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Multidetector CT of High-Risk Patients with Occult Gastrointestinal Stromal Tumors

¹ Department of Surgery, E1, Osaka University Graduate School of Medicine, Yamada-oka 2-2, Suita 565-0871, Japan.
² Department of Radiology, Osaka University Graduate School of Medicine, Suita 565-0871, Japan.

Received March 12, 2002; accepted after revision June 25, 2002.

 
Supported by grants from the Japanese Ministry of Education, Science, Culture, and Sports and the Ministry of Health and Welfare.

Address correspondence to T. Nishida.

Abstract

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OBJECTIVE. Stromal tumors are an important cause of occult gastrointestinal bleeding in patients who are middle aged or older. This study evaluated the size at which stromal tumors become symptomatic and necrotic and examined the role and limitations of multidetector CT in detecting gastrointestinal stromal tumors.

MATERIALS AND METHODS. Two hundred seventy-one patients with stromal tumors were retrospectively studied to examine the size of symptomatic, necrotic, or malignant stromal tumors. Next, five asymptomatic family members with germline c-kit mutations were prospectively screened to evaluate the role and limitations of multidetector CT.

RESULTS. In this retrospective study, two thirds of the patients with stromal tumors had symptoms and signs that were correlated with tumor size. Stromal tumors larger than 3 cm were accompanied by necrosis, whereas this finding was rare for those smaller than 3 cm. In the prospective screening, multidetector CT with IV infusion of contrast material showed gastrointestinal stromal tumors of more than 2 cm as slightly enhanced intramural or extramural nodules and also detected most gastrointestinal stromal tumors between 1 and 2 cm. Stromal tumors of less than 3 cm were not accompanied by necrosis and appeared as slightly enhanced homogenous tumors with the administration of contrast media.

CONCLUSION. Screening with multidetector CT should be feasible for detecting symptomatic stromal tumors of unknown location in the gastrointestinal tract.

Introduction

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Stromal tumors in the gastrointestinal tract are the most common submucosal tumors in humans. They account for 1-3% of gastric neoplasms, 20% of small intestinal tumors, and 0.2-1% of colorectal tumors [1,2,3]. These stromal tumors occur mainly in patients who are middle-aged or older, and their major symptoms include gastrointestinal bleeding, anemia, abdominal pain or dyspepsia, and abdominal mass [2, 4]. These symptoms are usually associated with relatively large tumors, which may accompany a poor prognosis. However, even small stromal tumors may cause these symptoms when associated with ulcer and necrosis. Stromal tumors are one of the important causes of gastrointestinal bleeding. Although stromal tumors are composed of leiomyomas, leiomyosarcomas, schwannomas, and gastrointestinal stromal tumors and classified according to histologic characteristics and ultrastructural features [1, 2], the distinction of these histologic types on pre-operative imaging studies is difficult.

Studies have reported that gastrointestinal stromal tumors, a major type of stromal tumor in the gastrointestinal tract, are frequently associated with mutations in the c-kit gene, which is considered causative for gastrointestinal stromal tumors [5,6,7]. Gastrointestinal stromal tumors with c-kit mutations more frequently show malignant features and are associated with poorer prognosis than gastrointestinal stromal tumors without them [8]. Thus, early detection and surgical therapy may improve the prognosis of patients with these tumors. Because 70% of stromal tumors occur in the stomach, endoscopy is considered to be useful for detection. Twenty percent of stromal tumors occur in the small intestine and fewer than 10% occur in the large bowel, where endoscopic examination is less useful. CT has proven useful in the detection of small-intestine tumors, large-bowel tumors, and gastric stromal tumors with exogastric growth. On CT, signs of necrosis are important for the diagnosis of stromal tumors [3, 9, 10].

To date, to our knowledge, there have been no reports describing the size of stromal tumors that become symptomatic, necrotic, or malignant. Also, the detectable size of stromal tumors on available radiography is not known. We therefore decided to retrospectively examine the size of stromal tumors that became symptomatic or necrotic and then conducted prospective screening for patients with germline c-kit mutations to determine whether CT can detect occult gastrointestinal stromal tumors in these patients. We then evaluated the role of CT in the diagnosis of stromal tumors.

Materials and Methods

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Study I: Retrospective Study
We reviewed the data for 271 patients (150 men and 121 women) with primary stromal tumors of the gastrointestinal tract who underwent surgery at Osaka University Graduate School of Medicine or one of its affiliated hospitals from 1985 to 2000. Histology of stromal tumors was performed by H and E staining and immunohistochemistry, as described previously [8]. The mean age of the patients at the time of diagnosis was 58 ± 13 years (median age, 60 years). The location of the tumors was as follows: 15 in the esophagus, 182 in the stomach, 16 in the duodenum, 35 in the small intestine, 11 in the large intestine, and 12 in the retroperitoneum or mesentery. At the time of diagnosis and during the follow-up period, distant metastasis was examined on sonography and CT or MR imaging. Fifty-seven patients expierenced recurrences, and 51 patients had died by June 30, 2001. The mean follow-up period was 4.3 ± 3.9 years (median, 3.1 years). The study was performed according to our institutional guidelines.

Statistical Methods
The Fisher's exact test and the chi-square test were used for statistical comparisons. Two-sided p values less than 0.05 were considered significant.

Study II: Prospective Study
The study was performed under the local institutional guidelines, and informed consent was obtained from all patients.

Five members of two family pedigrees were involved in the study. Mutations in the c-kit gene in these two family pedigrees were reported elsewhere [6, 11]. In the first pedigree, a 60-year-old woman and her nephew, who was 39 years old and the proband, had been identified as having multiple gastrointestinal stromal tumors with a germline mutation in exon 11 of the c-kit gene [6]. Their living family members were examined for mutations in the c-kit gene using extracted leukocyte DNA. A 22-year-old woman (patient 1) was identified as having the same mutation, whereas another member had no mutation. In the second pedigree, a 74-year-old man, the proband, had undergone operations twice for intestinal and gastric gastrointestinal stromal tumors and was diagnosed as having multiple gastrointestinal stromal tumors [11]. Later, he underwent DNA analysis for c-kit gene mutation, and a germline mutation in exon 17 of the c-kit gene was identified. His living family members also underwent DNA analysis, and his three sisters (patient 2, 70 years old; patient 3, 68 years old; and patient 4, 65 years old) and his son (patient 5, 36 years old) were identified as having the same germline mutation in exon 17. These five persons were screened for gastrointestinal stromal tumors by gastrointestinal fiberscopy and multidetector CT (MDCT).

Endoscopic Methods and CT Conditions
Gastrointestinal fiberscopy and MDCT were independently performed, with each examiner having no information about the results obtained from other examinations.

A gastrointestinal fiberscope (GIF-P20; Olympus Optical, Tokyo, Japan) was used for endoscopic examinations with an ultrasonic catheter using a 20-MHz model (EU-M20; Olympus America, Melville, NY). The probe was introduced into the esophagus through the gastrointestinal fiberscope. After fasting overnight, patients were injected intramuscularly with 20 mg of scopolamine-N-butyl bromide (Buscopan; Nippon Boehringer Ingelheim, Kawanishi, Japan), and endoscopy was performed.

CT was performed after overnight fasting. Each patient ingested 600 mL of tap water 2 hr before undergoing CT and then another 600 mL just before scanning. CT was performed using an MDCT scanner (LightSpeed QXi; General Electric Medical Systems, Milwaukee, WI). Five minutes before the examination, 20 mg of scopolamine-N-butyl bromide was injected IV. Unenhanced scanning was not performed. A total of 100 mL of nonionic contrast material was injected IV at a rate of 3 mL/sec using a power injector. Two-phase scans were obtained 30 sec (early phase) and 70 sec (delay phase) after the start of IV injection. All scans were obtained in a single breath-hold from the diaphragmatic dome to the pubis symphysis. The parameters were 120 kVp; 270 mAs; detector row configuration, 2.5 x 4 mm; pitch, 6; prospective reconstruction, 5 mm; and overlap reconstruction pitch, 1.25 mm.

Results

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Study I: Retrospective Study
Of the 271 patients for which data were examined, 160 had visited hospitals with some symptoms and signs, mostly abdominal pain, melena, hematemesis, anemia, or palpable mass. Among the other 111 patients, 97 were shown to have stromal tumors on upper gastrointestinal series or endoscopy during screening for gastric cancer. For the remaining 14 patients, stromal tumors were found incidentally during examinations or surgery for other diseases. With increasing tumor size, the number of patients with symptoms and signs increased (Table 1); bleeding and resulting anemia (54 patients) were most frequent, followed by palpable abdominal mass (44 patients) and abdominal pain (43 patients). The likelihood of the discovery of a palpable abdominal mass was correlated with tumor size but not with bleeding and abdominal pain.

Recurrence after initial surgery was also examined. Except for two patients who received local enucleation, recurrences after surgery were observed in patients with tumors larger than 3 cm, and the recurrence rate showed correlation with tumor size (Table 1). Relapse occurred with more than half the tumors over 8 cm. Similar results were obtained for the prognosis (data not shown). Although clinically malignant behaviors were observed mainly in tumors larger than 6 cm, a low but significant number of stromal tumors smaller than 6 cm recurred and resulted in a poor prognosis.

Finally, we examined patients for the presence of necrosis, which is considered to be a diagnostic sign of malignant stromal tumors in the gastrointestinal tract. Stromal tumors with macroscopic necrosis were observed for tumors greater than 3 cm, and necrosis was predominantly found in tumors larger than 6 cm, in agreement with the observation of recurrences and poor prognosis (Fig. 1 and Table 1).

View larger version (25K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 1. —Bar graph shows relationship between tumor size and presence of macroscopic tumor necrosis. Gray and black bars indicate number of patients with and without macroscopic necrosis, respectively. Frequency of tumors with necrosis rises with increases in tumor size (p < 0.0001).

Study II: Prospective Study
Endoscopy.—Screening endoscopic examinations were performed with endoscopic sonography. All five family members had neither symptoms nor signs of gastrointestinal stromal tumors. Endoscopy revealed two tumors of 2 cm each forming dumbbell-shaped submucosal tumors in the esophagogastric junction of one patient (patient 2). In another (patient 4), a less than 1-cm submucosal tumor was found in the corpus of the stomach. In a third patient (patient 5), 2.5- and 2.2-cm submucosal tumors were found in the esophagogastric junction, and two submucosal tumors of 1 cm each, as well as one tumor of 0.5 cm, were found in the gastric corpus (Figs. 2A and 2B). These tumors appeared to have arisen from the muscularis propria according to endoscopic sonography. One patient (patient 3) had undergone previous proximal gastrectomy, and no tumor was detected in the esophagus, remnant stomach, or duodenum. One other patient (patient 1) had no tumor in the esophagus, stomach, or proximal duodenum.

View larger version (164K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 2A. —36-year-old man with germline c-kit mutation (patient 5). Endoscopic sonogram shows submucosal tumors in cardia.

View larger version (147K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 2B. —36-year-old man with germline c-kit mutation (patient 5). Endoscopic sonogram also shows submucosal tumors in gastric corpus.

MDCT.—The summary of MDCT findings shows that seven tumors of more than 1 cm were detected on MDCT, whereas two tumors of less than 1 cm were not detected (Table 2). In three patients, MDCT identified six of eight submucosal gastric tumors, which were detected on endoscopy (Figs. 2C,2D,2E and 3). In one patient, two tumors in the esophagogastric junction appeared as dumbbell-shaped tumors on MDCT, and two 1-cm submucosal tumors in the corpus were visualized as slightly enhanced intramural tumors by IV contrast medium (Figs. 2C,2D,2E). A 5-mm tumor was not detectable. Two tumors in another patient clearly appeared as slightly enhanced with IV contrast medium (Fig. 3). These tumors appeared to have originated from the muscle layer of the stomach. A small gastric tumor in one patient identified by a gastrofiberscope could not be detected on MDCT (Table 2). In one patient, no tumor was identified in the remnant stomach, and a nearly 1-cm enhanced tumor protruding into the lumen was identified in the proximal jejunum (Fig. 4). All tumors detected on CT showed homogenous patterns and no sign of necrosis. CT revealed no tumor in one patient.

View larger version (131K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 2C. —36-year-old man with germline c-kit mutation (patient 5). CT scan shows slightly enhanced submucosal tumors in cardia.

View larger version (115K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 2D. —36-year-old man with germline c-kit mutation (patient 5). CT scans also show submucosal tumors in gastric corpus as slightly enhanced intramural tumors.

View larger version (124K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 2E. —36-year-old man with germline c-kit mutation (patient 5). CT scans also show submucosal tumors in gastric corpus as slightly enhanced intramural tumors.

View larger version (146K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 3. —70-year-old woman with germline c-kit mutation (patient 2). CT scan shows submucosal tumors in cardia, which were slightly enhanced by IV infusion of contrast medium.

View larger version (153K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 4. —68-year-old woman with germline c-kit mutation (patient 3). CT scan shows jejunal submucosal tumor growing into intestinal lumen and enhanced by IV infusion of contrast medium.

Discussion

Top Abstract Introduction Materials and Methods Results Discussion References

 
Most stromal tumors in the gastrointestinal tract are diagnosed after becoming symptomatic, causing gastrointestinal bleeding, abdominal pain, and palpable mass, although recent data from a study of Japanese patients indicated that almost half of gastric stromal tumors are found on screening examinations [2]. The symptoms are usually associated with large tumors, which are thought to be a poor prognostic factor [1, 2, 8]. Surgery of large stromal tumors is sometimes followed by recurrence. Most clinicians consider stromal tumors larger than 5 or 6 cm as practically malignant. Our data indicate that more than one third of stromal tumors smaller than 6 cm cause symptoms and signs and that some show malignant behavior (Table 1). Thus, early diagnosis and detection of small stromal tumors are important.

More than two thirds of stromal tumors in the gastrointestinal tract occur in the stomach, where they can be detected by endoscopy. However, CT should be more useful for the detection of intestinal stromal tumors and the evaluation of extragastric or extraintestinal extension. Unfortunately, to our knowledge, no report has been published on the utility and limitations of CT detection. In our study (Figs. 2A,2B,2C,2D,2E,3,4), all four gastric tumors over 2 cm were detected on MDCT, and three gastric and intestinal tumors between 1 and 2 cm were also detected (100%). Most of these tumors appeared as slightly enhanced homogenous intramural lesions on MDCT, but two tumors less than 1 cm could not be detected (Table 2). No tumor has been detected in one patient on endoscopy or MDCT. It is unknown whether the patient had no tumor or whether MDCT and endoscopy could not detect her tumors. The patient was younger than most family members who had gastrointestinal stromal tumors [6, 11]. Most patients with familial or sporadic gastrointestinal stromal tumors appeared to have tumors after their 30s. These results indicate that tumors 2 cm or larger could be detected on MDCT, and even 1-cm tumors were detected when a proper slice was made. Of the 160 symptomatic patients, 151 (94%) had tumors larger than 2 cm (Table 1). Thus, the 2-cm detection level seems adequate for screening of symptomatic stromal tumors. Of course, the number of patients and tumors evaluated is limited, and most tumors were found in the stomach. Large group studies are required to establish the usefulness of MDCT for detection of occult stromal tumors in the gastrointestinal tract.

Most previous reports have described CT findings of large stromal tumors [3, 12, 13]. Helpful CT findings in identifying stromal tumors in the gastrointestinal tract include a well-delineated heterogeneous large mass showing interior growth or exterior growth or both. Large stromal tumors are usually accompanied by necrosis and liquefaction, which are well defined after IV administration of contrast materials [14]. Tumors may occasionally contain gas. Thus, large stromal tumors appear as heterogeneous masses and sometimes show signs of crescent-shaped necrosis or the "Torricelli-Bernoulli" sign [9, 10]. This last sign is observed on CT as a vertical stream of air bubbles arising from an ulcerating neoplasm into a fluid-filled viscus—for example, while the patient is upright. However, these findings are limited to large tumors, and most small tumors do not display air bubbles. Our data indicated that more than half of stromal tumors over 6 cm showed macroscopic necrosis, but this finding was rare in those below 5 cm (Fig. 1). These data were compatible with the findings of prospective screening that showed homogeneously enhanced tumors (Figs. 2A,2B,2C,2D,2E,3,4). Small stromal tumors tended to be located in the gastric wall and appeared as less enhanced lesions compared with large ones. Although preoperative differential diagnosis of malignant stromal tumors is difficult, invasion into neighboring structures and metastatic lesions is clearly a malignant feature. Large tumors (>5 cm) and tumors with apparent necrosis may be considered potentially malignant.

In summary, we conducted a retrospective study to examine the size of symptomatic or necrotic stromal tumors and a prospective study to evaluate the role and limitations of MDCT in the diagnosis of stromal tumors in patients with germline c-kit mutations. Two thirds of the patients with stromal tumors had symptoms and signs. Even with tumors less than 5 cm, one third of the patients were symptomatic, and some of the tumors were malignant. Most stromal tumors over 6 cm were accompanied by necrosis, which was rare in those less than 3 cm. Prospective screening examinations for patients with germline c-kit mutations have suggested that CT can detect most gastrointestinal stromal tumors more than 2 cm, showing that symptomatic gastrointestinal stromal tumors requiring therapeutic modalities are detectable. Thus, MDCT should be useful for detecting symptomatic gastrointestinal stromal tumors larger than 2 cm.

References

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