121 Clinical Analysis of Diagnosis and Treatment of Gastrointestinal Stromal Tumors (Report of 96 Cases) Yueliang Lou Xieliang Zhang Hua Chen Zhongli Zhan Cancer Hospital of Tianjin Medical University, Tianjin 300060, China. OBJECTIVE To investigate the pathological diagnos~s, surgical treatment and prognosis of gastrointestinal stromal tumors (GIST). METHODS The clinicopathological data of 96 post-operative cases w~th GIST were analyzed retrospectively, and expression of immunohistochemical staining of CDl17, CD34, SMA and S-100 was determined. RESULTS Immunohistochemical positive staining showed: CDl17, 79.1% (76/96); CD34, 58.3% (56/96); SMA, 35.4% (34/96); S-100, 9.3% (9/96). Twenty-three benign cases and 73 malignant cases were reported. The omentums were resected in 39 malignant cases. For the other 34 malignant cases the omentums were left intact. The recurrent and metastatic rates were 5.1% and 26.5%(P<0.05). The incisal section between the normal bowel and the tumor was >5cm in 46 cases, for the other 27 cases, the section was < 5cm. The recurrent and metastatic rates were 6.5% and 29.6% (P <0.05), respectively. The 5-year survival rates of benign and malignant GIST were 91.5% and 57.3%(P<0.05). CONCLUSION GIST were the most freuquent mesenchymal tumor seen in the gastrointestinal tract. The application of immunohistochemical markers CD117and CD34 are mutually beneficial for a final correct pathological diagnosis. The adaptation of a primary rational treatment, including the complete tumor resection and preventive omentectomy could reduce the recurrence of GIST. KEYWORDS- gastrointestinal, stromal tumors, recurrence, CDl17, CD34. Received January 18, 2004; accepted March 30, 2004. G astrointestinal stromal tumors (.GIST) are the most common primary heterogenous neoplasm of the gastrointestinal tract. Recently. following the application and development of histochemistry, immunohistochemistry and molecular biologic techniques, it was shown that most of the gastrointestinal leioneoplasms did not all originate from smooth muscle, but some came from nonoriented differentiated stromal stem ceils. In addition to the morphologic differences among the GIST that are extremely similar to those of leiomyoma and neurolemmoma, the difficulty in judging their biological behaviors makes the diagnosis and treatment of GIST very formidable. Up to now, only a few reports concerning the clinical diagnosis and treatment of this tumor have been published. In this article, the Chinese Journal of Clinical Oncolgy E-mail: COCR@eyou.com Tel(Fax): 86-22-2352-2919
Gastrointestinal stromal tumors/yueliang Lou et al 122 tunlor. MATERIALS AND METHODS During the period between Octoter 1985 to October 2001,96 patients among a total of 164 cases diagnosed a~ GIST, leiomyoma, leiomyosarcoma and neurolemmoma of the gastrointestinal tract were rediagnosed as GIST by way of histopathologic and immunohistochemical studies. These 96 cases (23 cases benign and 76 cases malignant) account for 0.8% of all the gastrointestinal malignancies treated in the hospital in the same period. Of the 96 cases, 46 cases were male and 50 cases were female. The patients" ages ranged from 12 to 76 years with the medium age being 52.8. Immunohistochemical staining,411 the surgical specimens were fixed in 4% formaldehyde, paraffin-imbedded, routinely sectioned and stained with hematoxylin and eosin. These H&E strained slides from all the patients were examined to establish the GIST diagnosis. Immunohistochemical staining was performed on these slides using the avidin-biotin peroxidase complex(abc) method. The agents were purchased from MaiXin Company. Every specimen was stained with CPll7, CD34, SMA and S-100 Ab (CDll7 from Enuision, others from S-P). The intensity limit of S-P staining was ignored, the appearance of brown color granule of tumor cells.~howed positive. Classification of GIST According to clinical pathology and the Emory standard (1999) u], GIST are classified as benign, borderline and malignant. Malignant criteria are as follows: (1)infiltrative(or tumor infihration involved ) (2)distant and regional vessel metastasis: the diameter of gastric GIST> 5.5 cm, of intestinal GIST> 4.0 cm; the Karyokinesis> 5/50 HPE: focus of tumor necrosis; typical heteromorphic tumor cell: active growth of tumor cells. When the tumor involves one or two malignant criteria, it is malignant GIST; if the tumor involves only one potential malignant index, it is regarded as borderline; without any index above, it is regarded as benign. Treatment Among these 96 cases, 2 cases from other hospitals, showed postoperative recurrence after 2 years; of the 73 nmlignant cases, in 40 cases the distance between the section plane of the bowel and the tumor was >5 cm, and in 27 cases the distance from the section to the tumor was <5 cm; in 39 cases omentectomy was performed at the primary operation, while in the other 34 cases, the omentum was left intact. Nine cases were operated on repeatedly, 2 patients were offered 3 and 4 operative treatments. Two cases had hepatic right lobe resection; in one case partial resection of the inferior vena cava was performed; in 3 cases partial bladder resection was conducted; the omentum was removed in 0 cases; in 23 cases lymphadenectomy was performed at the first operation, of these 2 cases (8.7%) had lymphometastasis. RESULTS Location, size and characteristics of the lesions In 96 GIST cases, the maximal diameter of the tumor was 24 cm, the minimal diameter was 3 cm, (median 8.2 cm). Among them, 46 cases were located in the stomach (47.9%), 32 cases in the small intestine (33.3%) and 18 cases in the colon and rectum(18.7%). The median tumor diameter of gastric GIST, small intestinal GIST and colon-rectum GIST was 6.4 cm, 10.8 cm and 8.8 cm, respectively. The location and size of the GIST are shown in Tablel. Table 1. The location and size of 96 cases of GIST Tumor Case'~ Gastric Small Colonic T character intestinal diameter Benign 23 13 5 5 54.3+1.2 <0.05 Mahgnanl 73 33 27 13 138.2+1.5 -- I'olal 96 46 32 18 -- -- Results of pathology According to the karyokinesis phase (>5/50 HPE), combined with the nuclear heteromorphic and capsule infiltration, histology revealed typical GIST (benign 23, malignant 73). The capsules of most GIST were uncompleted. Their section planes were smooth, grey in color, with some foci of hemorrhage and/or necrosis and cystic changes. Histopathologic classfication: (1) The percentage of the 74 cases (77.1%) of the type of spindle cells was similar to that previously reported (70%){z. The tumor cells showed long or short spindle features, the nucleus located at the center with a stem figure, with both blunt ends, containing less cytoplasm, microfilament at the nuclear section with
123 Chinese Journal of Clinical Oncology 2004/Volume l~ Number 2 Table 2. The relationstfip between the surgical operations and metastasis Case~. Omenlech,m} Non-omontectom~ ()perative ~.eetion>5em ()perati~e.ection~5em Total case,, 39 34 46 27 ]{el'tlrretlt and Meta~,tahc ca-e~,l,~) 2(5.2) 9(26.5) 3(6.51 8(29.6) looked like leio-myoblasts. Six cases 1.0.3 %) were of mixted type. Seventy-six cases were CDll 7 positive (,79.2%), CD34 positive in 56 cases (58.3%), 34 cases (33.4%) revealed SMA positivity and 9 cases (9.3%) were S-100 positive. Relationship between the surgical procedure and tumor prognosis In this group, 39 cases of malignant GIST received omentectomy in the first operation. For the other 34 cases the omentum was left intact. The distance between the section margin and the tumor was> 5 cm in 46 cases, and <5 cm in 27 cases. The relationship between the surgical procedure and the patients prognosis is shown in Table 2. Follow- up study Ninety-four cases (97.9%) were followed- up. the other 2 cases were lost. They were thought as dead since the day they were lost. The median period of follow-up was 5.6 years (2-18 years). The 5-year survival rate of malignant GIST was.57.3%; for benign GIST, the 5-year survival rate was 91.5%. The results regarding the procedures and different GIST are seen in Table 3. Table 3. The relationship between the surgical procedures, tumor classification and prognosis of GIST Categories Case.~ 5-year -.urvi~al ralel,e.'c) I' ~alue Omenteelomy 39 63. I xo,,,,,,,e,,t~,.~,,,,,~ 34 43.9 <0.05 5eclion>5cm 46 62.8 ",eclion ~ 5era 35 46.3 <0.05 Benign 23 91.5 Malignant 73 57.3 <0.()5 DISCUSSION Gastrointestinal stromal tumors are tile conunonest mesenchymal tumors of the gastrointestinal tract. In 1983. the concept of GIST was defined by Mazur and Dark as a kind of gastric nonepithelial tumor, showing neither immunohistochemical characteristic of Schwann cells nor microstructures of smooth muscle cell. In 1998, Hirota, et al. found the mutation of protooncogene c-kit in GIST, so GIST could be categorized by gene originatio I~1. Recent studies indicated that GIST showed the phenotype feature in immunohistochemical appearances and microstructure, and tissue origination that were similar to those of the intestinal cells of Cajal, all expressing c-kit. The nlutation of c-kit in GIST cells abnormally activated the c-kit tyrosinekinase activity without stimulating of stem cell factors. Their intracellular signals could not be controlled, thus leading to abnormal cell proliferation and apoptosis inhibition. Clinical features The majority of GIST occur ill patients from 40 to 70 years, but also occurred in youth, the median age being 58. The incidence in males is greater than that in females. GIST account for about 1% of all gastrointestinal tumors. A great majority of GIST occur in the stomach (60-70%), less commonly in the small intestines I20-30%) and rarely in the esophagus, colon and rectum (<10%). Some GIST are primary in the mesentery and retroperitoneum, unrelated to the tubular GI tract )4~,~. In this group of 96 patients the median age (female 52.1% )was 52.8 years, the younger age may be due to the widely application of B-ultrasound, CT and MRI resulting in earlier diagnosis. Usually there were not any clinical manifestations in the early stage, only the advanced cases of GIST showed different clinical features and nonspecific symptoms, including angina pectoris, an abdominal mass, nausea and loss of body weight. More than 40% of GIST presented with GI and abdominal cavity bleeding due to rupture of the tumor. The majority of GIST metastasis located in abdominal cavity through blood or transplantation, such as liver, omentum or peritoneum. The percentage of lymphatic system nletastasis was rare. In this group, only 2 cases refmted fiom other hospitals recun'ed within 2 years, one had the right hepatic lobe metastasis and the inferior vena
Gastrointestinal stromal tumors/yueliang Lou et al. 124 patients lymphadennectomy was performed. Two patients ( 8.7% ) had postoperative lymphatic metastasis, similar to previous reports(1.7-6%) ~:l. Pathologic observation Since GIST is composed of epitheloid cells and spindle-like cells(or mixed type), one group of tumor with spindle-like cells is about 70% of all, being judged as leiomyosarcoma before, while the other group of tumor with epitheloid cells or round cells is the rest 30%, being judged as leiomyoblastoma during the past time. In this study, spindle-like cell type was 71.1%, epitheloid cell type was 16.7% (lcase), mixed type was 10.2%. GIST's marked sign was CDll 7 specially over expression, CD117 positive rate was about 82%; CD34 positive rate was about 60%-70% i~-t,1; SMA positive rate was more than 4(t%; S-100(neuro-tissue lnarker) positive rate was about 5%. But Desmin (typical muscle's intermediate filament protein) was rarely positive in these tumors, neurofilament, neurofibril protein was usually negtive. Oppositively, SMA, Desmin is positive while CDI]7 negtive in leiomyoid tumor, and S-100 positive while CD117 negtive in heurilermmona. In all of these 96 cases. there were 76 cases which expressed CDIlT, the positive rate was 79. 1%, 56 cases expressed CD34., the positive rate was 58.3%, 34 cases expressed NSE, the positive rate was 58.3%, 9 cases expressed S-100, the positive rate was 9.3%. These results are coincident with the other records. Treatment Since GIST are not sensitive to radiotherapy or chemotherapy, surgical operation is the only effective treatment. Complete tumor resection at the primary operation has the most important impact on a patient's prognosis. GIST, different from GI adenocarcinoma. yield less lymph node metastasis, so lymphadenectomy and lymph detection are rarely necessary. Compared with other soft-tissue sarcomas, GIST have fragile pseudosacs. During the operation, the tumor will easily rupture causing abdominal dissemination, so the operation should be performed carefully to prevent it ml. All the resected tumor tissue should be cleared up carefully and the specimens from different organs should be examined pathologically. In this group, for the cases of omentectomy, the recurrent and metastasis rate was 5.3%; for the cases without the omentectomy, the recurrent and metastasis rate was 26.3%: for the cases in ~hich the length from the tumor resection line to the normal bowel was >5 cm, the recurrent rate was O.5%: for the cases in which the length from the tumor resection line to the normal bowel was ~<5 cm, the recurrent rate was 29.6%. According to our experience, the concept can be developed as follows: ~]) in considering GIST treatment, the omentectomy should be performed. (2) prevention of tumor contamination is the key step to preventing tumor transplantation and hepatic metastasis. (3) getting the safe margin of the tumor resection and tumor size(>10 cm) are also the important influencing factors on the patient's specific survival rate. An investigation from the M.D. Anderson cancer cente (191 cases) demonstrated that, for small tumors(<5 cm), complete resection without tumor rupture, and a low stage of the tumor suggest a better prognosis. But only 10% of the GIST patients after a long follow-up were surviving without tumors fro. Though GIST are not sensitive to radiotherapy or chemotherapy, the development of a molecular target treatment of GIST is developing with use of lmatinib, a type of selective tyrosinekinase inhibitor. It could be effective in GIST(c-kit) tyrosinekinase, and interrupts the transduction of cell signaling passways, hence playing a role in treatment. At present, Imatinib was used in GIST patients who had metastasis and unresected lesions. In Demetri's report n2j, the effective rate was 54%. Prognosis The prognosis of GIST is very poor. M.D.Anderson Cancer Center reported only 13 cases of 132 GIST cases with peritoneal metastasis had survived more than 68 months. In recent years, an American research group also performed cytoreductive surgery (including peritoneum resection) in recurrent GIST cases, to reduce the residual lesions less than 3cm. Combined with thermoperfusional chemotherapy, the effect was encouraging. In this group of 96 cases, 9 cases received multi-operations, 2 patients were operated 3 and 4 times. The recurrent rate of the preventive omentectomy group and operative section>5cm group was 5.3% and 6.5% respectively, significantly lower than those of a non-omentectomy group (23.3%) and operative section ~< 5cm group(29.7%). It seems that a reasonable first operation and preventive omentectomy could reduce the recurrence of GIST. REFERENCES 1 Emory Ts, Sobin LH, Lukes L, et al. Prognosis of
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