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Annals of Clinical & Laboratory Science 37:15-21 (2007)
© 2007 Association of Clinical Scientists

Diagnosis and Treatment of Gastrointestinal Stromal Tumors of the Stomach: Report of 28 Cases.

Yafu Wu, Xinhua Zhu and Yitao Ding
Department of General Surgery, Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, China

Address correspondence to Yafu Wu, M.D., Department of General Surgery, Affiliated Drum Tower Hospital, Zhongshang Road 321, Nanjing 210008, China; tel 86 25 8330 4616; fax 86 25 8331 7016; e-mail drzhuxh{at}hotmail.com.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
We retrospectively analyzed 28 patients with gastric gastrointestinal stromal tumors (GISTs) at our hospital to investigate their clinical features, diagnosis, and treatment. All patients underwent surgical resection. There were 18 cases with subtotal gastrectomy, 8 cases with partial gastrectomy, 1 case with total gastrectomy, and 1 case with subtotal gastrectomy combined with right hemihepatectomy. Based on pathological findings, the tumors were benign in 16 cases (57%), borderline in 2 cases (7%), and malignant in 10 cases (36%). The tumor diameter was significantly correlated with the malignancy of gastric GISTs (3.5 ± 1.6 cm in benign tumors, vs 7.5 ± 1.3 cm in malignant tumors, p <0.05). Immunohistochemical staining for CD117 and CD34 was positive in 26 (93%) and 17 (61%), respectively. The mean follow-up period ranged from 6 to 60 mo in 23 of the patients, and the other 5 patients (all with benign tumors) were lost to follow-up. No recurrence or metastasis was found in patients with benign gastric GISTs. Four cases of malignant GISTs (17%, 4/23) had liver metastasis or intra-abdominal dissemination, and 2 of them received a second resection for liver metastasis. Four cases of malignant gastric GISTs died with tumors more than 10 cm in maximum diameter, 3 of them died of liver metastasis and multiple organ failure, and 1 died of myocardial infarction. Excluding 2 patients with benign tumors that were followed for <3 yr, the 3-yr survival rate was 81% (17/21) in this group, and 60% (6/10) in the patients with malignant gastric GISTs. In conclusion, the prognosis is related to the tumor size and the number of mitoses seen on histological examination. Positive detection of CD117, combined with other markers and pathological features, is of great importance in the differential diagnosis of gastric GISTs. Complete resection with negative margins remains the fundamental objective in the surgical management of gastric GISTs.

Keywords: gastrointestinal stromal tumors, CD117 marker, c-KIT proto-oncogene, gastric malignancies


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Gastrointestinal stromal tumors (GISTs) of the stomach represent a heterogeneous group of mesenchymal neoplasms of the gastric wall. While they include truly malignant as well as benign forms, they embody a spectrum of malignant potential predicted primarily by size and mitotic activity. Diagnosis is complex and always requires immunohistochemical staining, since it is based on positivity for specific immunophenotypic markers. Despite recent advance in chemotherapeutic regimens, such as introduction of targeted therapy with inhibitors of tyrosine kinase receptors, surgical resection is still considered the most effective treatment for GISTs [1]. We reviewed our experience with gastric GISTs during the 6 yr from 2000 to 2005 to assess the feasibility and outcome of surgical resection.


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
The subjects were 14 men and 14 women with a mean age at diagnosis of 63.5 yr (range: 35–84) who underwent surgical resection for different types of gastric GISTs (Table 1Go). All patients were symptomatic on presentation; the most common symptom was abdominal pain and distension, which occurred in 11 patients (39%). Other clinical manifestations included: alimentary tract hemorrhage in 9 patients (32%), abdominal mass in 6 patients (21%), significant weight loss in 3 patients (11%), intestinal obstruction in 1 patient (3.6%), and hepatic metastasis in 1 patient (3.6%). Anemia was common in gastric GISTs, and we found severe anemia (blood Hb ≤60 g/L) in 3 patients, intermediate anemia (blood Hb 60 to 90 g/L) in 8 patients, and slight anemia (Hb 90 to 110 g/L) in 2 patients. Nine patients manifested more than a single complaint or physical finding. The mean duration of symptoms before presentation was 7 mo, ranging from 3 days to 5 yr.


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  		Table 1. Clinical characteristics of 28 patients with gastric stromal tumors (GISTs).
 
Gastro duodenal endoscopy was done in all patients. Endoscopic abnormalities were seen in 26 patients, including submucosal mass in 10 patients, mucosal ulcer and protrusion in 15 patients, and a polypoid tumor in 1 patient. Endoscopic pathological diagnosis of gastric GIST was reached in only 2 patients (7%), one patient was misdiagnosed as gastric cancer, and in other patients, the endoscopic diagnosis was chronic gastritis. Fifteen patients received endoscopic ultrasonography, which demonstrated parenchymal masses in the gastric wall with multiple cystic lesions and occasional calcification in 8 patients. Upper gastrointestinal radiography was done in 15 patients, revealing a smooth filling defect without mucosal abnormality in 6 patients. Computed tomography (CT) and ultrasonography of the abdomen were done in 20 patients, of whom 15 showed a well-marginated soft tissue mass consisting of externally solid and internally cystic components with dense calcification in the central region, displacing the gastric wall. One patient showed metastases to the right anterior and posterior lobes of the liver, with diameters of 3.0 cm and 1.8 cm, respectively.

Histopathological examination of surgical specimens was carried out using standard hematoxylin and eosin staining (H&E), as well as specific immunohistochemical techniques. The surgical pathology reports included the tumor size, cellular pattern, stromal background, stage, and number of mitosis per high-power field (HPF). Immunohistochemical staining was performed using a Dako En Vision System according to the manufacturer’s instructions, with primary antibodies including rabbit polyclonal anti-human CD117 (Dako, 1:400), CD34 (Dako, 1:50), SMA (alpha-smooth muscle actin) (Dako, 1:50), and S-100 protein (Dako, 1:1,000). Diaminobenzidine was used as the chromogen. The slides were boiled in citrate buffer for 10 min in a microwave oven for antigen retrieval of CD117 and CD34. The gastric GISTs were categorized on the basis of their histopathologic features and the immunohistochemical staining results for CD117, CD34, SMA, and S-100. The diagnostic criteria are summarized in Table 2Go. Briefly, all the mesenchymal tumors with CD117 positivity were diagnosed as GISTs. The CD117-negative and CD34-positive cases, and those negative for all of the immunomarkers, which had the histopathologic features of GISTs were diagnosed as "consistent with GIST." The criteria used to classify the tumors as benign, borderline, or malignant are outlined in Table 3Go [2]. Data were presented as percentages of patients or mean ± SD. Numerical data were compared by an independent two-sample t test (p <0.05 was statistically significant).


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  		Table 2. Immunohistochemical findings used for the diagnosis of GISTs.
 

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  		Table 3. Criteria for classifying the gastric stromal tumors.
 

   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
All patients underwent surgical resection. The different operative procedures performed during this study are listed in Table 4Go. Resections included subtotal gastrectomy in 18 patients (64%), partial gastrectomy in 8 patients (29%), total gastrectomy in 1 patient (3.6%), and subtotal gastrectomy with right hemihepatectomy in 1 patient (3.6%). Only 1 patient received Imatinib therapy (400 mg/day) following subtotal gastrectomy combined with right hemihepatectomy; the other patients did not receive chemotherapy or radiotherapy. No serious operative complication was found in this group, and postoperative mortality was nil.


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  		Table 4. Surgical procedures in 28 patients with GISTs.
 
Anatomic locations and pathologic features of the tumors are listed in Table 5Go. The most common origin was the posterior wall of the gastric body (8 patients; 29%), followed by the anterior wall of gastric body (6 patients; 21%), posterior wall of the antrum (6 patients; 21%), posterior wall of the fundus (4 patients; 14%), anterior wall of the antrum (3 patients; 11%), and anterior wall of the cardia (1 patient; 3.6%). The tumors ranged varied in greatest diameter from 2.5 cm to 15 cm, with a mean of 6.7 cm. In the 16 benign tumors, the diameters averaged 3.5 ± 1.6 cm, and they showed expansive growth with distinct margin, encapsulated by a thin, fibrous membrane. On section, the solid area was whitishgrey and relatively firm. In the 2 borderline tumors, the diameters were 3.4 and 7.0 cm; they had distinct margins, and the solid area showed liquification, hemorrhage, or necrosis. In the 10 malignant tumors, the greatest dimension averaged 7.5 ± 1.3 cm, and the cut surface had delicate texture. The solid area looked like fish flesh, and was often combined with hemorrhage and necrosis on section. There was always local infiltration and/or metastasis of the malignant tumors. The difference of size between the benign and malignant tumors was significant (p <0.05).


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  		Table 5 Anatomic and pathologic characteristics of GISTs.
 
Microscopic examination showed ulceration on the surface of the tumor in 16 patients, and 2 tumors infiltrated or adhered to the surrounding tissue. No metastasis to surrounding lymph nodes was found. Benign cellular patterns such as hyaline changes and cystic changes were observed in 16 cases, which included 14 benign cases, 1 borderline case, and 1 malignant case. Necrosis was found in 9 cases, including 1 borderline case and 8 malignant cases (Fig 1AGo). Mucosal invasion was found in 4 malignant cases. Dystrophic calcification was found in 2 benign cases. The mitotic count was low (<5/50 HPF) in 61% (17/28) of the tumors, intermediate (5–10/50 HPF) in 18% (5/28), and high (>5/50 HPF) in the remaining cases (21% 6/28) (Table 5Go, Fig 1BGo).


Figure 1
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  		Fig 1 Photomicrograph of representative findings of gastric GISTs. Upper panel (1A): tumor cells surrounded by ischemic necrosis; lower panel (1B): two mitotic figures in this high-power field; (H&E stain).

 
Immunohistochemical findings were important in reaching a definite diagnosis, as summarized in Table 5Go and illustrated in Fig 2Go. CD117 expression was positive in 26 cases (93%) and its expression was generally diffuse in the cytoplasm and along the cytoplasmic membrane of tumor cells; in 2 cases, aperinu clear dot-like pattern was predominant rather than membranous staining. Focal cytoplasmic CD117 expression was observed in 4 cases. Immunohistochemical staining for CD34, SMA, and S-100 protein was positive in 17 (61%), 19 (68%), and 13 (46%) cases, respectively.


Figure 2
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  		Fig 2. Expression of CD117 and CD34 in gastric GISTs. Upper panel (2A): the intermediate positive expression of CD117 was diffuse in the cytoplasm and along the cytoplasmic membrane of tumor cells; middle panel (2B): locally positive expression of CD117; lower panel (2C): strongly positive expression of CD34. (Immunohistochemical staining with DAB chromogen; high-power magnification.)

 
The mean follow-up period ranged from 6 to 60 mo in 23 patients; the other patients (all with benign tumors) were lost to follow-up. No recurrence or metastasis was found in 11 benign and 2 borderline cases. Four of 10 malignant gastric GISTs (40%) developed liver metastasis or intra-abdominal dissemination during the period of the study, and 2 had recurrences in <12 mo. Two recurrent patients received a second resection for liver metastasis following imatinib mesylate therapy, 2 other recurrent patients received only imatinib mesylate therapy. Four malignant cases died with tumor diameters >10 cm, 2 of them died of liver metastasis and multiple organ failure after first operation and 1 died of myocardial infarction at 1 yr post-surgery. One of the patients with second resection died of liver metastasis and the other one survived without recurrence for >2 yr. Excluding 2 benign patients with follow-up period <3 yr, the 3-yr survival was 81% (17/21) in this group and 60% (6/10) in the group with malignant GISTs.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Gastrointestinal stromal tumors (GISTs) are rare neoplasms that may arise in virtually any part of the gastrointestinal tract, although a majority of these tumors (60–70%) are present in the stomach [3,4]. In our series of patients, about half of gastric GISTs were located in the gastric body, with one-quarter in the gastric cardia and antrum, respectively. The male to female ratio was equal. The patients with gastric GISTs ranged in age from 10 to 87 yr and the peak age was between 50 and 70 yr [5]. The mean age in our group is 63.5 yr. Malignant GISTs seem to occur more often at a younger age [5]. The symptoms associated with primary gastrointestinal stromal tumors are usually vague and nonspecific. The non-specificity of the symptoms is a contributing factor in delayed diagnosis associated with GISTs [6]. Despite the fact that most patients in our series were symptomatic and had some combination of bleeding, pain, and abdominal mass, the mean duration of symptoms before referral to the surgical service was 7 mo. About one-third of patients in this study experienced gastrointestinal bleeding and anemia. This finding is consistent with other reports in which gastrointestinal bleeding was one of the most frequent clinical manifestation [6,7]. Abdominal mass and significant weight loss may appear in malignant cases and their ratios in our group are 21% and 11%, respectively.

By analysis of the utility of the frequently ordered diagnostic studies that were performed before surgical exploration, the most frequently ordered diagnostic test in our series was upper-GI endoscopy. Endoscopy may identify submucosal lesions, with or without ulceration, from which only 50% are preoperatively diagnosed by histopathology [8]. Recent studies suggest that endoscopic ultrasonography can help to differentiate between gastric GISTs and other gastric lesions; the characteristics associated with malignancy include tumor diameter >4 cm, irregular extraluminal border, echogenic foci, and cystic spaces [9]. Ando et al [10] reported that biopsy under endoscopic ultrasonograpy and selective arteriography may help in diagnosis [10], and our department is evaluating fine needle aspiration of the tumors with endoscopic ultrasonograpy. It is our impression that these studies add little to deciding about the extent and type of the operation. This is due to the fact that most of the lesions were extraluminal with an intact mucosa. Computed tomography (CT) scans are critical to determine the anatomic extent of a gastric stromal tumor lesion during evaluation before operation, and CT was most useful in determining the tumor size and its relation to the contiguous organs, as well as confirming the presence or absence of distant metastases. No other imaging test that was evaluated in this study (including upper gastrointestinal contrast study and abdominal ultrasound scanning) was more sensitive than CT for the detection and staging of a gastric GIST.

It has been recently proposed that GISTs develop from the interstitial cells of Cajal [11], since the same immunohistochemical markers identify GISTs. Presence of c-KIT proto-oncogene (CD117) represents a histological feature of these tumors [11]. Other studies also demonstrated the diagnostic role of CD117 expression, and CD117 expression has been proposed as the most sensitive and specific phenotypic marker of GISTs [12–14]. CD117 immunostains positively in GISTs with very rare exceptions, due to artifacts, sampling errors, or lack of c-KIT caused by clonal evolution or mutations [2,15]. The postive ratios of CD117 and CD34 in this study were 93% (26/28) and 61% (17/28), which are consistent with a previous report [16]. Two CD117-negative and CD34-positive cases with the histopathologic features of GISTs were diagnosed as "consistent with GISTs" (Table 2Go). GISTs characteristically stain positively for CD 117 and CD 34, but less commonly for SMA and S100, which are expressed typically by leiomyo-sarcomas and schwannomas, respectively [17].

There are difficulties in classifying benign or malignant GISTs using the standard criteria commonly used for other tumors, and most authors agree that tumor size and the number of mitoses per HPF are the most important factors related to prognosis [2,12,18]. These findings allowed Fletcher et al [2] to propose a "risk of aggressive behavior" classification of GIST based only on tumor size and HPF mitotic count. The criteria we used in classifying the tumors as benign, borderline, or malignant are based on these results. Our study confirms that the size of the tumors and the mitotic count are highly related to the prognosis. Patients with gastric GISTs <5 cm in diameter have a significantly higher 3-yr survival rate than patients with bigger tumors (100% for <5 cm vs 60% for >5 cm, p <0.05). We also confirm that the number of mitosis per HPF is related to prognosis. Similar results have been reported by Brennan et al [19].

Surgical resection is still the gold standard treatment for GISTs, allowing a cumulative survival of almost 50% at 3-yr and 35% at 5 yr [11,19,20]. The surgical procedures in this group were performed in relation to the tumor size, location, and pathological diagnosis during operation. Like other soft tissue sarcomas, GISTs rarely metastasize tolymphnodes, and thus surgically mphadenectomy for gastric GISTs is seldom warranted [21]. If gastric GISTs have infiltrated the surrounding organs, combined multiple organ resection may be performed to avoid rupturing the tumor. Markku et al [5] proposed that outcome is strongly dependent on tumor size and mitotic activity, and metastasis is not an independent prognosis factor. Active resection may still be adopted for a resectable metastatic lesion. One case with liver metastasis in our group received subtotal gastrectomy combined with right hemihepatectomy, and the patient survived without recurrence during 3-yr follow-up. Our study also shows that complete resection with negative margins and avoiding rupture of the tumors remain fundamental surgical principles in the management of gastric GISTs.

There are differing opinions about the safe margin of the tumor during resection. Based on the pathological diagnosis and follow-up results of our group, we find a margin of 2–3 cm is enough for benign tumors, 3–5 cm for borderline tumors, and >5cm for malignant tumors. Recurrence and relapse of gastric GISTs usually occur within 3 yr after surgery, and the recurrence may be local relapse, hematogenous metastasis, or peritoneal dissemination [21]. Hematogenous metastasis to the liver is predominant, followed by peritoneal dissemination and local relapse. Two cases with liver metastases in our group received second resection, and one of them recovered well without recurrence at >2 years. This study suggests that active resection for metastasis might be effective in those malignant gastric GISTs with recurrence or metastasis if there is a surgical indication. It is reported that the 1-yr and 5-yr survival rates are 69% and 28–35% respectively. Even if the tumor is perfectly resected, the 5-yr survival rate is 48–65% at best [19]. The survival rate in our group was better than in previous reports, and the reason may be the higher incidence of benign tumors.

A combined European/Australian study [22] has been started to test the effectiveness of a new chemotherapy regimen based on imatinib mesylate (STI-571), a tyrosine kinase receptors inhibitor [23] that is highly selective for GISTs and suitable for targeted therapy, based on the c-KIT expression (CD117) of these tumors. Preliminary results of the first phase trials demonstrated up to 80% of partial response inpatients suffering from metastatic or recurrent GISTs treated by imatinib. Similar results have been obtained in a phase II and III study, started in the United States, on unresectable or metastatic GISTs [24]. Among 5 patients with malignant GISTs who received imatinib therapy in our group, no recurrence or metastasis was found in 1 case combined with right hemihepatectomy and in 2 cases with second resection for liver metastasis, while the tumor size of the other 2 patients with unresectable liver metastasis was reduced and they both died of multiple organ failure in 6–8 months. Adjuvant or palliative therapy by oral administration of imatinib is now considered mandatory for unresectable or metastatic diseases as suggested by a recent review by Bucher et al [20,25], while its role in potentially resectable GISTs or in neo-adjuvant regimens has yet to be demonstrated.

Our experience confirms that gastric GISTs are uncommon and often aggressive cancers. Complete resection with an attempt to remove all gross disease and achieve negative margins remain fundamental surgical principles in the management of gastric GISTs. As the incidence of lymph node involvement is low, extended lymph node dissections are not warranted. The prognosis is related to the tumor size and the number of mitoses per HPF. A larger patient series with longer follow-up is needed for better evaluation of prognostic factors affecting survival and recurrence of gastric GISTs. Imatinib therapy should be used for patients not suitable for surgery due to poor general condition or when complete resection is not technically possible. Its role in adjuvant settings after complete resection is controversial.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Pierie JP, Choudry U, Muzikansky A, Yeap BY, Souba WW, Ott MJ. The effect of surgery and grade on outcome of gastrointestinal stromal tumors. Arch Surg 2001;136:383–389.[Abstract/Free Full Text]
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