Upsala J Med Sci 87: 135-142, 1982 A Clincal Study of 30 Gastric Carcinoids Henry Johansson and Erik Wilander D e p a r t m e n t s of Surgery a n d P a t h o l o g y , University Hospital, U p p s a l a , Sbt'eden ABSTRACT The c l i n i c a l p i c t u r e i n 30 p a t i e n t s operated on f o r g a s t r i c c a r c i n o i d s was s t u d i e d r e t r o s p e c t i v e l y . There were 1 2 men and 18 women, w i t h an age range of 32-79 y e a r s (mean 57 y e a r s ) . The tumours were l o c a t e d i n the corpus a r e a of t h e stomach i n more than h a l f of t h e p a t i e n t s and i n o n e - t h i r d were r e l a t i v e l y small ( < - 1 cm). Four p a t i e n t s had m u l t i p l e tumours. Metastases were found i n e i g h t p a t i e n t s , mostly t h o s e w i t h l a r g e r primary tumours. In no case was the c a r c i n o i d syndrome present. of the stomach, such a s polyps, u l c e r and carcinoma. Barium c o n t r a s t s t u d y and gastroscopy d i d n o t r e v e a l t h e t r u e n a t u r e of the g a s t r i c d i s e a s e and even biopsy of t h e stomach f a i l e d t o g i v e a c o r r e c t p r e o p e r a t i v e d i a g n o s i s i n f o u r of f i v e p a t i e n t s . Since six p a t i e n t s had a c h y l i a p r e o p e r a t i v e l y , i t i s empha- s i z e d t h a t the p o s s i b i l i t y of a g a s t r i c c a r c i n o i d , e s p e c i a l l y i n the corpus a r e a , i s more l i k e l y i n a s s o c i a t i o n with this c o n d i t i o n . The p a t i e n t s presented symptoms s i m u l a t i n g t h o s e of more common a f f e c t i o n s INTRODUCTION A g a s t r i c c a r c i n o i d i s a r a r e type of malignant b u t slowly growing e p i t h e l i a l tumour of the stomach. I t has been d e s c r i b e d i n s e v e r a l c a s e r e p o r t s ( 2 ) , b u t few comprehensive i n v e s t i g a t i o n s have been made on the c l i n i c a l p i c t u r e of p a t i e n t s w i t h this tumour (2,5). The p r e s e n t s t u d y was undertaken w i t h t h e aim of g a i n i n g f u r t h e r knowledge about t h e age and sex d i s t r i b u t i o n of t h e p a t i e n t s , t h e symptomalogy, and t h e s i z e , l o c a t i o n and frequency of m e t a s t a s e s i n an u n s e l e c t e d m a t e r i a l of g a s t r i c c a r c i n o i d s . MATERIAL A N D METHODS All a v a i l a b l e g a s t r i c c a r c i n o i d s recorded i n the Cancer R e g i s t r y of t h e National Board of Health and Welfare i n Sweden between 1958 and 1974 and i n t h e l o c a l r e g i s t e r a t t h e Department of Pathology i n Uppsala between 1975 and 135 1980 were collected. The tumours were a l l obtained a t surgical resection and no autopsy material was included i n the investigation. The paraffin blocks were c u t i n t o about 4 um thick sections and stained w i t h haematoxylin-eosin a n d with the Grimelius argyrophil s t a i n ( 3 ) . The findings in routinely stained sections a t l i g h t microscopy and the frequency of argyrophil tumour c e l l s were decisive in the characterization of the tumours. Only tumours w i t h a morphology of fore-gut carcinoids ( 1 3 ) and with an argyrophil reaction i n the majority of the tumour c e l l s were accepted f o r the study. With these c r i t e r i a , the material comprised a t o t a l of 30 patients with carcinoids. The location of the tumours w i t h i n the stomach was established from the morphology of the g a s t r i c mucosa bordering the tumours , the surgical records a n d the g a s t r i c X-ray report. Tumours in the pyloric area were a l l closely adjacent t o Brunner's gland. These tumours were included i n the study provided t h a t a t l e a s t some p a r t of the tumour was growing in the area o f the antral mucosa. The s i z e of the tumours was given in the histopathological reports in a few cases, b u t otherwise was estimated by measuring the l a r g e s t diameter of the tumour in the paraffin block. In f o u r patients with y l t i p l e tumours the s i z e of the l a r g e s t tumour was noted. hospital in which the p a t i e n t was operated u p o n . Clinical information was obtained from the medical case records a t the RESULTS Sex and age d i s t r i b u t i o n O f the 30 p a t i e n t s , 12 were men and 18 were women. The age range of the p a t i e n t s was 32-79 years and the mean age 57 years (M:61; F:55). Tumour location The d i f f e r e n t locations of the tumours among men a n d women a r e given in Table I. I t i s seen t h a t most tumours were found in the corpus area o f the stomach a n d t h a t there was a female preponderance in a l l locations (except the c a r d i a ) . There were no noteworthy variations in age d i s t r i b u t i o n i n r e l a t i o n t o tumour location, except t h a t the three women with multiple carcinoids in the corpus were considerably younger (range 32-41 years, mean 37 y e a r s ) than the r e s t of the patients. 136 Table I . Locations of the g a s t r i c carcinoids i n 30 p a t i e n t s , d i s t r i b u t e d by sex. Area of stomach Men Women Total - cardi a 1 1 corpus 6 10 16') antrum 3 4 7 pylorus 2 4 6 Total 12 18 30 X ) One o f the men and three of the women with carcinoids located i n the corpus had multiple tumours. Tumor s i z e Ten of the 30 tumours were 1 cm i diameter o r smaller. The l a r g e s t tumours were found i n the a n t r a l area. F o u r patients (one male a n d three females) presented multiple tumours ( 2 , 3, 5 and more than 5, respectively). They were a l l located in the corpus of the stomach, and three of them were 1 cm or l e s s i n diameter. Metastatic spread Metastatic turnour g r o w t h was observed in eight of the 30 p a t i e n t s ; a l l h a d lymph node i n f i l t r a t i o n a n d three of the e i g h t a l s o had metastases of the l i v e r . There was a r e l a t i o n between the s i z e of the primary tumour and the frequency o f metastases (Table 1 1 ) , in t h a t tumour spread was more common in association with l a r g e r tumours. Table I 1 . The occurrence of lymph node a n d / o r l i v e r metastases in associa- tion with g a s t r i c carcinoids of d i f f e r e n t locations i n r e l a t i o n t o tumour s i z e . Area of stomach 0-1 cm 1-2 cm 2-3 cm 3-5 cm 5- cm Total 1/10 3/13 o/ 1 3/3 1/3 8/30 137 Symptomatology a r e g i v e n i n T a b l e 111. B e s i d e s g a s t r i c p a i n , t h e most pronounced c l i n i c a l s i g n s were haematemesis and melaena. These l a t t e r symptoms c o u l d be e x p l a i n e d b y t h e presence o f u l c e r a t i o n o f t h e mucosa c o v e r i n g t h e tumour, s i n c e u l c e r a - t i o n was observed i n 18 o f t h e 30 cases a t l i g h t m i c r o s c o p y . Two p a t i e n t s underwent X-ray e x a m i n a t i o n o f t h e stomach f o r i n v e s t i g a t i o n o f anaemia o f unknown cause, and had no s u b j e c t i v e g a s t r o i n t e s t i n a l symptoms. Seven p a t i e n t s had c o n c o m i t a n t a c h y l i a . T h i s was diagnosed p r e o p e r a t i v e l y i n s i x p a t i e n t s , and h a l f o f t h e s e had an a s s o c i a t e d p e r n i c i o u s anaemia. The g a s t r i c c a r c i n o i d s o c c u r r i n g i n an a c h y l i c stomach were a l m o s t e x l u s i v e l y l o c a t e d i n t h e corpus a r e a and tended t o be m u l t i p l e ( 1 0 ) . There was no c l i n i c a l s i g n s o f c a r c i n o i d syndrome o r o t h e r e n d o c r i n e a b n o r m a l i t y r e c o r d e d i n any o f t h e p a t i e n t s . The main symptoms w h i c h o c c u r r e d b e f o r e t h e o p e r a t i o n f o r g a s t r i c c a r c i n o i d T a b l e 111. M a i n symptoms l e a d i n g t o a d m i s s i o n t o h o s p i t a l and f u r t h e r i n v e s t i g a t i o n o f 30 p a t i e n t s w i t h g a s t r i c c a r c i n o i d s . Tumours l o c a t e d i n : Symptoms C a r d i a Corpus Antrum P y l o r u s T o t a l g a s t r i c p a i n melaena haematemesis anaemia vomi ti ng w e i g h t 1 oss ti redness d y s p e p s i a d i a r r h o e a d y s p h a g i a 1 6 8 8 5 4 2 1 1 1 1 5 12 1 11 9 1 9 2 8 3 7 2 6 3 4 1 3 2 P r e o p e r a t i v e i n v e s t i g a t i o n and d i a g n o s i s i n v e s t i g a t i o n s c o n s i s t e d m a i n l y o f X-ray e x a m i n a t i o n o f t h e stomach and g a s t r o s c o p y , sometimes w i t h a s i m u l t a n e o u s g a s t r i c b i o p s y . G a s t r i c X-ray was n o t p e r f o r m e d i n f i v e p a t i e n t s . I n t h r e e o f them t h e reason was an emergency e x p l o r a t i v e l a p a r o t o m y f o r a m a j o r haematemesis. I n one p a t i e n t g a s t r o s c o p y r e v e a l e d a tumour of t h e c a r d i a and i n one p a t i e n t t h e g a s t r i c c a r c i n o i d was an a c c i d e n t a l f i n d i n g d u r i n g o p e r a t i o n f o r c h r o n i c g a l l b l a d d e r d i s e a s e . Four p a t i e n t s had normal g a s t r i c r a d i o g r a p h s . They were o p e r a t e d on e i t h e r because o f p a t h o l o g i c a l f i n d i n g s a t g a s t r o s c o p y ( 3 p a t i e n t s ) o r because o f s e v e r e A c c o r d i n g t o i n f o r m a t i o n i n t h e c l i n i c a l case r e c o r d s , t h e p r e o p e r a t i v e haematemesis of u n k n o w n origin (one p a t i e n t ) . Gastric biopsies were performed in f i v e p a t i e n t s . The histopathological diagnoses of the g a s t r i c t i s s u e material were ulcera- tion (one c a s e ) , g a s t r i t i s (one c a s e ) , undifferentiated carcinoma ( 2 cases) and carcinoid (one c a s e ) . After re-examination of the cases diagnosed a s undiffer- i t became entiated carcinoma, including Grimelius staining of the tumour obvious t h a t the specimens originated from g a s t r i c carcinoids. A survey of the putative preoperative diagnoses arrived a t n a t i o n and/or gastroscopy, sometimes with g a s t r i c biopsy, i s g The most common preoperative diagnosis was g a s t r i c polyp(s) ( 9 rom X-ray exami- ven i n Table IV. p a t i e n t s ) . In one of these patients multiple g a s t r i c carcinoids were subsequently disclosed a n d in another p a t i e n t multiple adenomatous mucosal polyps were found i n addi- tion t o a g a s t r i c carcinoid. Table IV. Putative preoperative diagnosis leading t o surgery i n p a t i e n t s with g a s t r i c carcinoids. Preoperative No. of Comments diagnoses pa t i ents POlYP(S) ulcer carcinoma not known tumour, n o t specified 3 pyloric s t e n o s i s 1 neuri noma ( ? ) 1 g a l l stone 1 carci noid 1 2 cases with multiple polyps explorative laparotomy because of haematemesis the g a s t r i c tumour was an accidental finding a t opera- ti on Total 30 Type of operation tumours were extirpated by a B i l l r o t h I or I1 g a s t r i c resection, especially those located i n the more d i s t a l p a r t of the stomach. Many smaller tumours i n the corpus area were removed by local resection. A subtotal o r t o t a l gastrec- tomy was performed i n some p a t i e n t s w i t h large o r multiple tumours. The g a s t r i c carcinoids were removed by d i f f e r e n t surgical methods. Most 139 Survival and follow-up mortality of 7 per cent. three patients died from metastatic disease and one developed a local recur- rence. Two of the 30 p a t i e n t s died a f t e r surgery, corresponding t o a post-operative Twenty-two p a t i e n t s were observed f o r one year o r more. During t h i s period Of 15 patients followed f o r a period of f i v e years o r longer, 10 a r e s t i l l a l i v e and symptom-free. DISCUSSION By d e f i n i t i o n , carcinoids a r e endocrine tumours in which the tumour c e l l s contain endocrine secretory granules a t the electron microscopic l e v e l . Since the Grimelius s i l v e r s t a i n causes a reaction i n almost a l l g a s t r o i n t e s t i n a l endocrine c e l l s ( 4 ) , though without discriminating between them, t h i s staining procedure was used t o i d e n t i f y the tumours (11,lZ). Although the chemical back- ground of the argyrophil reaction i s unclear, i t i s k n o w n from u l t r a s t r u c t u r a l studies t h a t the s i l v e r s t a i n i s s p e c i f i c f o r endocrine secretory granules (4), a n d tumours which lack an argyrophil reaction in the majority of t h e i r c e l l s cannot be regarded unquestionably as endocrine; f o r t h i s reason a few tumours which were primarily c l a s s i f i e d as g a s t r i c carcinoids in the Swedish Cancer Registry were n o t accepted f o r the study. I t i s emphasized t h a t s t r i c t c r i t e r i a f o r the d e f i n i t i o n of endocrine tumours improves the p o s s i b i l i t y of identifying t h e i r c h a r a c t e r i s t i c s . Although based on a retrospective study, o u r findings demonstrate the d i f f i c u l t i e s i n the diagnosis of g a s t r i c carcinoids. Most p a t i e n t s presented symptoms such as pain, haematemesis a n d / o r melaena, anaemia, vomiting a n d loss of weight, which a r e common signs i n much more frequent pathological conditions of the stomach such as ulcer disease and carcinoma. Thus, the infrequent g a s t r i c carcinoids can hardly be suspected from the c l i n i c a l symptoms. the presence of g a s t r i c carcinoids, since with these methods the tumours resemble polyps, ulceration or g a s t r i c carcinoma. The most accurate diagnostic procedure appears t o be g a s t r i c biopsy, b u t even w i t h t h i s the diagnosis seems unreliable, since discrimination from undifferentiated carcinoma of the stomach, in p a r t i c u l a r , can be d i f f i c u l t . Additional staining of the biopsy material with the Grimelius argyrophil s t a i n i s apparently useful, b u t a p r e r e q u i s i t e for the use of this procedure i s , of course, t h a t a possible diagnosis of g a s t r i c carcinoid i s considered. possible, be treated primarily with surgery just l i k e carcinoids of the g a s t r o i n t e s t i n a l in general (1,7,8). In g a s t r i c carcinoids l e s s than 1 cm in B o t h X-ray of the stomach and gastroscopy seem i n s u f f i c i e n t f o r establishing When the diagnosis i s confirmed, carcinoids of the stomach should, i f 140 d i a m e t e r complete l o c a l e x c i s i o n may be adequate i f t h e r e a r e no s i g n s o f i n v a - s i o n o f t h e m u s c u l a r i s p r o p r i a o r lymph node i n v o l v e m e n t . Tumours l a r g e r t h a n 1 cm s h o u l d b e t r e a t e d b y g a s t r i c r e s e c t i o n o r g a s t r e c t o m y . I f lymph node metas- t a s e s a r e found, t h e g a s t r i c s u r g e r y s h o u l d be combined w i t h e x c i s i o n o f a l l a c c e s s i b l e nodes and such tumour cases s h o u l d t h u s be t r e a t e d as f r a n k carcinumas. It has been c l a i m e d t h a t g a s t r i c c a r c i n o i d s a r e m o s t l y l o c a t e d i n t h e a n t r a l a r e a ( 6 ) . The f i n d i n g s i n t h e p r e s e n t s t u d y a r e n o t i n agreement w i t h t h i s o b s e r v a t i o n , as more t h a n h a l f of t h e tumours were f o u n d i n t h e corpus of t h e stomach. The c a r c i n o i d syndrome i s seldom seen i n a s s o c i a t i o n w i t h c a r c i n o i d tumours o f t h e stomach (14). I n o u r s e r i e s none o f t h e p a t i e n t s p r e s e n t e d symptoms i n d i - c a t i n g such a syndrome. When i t does appear, t h e g a s t r i c c a r c i n o i d syndrome d i f f e r s f r o m t h e c l a s s i c a l type. P a t i e n t s w i t h t h e g a s t r i c c a r c i n o i d syndrome have a t y p i c a l f l u s h , and d i a r r h o e a i s u s u a l l y n o t a p r o m i n e n t symptom. A l t h o u g h r e l a t i v e l y s l o w l y growing, c a r c i n o i d s a r e m a l i g n a n t tumours w i t h an a b i l i t y t o m e t a s t a s i z e . I n t h e p r e s e n t s e r i e s m e t a s t a s e s were p r e s e n t a t t h e t i m e o f o p e r a t i o n i n 26% o f t h e cases. A r e l a t i o n was f o u n d between tumour s p r e a d and s i z e o f tumour, i n t h a t metastases were more f r e q u e n t i n t h e l a r g e r tumours. The s u r v i v a l r a t e s were a l s o i n f l u e n c e d b y t h e tumour s i z e and s p r e a d o f t h e d i s e a s e . The 5-year s u r v i v a l r a t e , as f a r c o u l d b e e s t i m a t e d , was 67 p e r c e n t . Recent i n v e s t i g a t i o n s have shown t h a t g a s t r i c c a r c i n o i d s o c c u r r e l a t i v e l y f r e q u e n t l y i n a s s o c i a t i o n w i t h a c h y l i a , e s p e c i a l l y t h o s e w h i c h a r e l o c a t e d i n t h e c o r p u s a r e a o f t h e stomach and t e n d t o be m u l t i p l e ( 9 , l O ) . It has a l s o been suggested t h a t g a s t r i c c a r c i n o i d s w h i c h d e v e l o p i n an a c h y l i c stomach may have a p a t h o g e n e s i s s i m i l a r t o t h a t proposed f o r carcinoma o f t h e stomach i n a s s o c i a t i o n w i t h a c h y l i a and p e r n i c i o u s anaemi ( 1 0 ) . 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