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Digestive Diseases and Sciences, Vol. 47, No. 7 (July 2002), pp.

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CASE REPORT

A Rare Case of Huge Gastrointestinal Stromal Tumor (GIST) of the Stomach Extending into the Posterior Mediastinum
HIDEKI MACHISHI, MD, PhD,* YOSHIKATSU OKADA, MD, PhD,* MORITAKA NAGAI, MD, PhD,* NAOYA NODA, MD,* TOMOHIDE HORI, MD,* TAKASHI SHIMONO, MD, PhD, and TOSHIO FUKUDOME, MD, PhD
KEY WORDS: gastrointestinal stromal tumor; prognostic indicator; DNA content; MIB-1.

It has recently been proposed that tumors deriving from mesenchymal cells of the gastrointestinal wall be given the general name gastrointestinal stromal tumor (GIST). Based on analysis of the immunohistochemical and electron microscopic ndings, Rosai (1) classied GISTs into four major types: (1) smooth muscle, (2) neural, (3) combined smooth muscle and neural, and (4) uncommitted. Many authors have reported using this classication to type tumors mainly by immunohistochemical analysis. When analyzed immunohistochemically, myogenic tumors are positive for desmin, vimentin, and -smooth muscle antigen (SMA), and neurogenic tumors are positive for S-100 protein and neuron-specic enolase (NSE) (1, 2). The biological behavior and outcome of GISTs can be difcult to predict, and many morphological prognostic indicators, such as size, mitotic count, cytologic grade, and tumor necrosis, have been reported (1, 2). However, it is difcult to make predictions on the basis of morphological prognostic indicators alone, and new parameters, including DNA content and proliferative index measurements such as the MIB-1 labeling index, have recently come into use as objective prognostic indicators (3, 4). In this report, we describe a case of a huge GIST of the stomach that had extended into the posterior mediastinum, a rare occurrence according to the litManuscript received November 20, 2000; accepted June 10, 2001. From the *Department of Surgery, Yamamoto General Hospital, and Departments of Thoracic Surgery and Second Pathology, Mie University, Mie, Japan. Address for reprint requests: Hideki Machishi, 3-11, Kotobukicho, Kuwana-shi, Mie, 511-0061, Japan.

erature. We completely resected the lesion and immunohistochemically characterized it ( -SMA, vimentin, NSE, S-100 protein) to evaluate the direction in which it was tending to differentiate, and assesed the prognostic indicators (morphological indicators, DNA content, and MIB-1 labeling index) in terms of prediction of the biological behavior and outcome. CASE REPORT
The patient was a 61-year-old woman with anorexia and back pain that she had rst noticed in September 1998. She consulted her local physician, who discovered an abdominal tumor as a result of an upper gastrointestinal barium series and abdominal US examination. The patient was sent to our hospital for further examination and treatment on October 8, 1998. On admission, a poorly demarcated xed tumor was detected in the epigastrium. The laboratory data did not show any abnormal ndings. An upper gastrointestinal barium series showed that the area from the lower esophagus to the lesser curvature of upper body of stomach was compressed dorsally (Figure 1A). Gastroscopy showed the elevated lesion with a bridging fold in the posterior wall of the lesser curvature of the upper body of the stomach and the top of the lesion was ulcerated (Figure 1B). Two biopsies failed to yield a denitive diagnosis. Abdominal computed tomography (CT) showed a huge tumor, about 20 cm in the maximum diameter, extending from just below the tracheal bifurcation to the superior margin of the pancreas that contained an area of central necrosis. The tumor was markedly enhanced and was compressing the inferior vena cava (Figure 2A,B). On abdominal magnetic resonance imaging (MRI), the tumor exhibited a low intensity signal on the T1-weighted image and a high intensity signal on the T2-weighted image, and a tumor extending from just below the tracheal bifurcation to the superior margin of the pancreas and severe compression of the inferior vena cava were visualized in the sagittal and coronal views on the T1-weighted images (Figure 3A,B).
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HUGE GIST OF THE STOMACH

Fig 1. An upper gastrointestinal barium series: (gastroscopy) (A) The area from the lower esophagus to the lesser curvature of upper body of stomach was compressed dorsally. (B) The elevated lesion with a bridging fold in the posterior wall of the lesser curvature of the upper body of the stomach and the top of the lesion was ulcerated.

Selective celiac trunk arteriography showed that the tumor was supplied mainly by the left gastric artery and the inferior phrenic artery. The tumor was hypervascular, but no encasement was detected. Venography of the inferior vena cava showed compression, but no evidence of tumor embolism. Based on these ndings, we performed surgery with a preoperative diagnosis of huge leiomyosarcoma with extension into the posterior mediastinum. The same ndings were observed intraoperatively as on the preoperative diagnostic images. We were able to com-

pletely excise the tumor with part of the lower lobes of the lungs, lower esophagus, and stomach, and we dissected the regional lymph nodes. The tumor measured 20 15 10 cm and was located mainly on the posterior wall of the fornix and growing extramurally (Figure 4A). An elevated lesion with ulceration was observed on the mucosal surface (Figure 4B). Histologically, spindlelike cells with moderate dysplasia were arranged in broad interlacing fascicles, and the mitotic counts were less than 1 per 10 high-power elds (HPF)

Fig 2. Abdominal computed tomography (CT) showed a huge enhanced tumor, about 20 cm in the maximum diameter, extending from just below the tracheal bifurcation to the superior margin of the pancreas that contained an area of central necrosis (A and B). The tumor was compressing the inferior vena cava (arrow).
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Fig 3. Abdominal magnetic resonance imaging (MRI). A tumor extending from just below the tracheal bifurcation to the superior margin of the pancreas, with severe compression of the inferior vena cava, was visualized in the sagittal (A) and coronal (B) views on the T1-weighted images.

(Figure 5). No evidence of metastasis was observed in the regional lymph nodes. In the immunohistochemical analysis, the myogenic markers, -SMA and desmin, were negative, but the neurogenic markers, S-100 protein and NSE, were positive (Figure 6A,B). CD34 and c-kit, which are specic markers of GISTs, were positive (Figure 7A,B). The nuclear DNA ploidy pattern was diploid, and the MIB-1 labeling index was 1% or less. Based on these ndings, the nal diagnosis was neural-type GIST with low-grade malignancy. The postoperative course was uneventful, and the patient left the hospital about one month after the operation. At present, 25 months after the operation, the patient is in good health and free of recurrence.

DISCUSSION The concept of gastric stromal tumor was introduced after Stout (5) classied benign and malignant mesenchymal tumors of the stomach as leiomyomas and leiomyosarcomas, respectively, in 1953. Immunohistochemical and electron microscopic analyses later allowed more detailed evaluation of the histogenesis of stromal tumors. Rosai (1) referred to mesenchymal tumors generically as GISTs and classied them into four major types: a smooth muscle, a neural, combined smooth muscle and neural, and uncommitted.

Fig 4. The resected specimen. (A) The tumor measured 20 15 10 cm and was located mainly on the posterior wall of the fornix and growing extramurally. (B) An elevated lesion with ulceration was observed on the mucosal surface.

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Fig 5. Spindlelike cells with moderate dysplasia were arranged in broad interlacing fascicles, and the mitotic counts were less than 1 per 10 high-power eld (HPF).

CD34 is a hematopoietic progenitor cell antigen that is also expressed in endothelial cells and some mesenchymal cells, and it has been reported that most GISTs are specically positive for CD34 (6). Moreover, it has recently been reported that CD117, the c-kit protooncogene product, is expressed not only in subsets of hematopoietic stem cells, mast cells, and melanocytes, but in most GISTs and that it is a more sensitive marker than CD34 for GISTs (7). Because the interstitial cells of Cajar (ICCs), which are intercalated between the autonomic nerves and the muscle walls of the gastrointestinal tract and now recognized as forming an integral part of the physiology of gut motor functions, are positive for both CD34 and CD117 proteins, many investigators have suggested that GISTs may originate from ICCs(8, 9). Since the tumor cells in our patient were positive for NSE, S-100 protein, CD34, and CD117, we diagnosed the lesion as a neural-type GIST.

Because GISTs are usually radioresistant and insensitive to chemotherapeutic agents, the only curative therapy is complete surgical excision with negative histologic margins. The tumor in our case was huge, 20 15 10 cm, and extended into the posterior mediastinum. Although no such advanced tumors have been reported in the literature, we were able to completely excise the tumor with part of the lower lobes of the lungs, the lower esophagus, and stomach. Many morphological indicators such as size, mitotic count, cytologic grade, and tumor necrosis, have been reported as prognostic indicators of GISTs, and a high mitotic count has generally been accepted as the best prognostic indicator. Suster (2) proposed that the presence of two or more of the following morphological indicators within a single lesion should be regarded an indication of malignancy: (1) size 5 cm in diameter, (2) inltration of adjacent structure, (3) presence of tumor necrosis, (4) increased nuclear cytoplasmic ratio, (5) mitotic counts of 15 per 10 HPF, and (6) inltration of overlying mucosa by the tumor. Because our patients lesion fullled criteria 1, 3, and 6, it was diagnosed as a malignant GIST. However, the biological behavior of GISTs can be difcult to predict on the basis of morphological indicators alone. New parameters such as DNA content and proliferative index measurements have been used as objective determinants of the biological behavior and outcome of GISTs. A recent study on the prognostic indicators with DNA content and MIB-1 showed that DNA content is not an independent prognostic indicator, but that it is signicantly correlated with survival, whereas the MIB-1 labeling index is an independent prognostic factor (3, 4). Because

Fig 6. The immunohistochemical stain for the neurogenic markers, NSE (A) and S-100 protein (B). ABC method. Both were positive ( 200).
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Fig 7. The immunohistochemical stain for CD34 (A) and CD117 (B), which are specic markers of GISTs. ABC method. Both were positive ( 200).

our patients tumor DNA content was diploid, the MIB-1 labeling index was low (10% or less), and the mitotic count was 1 per 10 HPF, we made a diagnosis of low-grade malignancy. There is no evidence of recurrence at present, 25 months after the operation. As a result of advances in molecular biology, some molecular markers have been found to be useful in evaluating prognosis. More recently, several authors have reported mutation of a specic region, exon 11 (the juxtamembrane domain), of the c-kit protooncogene, whose product (CD117) stains specically in GISTs (10, 11). The role of c-kit gene mutations as a prognostic indicator is controversial. Taniguchi et al (12) retrospectively examined the correlation between c-kit gene mutations and outcome by using parafn-embedded sections and reported that they are an independent prognostic indicator. Sakurai et al (13) however, reported that c-kit gene mutations are not always linked to a poor outcome. On the other hand, in the last few years, the literature regarding telomerase activity, which plays an important role in the development and/or progression of neoplastic cells, has been growing rapidly. Sakurai et al (14) also reported that telomerase activity might be a useful marker for evaluating malignant potential in GISTs. We expect these molecular biological markers to be studied further and evaluated more detail in relation to biologic behavior and outcome in the future. There have been a few case reports of recurrence in the liver or peritoneum after 10 years or more, even when diagnosed as benign or low-grade malignant GIST at the time of the rst operation (15, 16). DeMatteo et al (17) recently analyzed 200 cases of GIST and reported that after complete resection, the disease-free survival rate at 5 years was 45% and the

recurrence rate was 40%; the tumor size 10 cm was predictive of survival. They also reported that because of the lack of any effective alternative therapies, all patients with recurrent disease were considered for a second surgical resection and that the survival of patients who had undergone complete resection of recurrent tumor was better than that of patients who had undergone incomplete resection. Mudan et al (18), working at the same institution as DeMatteo et al, analyzed 60 patients with recurrent GIST and reported that survival following recurrence of GISTs is largely determined by the disease-free interval (DFI) between the initial operation and recurrence and that even if the DFI is short, a second resection should be reserved for symptom control. Therefore, although our patient was diagnosed as having a lowgrade malignancy, a very careful, consistent, longterm follow-up is considered necessary. If recurrence is detected, appropriate therapy, such as a complete second resection, should be performed according to the pattern of recurrence. REFERENCES
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