Gastrointestinal stromal tumors
INTRODUCTION
Gastrointestinal stromal tumors (GIST) are mesenchymal tumors which typically arise in association with the muscularis propria of gastrointestinal (GI) tract wall [1]. They are most frequent in the stomach (60%), but also can occur in the small bowel (30%) or elsewhere, including the colon and rectum (5%), esophagus (<5%) [2]. In addition, GIST may occur as a primary tumor of the omentum, mesentery or retroperitoneum[3]. They account for 1-3 % of gastric neoplasms, 20% of small bowel tumors and 0.2-1% of colorectal tumors[4-6]. These tumors arise pathologically from the wall of the gastrointestinal tract and can be characterized as benign, borderline, low or high malignant potential based on the pathologic appearance. CT plays an important role for the diagnosis and staging of these neoplasms as CT can identify the tumor and assess for local spread or distant metastases.
This paper reviews the role of CT in the detection and characterization of gastrointestinal stromal cell tumors. The optimal CT technique for visualization of small bowel tumors will be reviewed and a variety of GIST will be illustrated. Pathologic correlation will also be included.
CLINICAL PRESENTATION
Most GIST occur in older patients, typically between the ages of 50-60[2]. Sporadic examples are rare before the age of 40[2]. However, GIST can be familial and such tumors present in younger patients, often in their 30's[7].
Stromal tumors can be the cause of occult gastrointestinal bleeding in patients who are middle aged or older. In addition to gastrointestinal bleeding, patients may present with anemia, abdominal pain, dyspepsia or a palpable abdominal mass[5]. These symptoms usually occur with larger tumors, but even small tumors can undergo necrosis and ulceration, thereby producing pain or bleeding. In a study by Nishida et al, of 271 patients with stromal tumors, 2/3 had symptoms that correlated with tumors size[8]. Tumors larger than 3 cm were more likely to demonstrate necrosis than tumors less than 3 cm[8].
Visceral obstruction is rare. In the study by Burkhill et al, of 61 patients who underwent CT following diagnosis, 1 developed small bowel obstruction, 1 developed unilateral renal obstruction, and there were no cases of biliary obstruction[9].
PATHOLOGY
GIST are a subset of a more broad category of mesenchymal tumors of the gastrointestinal tract which also includes leiomyomas, leiomyosarcomas, and schwannomas. In the past, this group of tumors had been regarded as smooth muscle tumors, but with the development of more specific diagnostic techniques, GIST are believed to display differentiation along the lines of interstitial cells of Cajal[10].
With the exception of the esophagus, where leiomyomas predominate, most spindle cell tumors in the gastrointestinal tract are GIST. Grossly, GIST are soft, fleshy lobulated masses that may have internal necrosis and cystic degeneration (Figure 1). GIST are composed of spindle (70%) (Figure 2) or epitheliod (30%) cells[11], although some examples display a mixture of the two cell types. Epithelioid examples were referred to as "leiomyoblastoma" in early literature. The vast majority of GIST express a mutant form of c-kit (CD117) (Figure 3) that can be detected on routine immunohistochemical staining[12] although a small percentage [2-5%] of otherwise typical GIST lack c-kit mutations and thus no c-kit/CD117 protein is detected immunohistochemically. Such c-kit negative tumors have mutations in platelet derived growth factor receptor alpha, another tyrosine kinase, in about a third of cases[13].
C-kit is a growth factor receptor with tyrosine kinase activity[14]. It is thought that mutations in the c-kit gene are causative for the development of gastrointestinal tumors[7, 15, 16]. Of course, detection of the c-kit protein immunohistochemically can be exploited for diagnosis, since it is found in both benign and malignant GIST. However, there are some problems with lack of antibody specificity[17].
Other spindle cell tumors such as leiomyomas and leiomyosarcomas lack c-kit mutations[16]. As above, leiomyomas occur most frequently in the esophagus as intramural lesions. True leimyosarcomas, sarcomas displaying smooth muscle differentiation, are very rare gastrointestinal tract tumors, in contrast to malignant GIST. Schwannomas are also distinct from GIST, and are always benign S100-positive spindle cell tumors usually found in the stomach. GI autonomic nerve tumors (GANTs) are probably a subset of GIST. [4].
GIST malignant behavior is best assessed by invasion of adjacent structures and distant metastasis[2]. Tumor location is a key factor in predicting outcome. For example, most [about 70%] gastric GIST behave in a benign fashion, whereas about half of duodenal GIST metastasize[18, 19]. Location is a key prognostic factor in these tumors[20].
Other factors that are have been correlated with aggressive behavior include large tumor size, presence of metastasis at surgery, high mitotic counts, high proliferation indices, tumor necrosis, and DNA aneuploidy (Figure 4). Emory et al report that although the tumor size and mitotic count do not always correlate with prognosis, patients whose tumors are less than 2 cm with no mitotic activity are at low risk of metastases whereas those with tumors larger than 5 cm with high mitotic counts have a greater tendency to metastasize[20]. There is, however, disagreement on several factors, and occasionally tumors that would be regarded as 'benign' by proposed criteria have metastasized. Some have advocated, therefore, that the term 'benign' not be applied to GIST at this time[21],a subject of current debate[17].
The liver is the most common site of metastases[22], followed by peritoneum. Other sites include retroperitoneum, pleura, lungs, bone, and subcutaneous tissue in relation to a laparotomy scar. No brain metastases were seen in 5/5 patients with GISTs who had follow up brain CTs[9].
DIAGNOSIS THE ROLE OF CT
Since most GIST occur in the stomach, they are often detected by endoscopy performed in patients with a variety of GI symptoms or, in Japan, many are detected on screening endoscopic exams for gastric cancer in asymptomatic patients[5]. CT plays an important role in detection of exophytic gastric GIST and is especially helpful in detection of GISTs of the small bowel and colon. New MDCT with the ability to obtain thin collimation and high resolution allows for detection of small tumors. In the study by Nishida et al, 4/4 gastric GIST > 2cm which were seen on endoscopy were detected by CT. An additional 1cm tumor in the jejunum not seen by endoscopy was identified by CT. A <1 cm submucosal tumor in the corpus of the stomach was missed. Furthermore, of 160 symptomatic patients, 151 had tumors larger than 2 cm. As all tumors 2cm or greater in size were detected with MDCT, these findings suggest that MDCT can be useful in screening symptomatic patients suspected of having GISTs[8].
CT TECHNIQUE
CT is considered to be the imaging modality of choice for the detection, staging, surgical planning and follow-up of patients with GIST. When imaging a patient with a suspected gastrointestinal tract neoplasms, including GIST, it is important to obtain a high quality data set.
CT PROTOCOL
Oral Contrast
Traditionally, high density oral contrast agents have been used for most abdominal CT imaging indications. However, water has certain advantages for imaging gastrointestinal tract neoplasms such as GIST. Water as oral contrast does not interfere with the 3D imaging of vessels or require extensive editing.
IV Contrast
IV contrast is essential for detection of the primary, identification of vascular encasement and for detection of the liver metastases. We use 120 cc of nonionic contrast injected at a rate of 3-4 cc/sec. Imaging during the portal venous phase is usually adequate, however, the addition of arterial phase imaging may be help for evaluation of arterial encasement or surgical planning.
Image Acquisition
The thin collimation and improved spatial and temporal resolution afforded by MDCT definitely improves visualization of small lesions. Using our Siemens Sensation 16, the 16 X 0.75mm collimator setting is utilized to obtain 0.75mm slices reconstructed at 0.5mm intervals for 3D imaging. For hardcopy review, 3mm slices are usually adequate.
3D imaging
All the data is then transferred to our 3D workstation (Leonardo- Siemens Medical Solutions, Malvern, PA) for volume rendering. The use of the 0.75 mm collimators creates isotropic data sets and therefore the 3D images of the pancreas and abdominal vessels is of excellent quality. All images are reviewed using InSpace software (Siemens Medical Solutions, Malvern, PA), which allows multiplanar reconstructions as well as interactive 3D volume rendering. The brightness, opacity, window width, and level can be adjusted in real-time in order to accentuate the wall of the gastrointestinal tract and optimize visualization of abnormalities. Manipulating trapezoidal transfer functions interactively modifies the image contrast and relative pixel attenuations in the final image. This function assigns color and opacity to each voxel and can be adjusted to alter the display instantaneously. The transfer function is applied to a histogram of the data set, with the x-axis representing Hounsfield units and the y-axis color or opacity. All voxels are incorporated into the display. Sliding the trapezoid higher along the x-axis excludes lower attenuation voxels from the display, therefore yielding images of the high attenuation collecting system. The process can be simplified by creating "presets" which can be applied quickly and then only minor adjustments are needed.
When evaluating the mesenteric vessels, volume rendering is the main algorithm used. However maximum intensity projection (MIP) can be helpful in some patients to visualize the very distal branches of the vessels. Modern 3D software allows instant switching between VR and MIP. We have found that 3D imaging is a valuable adjunct to traditional axial images for this clinical indication. The clinicians and surgeons also appreciable the value of 3D imaging for surgical planning.
CT APPEARANCE
GISTs can occur anywhere in the GI tract from the esophagus to the rectum, as well as the omentum, mesentery, and retroperitoneum. The majority of GISTs appear to be well-defined, extraluminal or intramural masses with varying attenuation based on size (Figure 5 & 6). Small tumors tend to appear homogeneous (Figure 7). The larger tumors (>6cm) frequently show central areas of necrosis or hemorrhage (Figure 8). Central gas and mural calcification are uncommon findings. In the study by Burkill et al reviewing scans in a population with a mean tumor size of 13cm +/- 6, 31/38 tumors were heterogenous, while homogenous tumors had a mean diameter of 6.4cm +/- 2.7[9]. Nishida et al reported similar data[8].
The above description applies to GISTs in all locations. However, there are features of GISTs that may be unique to location. Gastric GISTs commonly demonstrate extension into the gastrohepatic ligament, gastrosplenic ligament, and lesser sac, and frequently, the bulk of the tumor is seen in an extragastric location. The majority show peripheral enhancement. Furthermore, the cavities that develop from central necrosis or hemorrhage in the larger tumors may communicate with the gastric lumen and therefore contain fluid, air, or contrast material (Figure 9). In the study by Levy et al, 24/28 gastric GISTs (mean diameter 10.8 cm) showed extragastric extension[23]. 75% of cases were located in the gastric body, and only 11% in the antrum. This may help to distinguish gastric GISTs from solitary gastric carcinoids, which are most commonly seen in the antrum and typically have central ulceration. Differentiation from other mesenchymal neoplasms can be difficult.
Small intestinal GISTs demonstrate similar features of peripheral enhancement and central areas of low attenuation (Figure 10). They may appear as intramural masses or intraluminal polyps, and may show extension into adjacent mesentery. Encasement of adjacent small bowel, colon, and bladder can be seen. The appearance is different from small bowel adenocarcinoma, which typically appears as an annular lesion in the proximal small intestine. Lymphoma may share many features of small intestinal GISTs, but is notable for lymphadenopathy.
Anorectal GISTs most commonly present as a well-defined, eccentric mural masses that expand the rectal wall and may contain mucosal ulceration (Figure 11). The mass spreads via extension into the ischiorectal fossa, prostate, or vagina. Intraluminal polypoid masses are rarely seen in anorectal GISTs, but are more common in leiomyosarcoma. The lack of lymphadenopathy again serves to distinguish GISTs from lymphoma in the anorectal region. As in GISTs at other locations, central areas of hemorrhage can be seen.
Colonic GISTs are described as transmural tumors that involve the intraluminal and extraserosal surfaces of the colon. Other features include cystic change, hemorrhage, necrosis, or calcification. Colonic GISTs have been seen to exhibit circumferential growth and secondary dilatation of the affected colonic segment[23].
Esophageal, mesenteric, and omental GISTs may also contain central areas of hemorrhage, necrosis, or cystic change.
The most common site for GIST metastasis is the liver, followed by peritoneum. Ascites is very rarely seen. Liver metastasis appear isointense or hypointense to normal liver parenchyma on non-contrast images, and usually have a lesser degree of enhancement than normal liver parenchyma on portal phase contrast images. They can also appear cystic (Figure 9). Zonios et al note that metastatic GIST is often difficult to differentiate from cystic lesions due to metastasis from other primaries and amebic abscesses[24]. Recurrent tumors after surgical resection cal also appear very cystic and should not be mistaken for post-op fluid collections.
Like the primary lesions, liver metastases can show calcification, or central areas of necrosis or hemorrhage. It has also been observed that hepatic GISTs treated with STI-571, a tyrosine kinase inhibitor with high specificity for the c-kit protooncogene, also exhibited cystic-like change, with attenuation measuring 20-25 H, slightly greater than a true cyst.
TREATMENT AND PROGNOSIS
There is no general agreement on the prognosis of GISTs. 5 year survival ranges from 28% - 43%. This broad range seen in different studies is likely explained by the inclusion of tumors mistaken to be GISTs.
Surgical resection is the conventional therapy for GISTs. However, overall prognosis of patients with GISTs treated with surgery alone is discouraging. Rossi et al report that 10 out of 18 patients in their series developed recurrent disease following radical surgery[25] (Figure 12). Even in patients who undergo surgery to treat relapsed disease, medial survival drops to 15 months, compared to 50 months in primary cases.
Selective tyrosine kinase inhibitors, such as STI-571, have become the standard chemotherapy for metastatic or unresectable tumors[14]. These agents are currently the focus of several clinical trials including RTOG and ACRIN.
CONCLUSION
Gastrointestinal stromal tumors (GIST) are mesenchymal tumors that typically arise in association with the muscularis propria of gastrointestinal (GI) tract wall. CT can be a useful modality for the diagnosis, staging and follow-up of patient s with GIST. It is important for the radiologist to be familiar with proper CT technique for imaging these patients as well as the variety of CT appearance of the primary tumors and metastases.
References
1. Mazur MT, Clark HB. Gastric stromal tumors: reappraisal of histogenesis. Am J Surg Pathol 1983;7:507-519.
2. Miettinen M, Sarlomo-Rikala M, Lasota J. Gastrointestinal stromal tumors: recent advances in understanding of their biology. Hum Pathol 1999;30:1213-1220
3. Miettinen M, Monihan JM, Sarlomo-Rikala M, et al. Gastrointestinal stromal tumors/smooth muscle tumors (GISTs) primary in the omentum and mesentery: clinicopathologic and immunohistochemical study of 26 cases. Am J Surg Pathol 1999;23:1109-1118
4. Miettinen M, Lasota J. Gastrointestinal stromal tumors--definition, clinical, histological, immunohistochemical and molecular genetic features and differential diagnosis. Virchows Arch 2001;438:1-12
5. Nishida T, Hirota S. Biological and clinical review of stromal tumors in the gastrointestinal tract. Histol Histopathol 2000;15:1293-1301
6. Pannu HK, Hruban RH, Fishman EK. CT of gastric leiomyosarcoma: patterns of involvement. AJR 1999;173:369-373
7. Nishida T, Hirota S, Taniguchi M, et al. Familial gastrointestinal tumors with germline mutation of kit gene. Nat Genet 1998;19:323-324
8. Nishida T, Kumano S, Sugiura T, et al. Multidetector CT of high-risk patients with occult gastrointestinal stromal tumors. AJR 2002;180:185-189
9. Burkill GJ, Badran M, Al-Muderis O, et al. Malignant gastrointestinal stromal tumor: distribution, imaging features, and pattern of metastatic spread. Radiology 2003;226:527-532
10. Kindblom LG, Remotti HE, Aldenborg F, Meis-Kindblom JM. Gastrointestinal pacemaker cell tumor (GIPACT): gastrointestinal stromal tumors show phenotypic characteristics of the interstitial cells of Cajal. Am J Pathol 1998;152:1259-1269
11. Chen Y, Bechtold R, Savage P. Cystic changes in hepatic metastases from gastrointestinal stormal tumors (GISTs) treated with Gleevac (Imatinib Mesylate). AJR 2002;179:1059-1062
12. Sarlomo-Rikala M, Kovatich AJ, Barusevicius A, Miettinen M. CD117: a sensitive marker for gastrointestinal stromal tumors that is more specific than CD34. Mod Pathol 1998;11:728-734
13. Heinrich MC, Corless CL, Duensing A, et al. PDGFRA activating mutations in gastrointestinal stromal tumors. Science 2003;299:708-710
14. Sturgeon C, Chejfec G, Espat NJ. Gastrointestinal stromal tumors: a spectrum of disease. Surg Oncol 2003;12:21-26
15. Hirota S, Nishida T, Isozaki K, et al. Gain-of-function mutation at the extracellular domain of KIT in gastrointestinal stromal tumours. J Pathol 2001;193:505-510
16. Lasota J, Jasinski M, Sarlomo-Rikala M, Miettinen M. Mutations in exon 11 of c-Kit occur preferentially in malignant versus benign gastrointestinal stromal tumors and do not occur in leiomyomas or leiomyosarcomas. Am J Pathol 1999;154:53-60
17. Trupiano JKR, Stewart RE, Misick C, Appelman HD, Goldblum JR. Gastric Stromal Tumors A Clinicopathologic Study of 77 Cases With Correlation of Features With Nonaggressive and Aggressive Clinical Behaviors. Am J Surg Pathol 2002;26:705-714
18. Goldblum J, Appelman H. Stromal tumors of the duodenum: a histologic and immunohistochemical study of 20 cases. Am J Surg Pathol 1995;19:71-80
19. Brainard J, Goldblum J. Stromal Tumors of the Jejunum and Ileum: A Clinicopathologic Study of 39 Cases. Am J Surg Pathol 1997;21:407-416
20. Emory TS, Sobin LH, Lukes L, Lee D, O'Leary TJ. Prognosis of gastrointestinal smooth-muscle(stromal) tumors: dependence on anatomic site. Am J Surg Pathol 1999;23:82-87.
21. Fletcher CD, Berman JJ, Corless C, et al. Diagnosis of gastrointestinal stromal tumors: A consensus approach. Hum Pathol 2002;33:459-465
22. Baker ME, Pelley R. Hepatic metastases: basic principles and implications fro radiologists. Radiology 1995;197:329-337
23. Levy AD, Remotti HE, Thompson WM, Sobin LH, Miettinen M. Anorectal Gastrointestinal Stromal Tumors: CT and MR Imaging Features with Clinical and Pathologic Correlation. AJR 2003;180:1607-1612
24. Zonios D, Soula M, Archimandritis AJ, Revenas K. Cystlike hepatic metastases from gastrointestinal stromal tumors could be seen before any treatment. AJR Am J Roentgenol 2003;181:282
25. Rossi C, Mocellin S, Mencarelli R, et al. Gastrointestinal stromal tumors: from a surgical to a molecular approach. Int J Cancer 2003;107:171-176
Figures
Figure 1. Gross pathologic specimen of malignant small bowel stromal tumor.
Figure 2. H&E stain of benign small bowel stromal tumor showing smooth muscle and few mitotic figures.
Figure 3. Histology specimen of GIST showing positive staining for CD177/c-kit.
Figure 4. H&E stain of malignant small bowel stromal tumor showing high cellularity and many mitotic figures.
Figure 5. 47-year-old female presented to the emergency room complaining of dizziness and shortness of breath beginning 3-days prior to admission. She also had an episode of hematemesis as well as dark stool. Coronal 3D image of contrast enhanced CT demonstrates a 4 cm soft tissue mass projecting into the lumen of the stomach. The CT appearance is compatible with GIST. Endoscopy was performed and a biopsy confirmed a GIST.
Figure 6. 55-year-old man presented with palpable abdominal mass. Coronal 3D CT scan performed with intravenous contrast demonstrates a 12x9 cm enhancing mass apparently arising from the second portion of the duodenum. There was central necrosis in the mass as well peripheral enhancement. At surgical resection, a malignant gastrointestinal stromal tumor was found arising from the duodenal wall.
Figure 7. 45-year-old male with abdominal pain. Contrast enhanced CT reveals a 2.5 cm enhancing mass near the ligament of Treitz. A small Gist was resected at surgery.
Figure 8. 91-year-old female presented with increasing fullness in the left upper quadrant and weight loss. CT was ordered for further evaluation. Contrast enhanced CT demonstrates a large necrotic mass in the left upper quadrant with a nodular enhancing rim. The mass compresses the stomach. At surgery a large gastric GIST was resected.
Figure 9. 68-year-old male presented with bleeding. CT scan was performed for further evaluation. (A) In the left upper quadrant, there is a 15x7 cm predominately cystic mass, which appears to arise from the stomach. This mass displaces the stomach medially. (B) Air is seen within the mass. In addition, there are multiple cystic liver lesions. At surgery, a large malignant gastrointestinal stromal tumor was noted. There was infiltration into the perigastric soft tissues. In addition, the left lobe cystic liver lesions were biopsied and revealed metastatic GIST.
Figure 10. 35 year-old-male with pain. Coronal 3D image of contrast enhanced CT demonstrates a small mass in the region of the second portion of the duodenum. The mass demonstrates central necrosis. A duodenal GIST was resected at surgery.
Figure 11. 55-year-old male with rectal bleeding. (A) Non contrast CT of the pelvis demonstrates a soft tissue rectal mass (B) Pet scan shows that the mass is metabolically active. At Surgery, a rectal GIST was resected.
Figure 12. 49-year-old female with history of epigastric pain and fullness. The patient is status-post partial gastrectomy in 02/01, which revealed a gastrointestinal stromal tumor. (A) Contrast enhanced CT of the abdomen and pelvis demonstrates loculated low- density cystic lesions in the left upper quadrant abutting the stomach and near the surgical clips. (A) C Cystic lesion is also noted in the right lobe of the liver. Exploratory surgery revealed recurrent gastrointestinal stromal tumor with liver metastases.