CASE REPORT

Gastrointestinal Stromal Tumorof the StomachTaro Ishii, Yasushi Kuyama, Masayuki Obara, Masami Yamanaka and Tetsuo Imamura*

We report a case of gastrointestinal stromal tumor (GIST) of the stomach. The patient was a79-year-old womanwith two gastric submucosal tumors detected by ultrasonography. Proximalgastrectomy was carried out and the tumors were diagnosed as GIST by histological andimmunohistochemical investigations. Mesenchymal tumors of the gastrointestinal tract have beentraditionally regarded as largely leiomyomatous lesions. However, GIST and other tumors havebeen distinguished recently on the basis of tumor cell differentiation shown by immunohistochemi-cal studies. Wediscuss the concept and the immunohistochemical characteristics of GIST.(Internal Medicine 36: 392-397, 1997)

Key words: gastrointestinal stromal tumor (GIST), leiomyoma and leiomyosarcoma, histology,immunohistochemi stry

Introduction

Primary mesenchymal tumors of the gastrointestinal tracthave generally been considered to be smooth muscle tumors.However,recent immunohistochemical studies have shownthat gastrointestinal mesenchymal tumors are composed ofcells displaying smooth muscle or nerve sheath characteristics,or of cells with an unclear lineage. The last type is referred to asa gastrointestinal stromal tumor (GIST). Here we report a caseof GIST with intermediate malignancy arising in the stomach.

Case ReportIn October 1 994, a 79-year-old womanunderwent abdomi-nal ultrasonography at a local clinic where she had been undertreatment for hypertension and rheumatoid arthritis. That ex-amination revealed two masses (4 cm and 5 cm in diameter)adjoining the stomach and the pancreas; the patient was referredto our hospital and admitted in May 1995.On admission, her height was 156.5 cm and her weight was47 kg. The conjunctiva was slightly pale but not icteric. Therewas neither a palpable mass nor any tenderness in the abdomen.No superficial lymph nodes were palpable.The abnormal laboratory data were as follows: red blood cellcount, 339 x 104/mm3; hemoglobin, 7.9 g/dl; hematocrit, 26.6%;white blood cell count, 9, 100/mm3; erythrocyte sedimentationrate, 95 mm/h; C-reactive protein, 5.4 mg/dl; serum iron, 21 jag/dl; rheumatoid factor, 353.8 U/ml; rheumatoid arthritishemagglutination, x320; antinuclear antibody, xl60. Tumor

markers were within normal limits (Table 1). An uppergastrointestinal barium series showed two smooth hemispheri-cal tumors in the upper and middle parts of the body of thestomach (Fig. 1); the lesions were suspected to be gastricsubmucosal tumors. Gastroscopy revealed two elevated lesionswith a smooth surface on the lesser curvature of the upper andmiddle body of the stomach. The lesions were indistinct withthe patient in the left lateral position, but appeared clearly in thesupine position (Fig. 2).

Abdominal computed tomography showed two tumors incontact with the stomach and the pancreas. One was about 5 cmin diameter (Fig. 3a), and the other (adjacent to the middle bodyof the stomach) was about 4 cm in diameter and contained alow density area suggesting cystic change (Fig. 3b).Selective celiac trunk arteriography demonstrated a slightlyenlarged left gastric artery (Fig. 4a), and two hypervascularlesions with central avascularity were fed by this artery (Fig.4b). These findings suggested that the tumors were gastricleiomyosarcomas with extraluminal expansion. Laparotomywas performed on June 22, 1995. At laparotomy, the two

tumors were found on the lesser curvature of the middle andupper body of the stomach, and proximal gastrectomy wasdone.

Examination of the resected stomach showed two tumors(4.2 cm in greatest diameter; 5.2 cm from the oral side) locatedon the lesser curvature and growing extramurally (Fig. 5a). Thecut surface of each tumor was grayish-white and solid with anarea of hemorrhagic change in the distal tumor (Fig. 5b).

Histologically, both tumors revealed the same features, being

From the First Department of Medicine and *the Surgical Pathology, Teikyo University School of Medicine, TokyoReceived for publication July 26, 1996; Accepted for publication March 17, 1997Reprint requests should be addressed to Dr. Taro Ishii, the First Department of Medicine, Teikyo University School of Medicine, 2-1 1-1 Kaga Itabashi-ku

Tokyo173

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Table 1. Laboratory DataR e d b l o o d c e l l s 3 3 9 x l O 7 m m 3 T o t a l p r o t e i n 7 . 7 g / d lH e m o g l o b i n 7 . 9 g / d l A l b u m i n 3 . 8 g / d lH e m a t o c r i t 2 6 . 6 % T o t a l b i l i r u b i n 0 . 2 m g / d lP l a t e l e t s 2 9 . 7 x 1 0 4 / m m J A s p a r t a t e a m i n o t r a n s f e r a s e 1 0 I UW h i t e b l o o d c e l l s 9 , 1 0 0 / m m 3 A l a n i n e a m i n o t r a n s f e r a s e 5 I UE r y t h r o c y t e s ed i me n t a t i o n r a t e 9 5 r a r a / h L a c t a t e d e h y d r o g e n a s e 2 5 9 I UC - r e a c t i v e p r o t e i n 5 . 4 m g / d l A l k a l i n e p h o s p h a t a s e 1 0 4 I UC a r c i n o e m b r y o n i c a n t i g e n 0 . 9 n g / m l T o t a l c h o l e s t e r o l 1 4 4 m g / d lC A 1 9 - 9 5 . 9 U / m l T r i g l y c e r i d e 7 9 m g / d lD U P A N - 2 < 2 5 . 0 U / m l B l o o d u r e a n i t r o g e n 2 0 . 0 m g / d lR h e u m a t o i d f a c t o r 3 5 3 . 8 U / m l C r e a t i n i n e 0 . 9 m g / d lR h e u m a t o i d a r t h r i t i s h e m a g g l u t i n a t i o n x 3 2 0 U r i c a c i d 4 . 6 m g / d lA n t i n u c l e a r a n t i b o d y x 1 6 0 S o d i u m 1 4 5 m E q / /S e r u m i r o n 2 1 L i g / d l P o t a s s i u m 4 . 0 m E q / /T o t a l i r o n b i n d i n g c a p a c i t y 2 8 5 u g / d l C h l o r i d e 1 0 8 m E q / /F e r r i t i n 2 6 . 1 n g / m l

Figure 1. Double contrast barium meal studyshowing two hemispherical tumors in the upper bodyand middle body of the stomach.

Figure 2. Endoscopic picture showing two elevated le-sions with a smoothsurface and no ulceration.

characterized by fascicular and interlacing proliferation ofspindle cells (Fig. 6a). The spindle-shaped tumor cells had

rather large and hyperchromatic nuclei, with vacuolated cyto-plasm in some tumor cells (Fig. 6b). A few mitoses were seen(approximately 3/10 high power fields) in the tumor cells, andthe nuclear atypia suggested malignancy. On immunohisto-chemical examination, scattered tumor cells were positive forvimentin and a few tumor cells were positive for smooth-muscle actin (Fig. 7), but the lesions were negative for all othermuscle markers and neurogenic markers (Table 2). From theabove histological and immunohistochemical features, thesetwo tumors were diagnosed as gastrointestinal stromal tumor of

intermediate malignancy.

Discussion

GIST are gastrointestinal mesenchymal tumors for whichthere is an incomplete understanding of their cell lineage and forwhich the relationship with differentiated smooth muscle andSchwann cell tumors remains uncertain (1). Gastrointestinal

mesenchymal tumors constitute the largest category of primarynon-epithelial neoplasms of the stomach and small bowel. Mostgastrointestinal mesenchymaltumors with a spindle cell orepithelioid appearance have been traditionally viewed as smoothmuscle tumors, being classed as leiomyomas or leiomyosarco-mas whencomposedof spindle cells and as leiomyoblastomas

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Figure 3. Abdominal CT scans showing a tumor about 5 cm in diameter (a), and a tumor about 4 cm in diameter with a lowdensity area inside (b).

Figure 4. Celiac angiography shows a slightly enlarged left gastric artery (a) and twohypervascular lesions (b).

when composed ofepithelioid cells (2-6). In 1983, Mazur andClark pointed out that Schwanncell features rather than smoothmuscle cell features were present in some gastric mesenchymaltumors based on S- 100 protein positivity (2). Recent immuno-histochemical studies have suggested that gastrointestinal mes-enchymaltumors are not all of smoothmuscle origin and forma heterogenous group of several entities with distinctive clin-icopathological features. Miettinen et al (1) divided these

tumors into three major categories. 1) Tumors showing differ-entiation toward smoothmuscle cells, as evidenced immuno-histochemically by the expression of smooth-muscle actin anddesmin. 2) Tumors showing apparent differentiation towardneural elements, as indicated by the expression of S-100 pro-tein. 3) Tumors showing no differentiation toward either cell

type (smooth muscle or neural) even after exhaustive immuno-histochemical probing. A few studies have shown mesenchy-mal gut tumors with bidirectional differentiation, which reactwith both smooth muscle and neural markers (4, 7). Thisprovides a fourth category to add to the above three categories:4) Tumors showing dual differentiation toward smooth muscleand neural elements. Tumors in the third category, the lessdifferentiated tumors, are referred to as GIST. In the presentpatient, there were two spindle cell tumors of the type that wasdiagnosed as leiomyosarcoma before the description of GIST.They were immunohistochemically studied for the presence ofsmooth-muscle actin (S-M-actin), HHF35, desmin, myoglobin,vimentin, CD34, S-100, NSE, NFP, EMA, and KL-1. Therewas scattered vimentin positivity and S-M-actin was positive in

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Figure 5. a) On the serosal surface of the resected stomach, two tumor nodulesare seen growing extramurally on the lesser curvature, b) The cut surface of eachtumor is whitish and solid with hemorrhagic change in the distal lesion (left side ofthe figure).

a few tumor cells, but all the other muscle and neurogenicmarkers were negative. Thus, the histogenesis of the tumorsremained unknownand GIST of the stomach was the diagnosis.However, GIST is yet to be defined clearly as far as itshistogenesis as a tumor is concerned. For GISTcannot neces-sarily be ruled out even if the tumor shows negative immuno-histochemical evidence for a myogenic or neurogenic marker,and vice versa. The difficulty in the diagnosis of GIST isassociated with the fact that all attempts to identify GIST arefaced with various problems related to specimen fixation,antibody, technical failure, and judgment based on stainingresults. In the case of gastric leiomyoma, for example, Miettinenet al (1) reported a low positive rate of 20.9% for S-M-actinwhich was in direct contrast of that reported by Matsuda et al (8)who obtained a positive rate of 100%.

Several studies have shown that histologic indicators ofmalignancy, such as the mitotic rate, cellularity, tumor necrosis,

and tumor size, are significant prognostic indicators (5, 9-13). Appelman and Helwig found in their study of gastricepithelioid tumors that all of the lesions with more than 10mitoses per 50 high power fields (HPF) showed metastasis (9),and Appelmanalso noted that a high mitotic rate maybeanything over 5 mitoses per 50 HPF, if fastidious requirementsfor the definition of a mitotic figure are adhered to (10). Shiu etal (1 1) studied gastric leiomyosarcoma and reported that themitotic count was the most objective and reproducible featurefor determining whether a tumor was of low-grade or high-grade malignancy. They classified tumors with 1-9 mitoticfigures per 10HPFas low-grade and those with >10per 10HPFas high-grade. Ueyamaet al reported that the all patients withtumors having less than 5 mitotic figures per 50 HPF were aliveand well, and that gastrointestinal mesenchymal tumors shouldbe classified as malignant when the mitotic rate was >5 per 50HPF (5). Miettinen et al (1) assigned GIST to categories of

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Figure 6. a) Fasicular and interlacing proliferation of spindle shaped tumor cells (HE stain, originalmagnification x33). b) Tumor cells showing rather large and hyperchromatic nuclei with vacuolation of thecytoplasm. Note a mitotic figure (arrow) (HE stain, xlOO).

histological malignancy on the basis of the mitotic count asfollows; benign is <2 mitoses per 10 HPF, borderline is 2-5mitoses per 10 HPF, and malignant is >5 mitoses per 10 HPF.The present patient had tumors with approximately 3 mitosesper 10 HPF, and the lesions were graded as intermediate

malignancy.

Tumorsize is also regarded as an importantprognostic factor(5, 9-15). Appelman and Helwig reported that only 20% ofgastric leiomyosarcomas <6 cm in diameter showed metastasis,whereas 85% of those >6 cm in diameter had metastasis (16).Somestudies have shown that small tumors (<5 cm in diameter)confined to the stomach have avery favorable outcome (1 1 , 14).Yuasa et al stated that tumors with mucosal ulcerationtended to have a worse prognosis than those without ulceration( 14). In contrast, Shiu et al reported that the presence or absenceof ulceration showed no relationship to the 5-year survival rate( 1 1). In the present patient, the tumors were smooth and showedno central ulceration, but the lesions were 4.2 cm and 5.2 cm ingreatest diameter and one showedhemorrhagic change. There-fore, she requires careful follow up, although proximal gastrec-tomy was done.In Japan, only one case suggestive of GIST of the stomachhas been reported as far as we could determine (17). The termGIST refers to an ill-defined group of mesenchymal neoplasmsthat arise in the walls of the gastrointestinal tract. The histogen-esis of these lesions is still surrounded by considerable contro-versy as to whether they should be considered as leiomyogenicor neurogenic.

Table 2. ImmunohistochemistryO ra l sid e tu m o r A n a l sid e tu m o r

S -M -a c tin (+) i n a fe w tu mo r ce ll s ( +) i n a fe w tum or c el lsH H F 3 5 (- ) (- )D e s m in (- ) (- )M y o g lo b in (- ) (- )V im e n tin (+ ) sc atte re d (+ ) s c a tte re dC D 3 4 (- ) (- )S - 1 0 0 (- ) (- )N S E (- ) (- )N F P H (- )E M A (- ) (- )K L - 1 (- ) (- )

S-M-actin: smooth-muscle actin, HHF35: muscle actin, NSE: neuronspecific enolase, NFP: neurofilament protein, EMA:epithelial mem-brane antigen, KL-1 : keratin.

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Figure 7. Immunohistochemical staining for smooth-muscle actin. ABCmethod, a) Negative in almost alltumor cells, although positive in the vessel wall (center offigure) (x40). b) Positive in the cytoplasm ofa few tumorcells (arrows) (x80).

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