Igaku Shoin Ltd. Tokyo, 1973. 4. TAHARA,E: Fine structure of several types of endocrine cells in mouse gastric mucosa with special reference to the histologenesis. Hiroshima J.M. Sci. 20: 255-268, 1971. 5. TAW, E. and YAWA, A.: Experimental study on the histogenesis and differentiation of gastric cancer- ultrastructural observation on the gastric adenocarcinoma in rat induced by N-methyl-N'-nitro-N-nitorsouganidine. Tr.SOC. Path. Jap. LXI. 122, 1972 (in Japanwe). 6. TAEARA, E. and HIROSE, F.: Induction of gastric adenocarcinoma in mice by Xirradiation. 111) Elctron microscopic observetion on the development of gastric carcinoma in ICR strain. Proceedings of the Japanese Cancer Association. The 30nd Annual Meeting. 35, 1971 (in Japaneae). 7. KUBO, T. and WATANABE, H.: Neoplastic argentaffin cells in gastric and intestinal carcinoma. Cancer 27: 447-454, 1971. 8. SOQA,J.: Carcinoids: their changing concepts and a new histological classification.
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432, 1907. I.H., Corcorna, A.C., Udenfreind, S., Szoedsma, A. and Weiasbach. H.: Argent14. PAQE, affinoma as endocrine tumor. Lancet 1: 198-199, 1966. A.H., PLATT, D.S. and SNOW,P.J.D.: A 6-hydroxy16. CUPBELL, A.C.P., GOWENCLO~K, tryptophan-secreting carcinoid tumor. Gut. 4 : 61-67, 1963. W.A. and DOUTER, R.B.: Evidence for the release of brady16. OATES,J.A., PETTINQER, kinii in carcinoid syndrome. J. Clin. Invest. 45: 173-178, 1966. E.D. and SANDLER, M.: The classification of carcinoid tumors. Lancet 1: 17. WILLIAMS, 238-239, 1963. K., UAHARA, H. and HIRAIDE, K.: Some characteristic features 18. SOQA,J., TAZAWA,
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1099, 1968. 0.: Endocrine cell of the stomach and pancreae 27. S o w , E., CAPELLA,C. and VASSALLO, in statea of gastric hypersecretion. Rendic. R. Gastroenterol. 2: 147-168, 1970. J.M., STAQQ,B. and F'EARSE,A.G.E.: The G cells in pernicious anemia. Gut. 28. POLAK, 12: 319-323, 1971. J.M., COULLINQ, L., DOE, W. and PEARSE, A.G.E.: T w o typea of Zollinger29. POLAK,
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