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Radiological case of the month: Felipe Martinez, MD; Joseph A. Galiardi, MD; Thomas D. Olsavsky, MD.

CASE SUMMARY

A 60-year-old African-American man presented to the emergency room complaining of mild abdominal pain and a sensation of "fullness" in the left upper quadrant (LUQ) for the prior month. The pain had increased 24 hours prior to admission. The patient also reported a weight loss of 10 to 15 pounds during the previous 3 months. Upon examination, his vital signs were normal, and, upon physical examination, a questionable mass was felt in the abdomen because of dullness in the LUQ. The results of the patient's stool guaiac test were positive, and the complete blood count and metabolic panel were normal except for mild anemia.

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IMAGING FINDINGS

Upon admission to the emergency room, a frontal supine radiograph of the abdomen was obtained, which was normal (Figure 1). A subsequent abdominal ultrasound revealed the presence of a 12 x 14-cm mass with cystic and solid components in the LUQ (Figure 2). A computed tomographic (CT) scan of the abdomen with intravenous contrast showed a large solid and cystic mass that was suspected to originate in the stomach with extension to the pancreatic bed. Multiple hypodense lesions in the liver were identified as possible metastases (Figure 3). A positron emission tomography (PET) scan was performed, which showed a peripheral hypermetabolic lesion in the LUQ, but no hepatic lesions were seen (Figure 4).

The patient underwent surgery, during which a 10-cm gastric mass was removed. Pathologic examination revealed it to be a gastrointestinal stromal tumor (GIST) that had originated in the stomach and was positive in the antibody study for VIM, CD 34, and CD 117 (kit protein).

DIAGNOSIS

Gastrointestinal stromal tumor originating in the stomach

DISCUSSION

Gastrointestinal stromal tumors are rare neoplasms that arise from mesenchymal cells of the gastrointestinal (GI) tract. They represent <3% of all GI tumors. Previously, they were described as benign or malignant tumors of the GI tract (such as leiomyomas, leiomyosarcomas, or leiomyoblastomas), but immunohistochemical studies proved them to be a different clinical entity.

Mazur and Clark (1) first introduced the term GIST in 1983, when they reported that many of the GI nonepithelial mesenchymal tumors lack the immunohistochemical and ultrastructural features of smooth muscle and neural cells. Currently, GISTs are defined as GI tract mesenchymal tumors containing spindle or epithelioid cells that mark positive for kit protein (CD 117). Kit protein is the product of the c-kit proto-oncogene, located on chromosome 4q11-21. This protein is a tyrosine-kinase growth factor receptor present in 90% of GIST cells. The CD 117 protein is located in the cell membrane of all cells expressing the kit proto-oncogene. The extracellular fraction is a receptor for the stem-cell growth factor, while the intracellular portion is a protein kinase that regulates phosphorylation of different signal molecules that results in cellular division, apoptosis, adhesion, actin reorganization, and chemotaxis. (2)

Mutation of the kit proto-oncogene results in a CD 117 receptor that is constantly stimulated without the presence of the stem-cell growth factor. Mutations in the exon 11 of the kit proto-oncogene are identified in at least 65% of GISTs and are correlated with most of the metastatic capabilities of these tumors. They are also more common in the spindle cell variant. Mutations in exons 9 and 13 have been associated with lower mitotic counts. Some of the GISTs that lack the kit mutation appear to have mutations in another Class III protein kinase gene that encodes the platelet-derived growth factor. (3)

It is now believed that GISTs arise from precursor GI cells that differentiate into the interstitial cells of Cajal. These are pacemaker cells within the GI tract wall that control the autonomous contractions of the gut. This hypothesis is based in the ultrastructural similarities of GIST and Cajal cells. Both types of cells express the CD 117 protein, but Cajal cells do not stain for CD 34 nor for other muscle cell antigens frequently seen in GIST cells. The typical GIST cell is recognized because of its expression of CD 117, CD 34, vimentin, and, rarely, smooth muscle actin. (4)

Usually, GISTs present in adults aged 50 to 60 years. Most frequently, they are solitary, well-circumscribed tumors with a pseudocapsule. Approximately 70% occur in the stomach, 20% in the small intestine, and 10% elsewhere in the GI tract (rectum, omentum, and peritoneum).

There is no known relation with gender, ethnicity, or occupation. It rarely presents in children or young adults, but when it does, an association with neurofibromatosis 1 and Carney's triad (gastric stromal tumor, extra-adrenal paraganglioma, and pulmonary chondroma) has been noted. (5)

The annual incidence is 15 per million and the prevalence is approximately 130 per million. The tumor usually grows parallel to the bowel loops and stomach, causing ulceration of the lumen only in late stages. This may explain why the median tumor size at diagnosis is 8 cm, but there are cases reported in which a tumor is as large as 40 cm. (2)

The clinical presentation of GISTs is variable and depends on the size and the organ involved. Most small tumors (<2 cm) are asymptomatic and are diagnosed as incidental findings during surgical procedures or imaging studies of an unrelated pathology. Abdominal pain and GI bleeding are the most common symptoms. The degree of bleeding varies from massive hematemesis to occult blood loss and is due to ulceration of the underlying mucosa by the tumor, which is usually large in size. Lesions that arise from the small bowel and the stomach usually present with bleeding, while lesions of the esophagus and rectum present with obstruction or altered bowel movements. (4)

Imaging studies are of significant importance in the evaluation and localization of known or suspected lesions. Radiography (with or without barium contrast) has little or no role in the evaluation of this type of lesion. Occasionally, large lesions with calcification or displacement of structures may raise the question of an underlying lesion. With transabdominal ultrasound, the tumor usually appears as a homogenous hypoechoic mass in close relation to the GI tract. Varying degrees of heterogeneity within the mass can be seen and correspond to necrotic and cystic changes.

CT imaging is useful in evaluating the size, location, and local invasion of the tumor and in evaluating metastases. Small tumors appear as smooth, sharply defined intramural masses with homogenous attenuation (similar to muscle) and with moderate contrast uptake. Large lesions tend to present as heterogeneous masses with irregular heterogeneous central areas (representing necrosis and cavitation) with enhancing peripheral borders that represent viable tumor. Tumors are usually well circumscribed, but invasion to neighboring organs or metastases are clearly signs of malignancy. CT is also very useful in the evaluation of metastases (especially to the liver), which show heterogeneous enhancement after intravenous contrast administration. Gastrointestinal stromal tumors rarely present with local lymph node invasion. When a large tumor presents with lymph node enlargement, lymphoma or adenocarcinoma is a more likely diagnosis. (6,7)

Magnetic resonance imaging usually gives no additional information beyond that which CT gives, except for tumors located in the anorectal region because of multiplanar information. Typically, the solid part of the tumor shows a low-to-intermediate signal intensity on T1-weighted images and a high signal intensity on T2-weighted images and enhances after gadolinium administration.8 Hemorrhagic changes within the tumor show low-to-high signal intensity on both T1- and T2-weighted images. (9)

Functional imaging can be more accurate than anatomical imaging when assessing metastases and response to treatment. Thus, PET that uses 18F-fluoro-2deoxyglucose has proven to be an excellent complementary study in the evaluation of these patients. Studies prove that PET and PET/CT are better than CT alone when evaluating therapeutic response. (8)

Surgical resection is the treatment of choice and, because these tumors lack a true capsule, en bloc resection with wide adjacent margins must be done. Lymph node resection is not indicated. The morbidity associated with the procedure depends on the organ location, invasion, and size of the tumor. Tumor rupture during the surgical procedure is associated with peritoneal recurrences due to seeding of peritoneal implants. Incomplete resection should be done only as a palliation of pain, bleeding, or mass effect. The use of conventional chemotherapy does not show significant changes in morbidity or mortality. Radiotherapy has not been studied in depth and previously was used only as a palliation method in selected cases. (4)

Imatinib mesylate (Gleevec, Novartis Pharmaceuticals Corporation, East Hanover, NJ), a protein kinase inhibitor, was approved by the Food and Drug Administration for treatment of these tumors in 2002 and appears to be the first effective systemic therapy for unresectable local tumors, recurrences, and metastases. Imatinib prevents protein-kinase proteins from transferring phosphates from adenosine triphosphate (ATP) to the tyrosine residues of its substrate by joining to the ATP-binding site of the enzyme. This prevents further downstream signaling, thus promoting reduced cellular proliferation and apoptosis.

Imatinib is well absorbed orally, and the dose varies from 400 to 800 mg/day. A serum concentration of 1 [micro]mol/L is considered necessary for adequate treatment. Reduction of >50% in tumor size has been described in two thirds of GIST patients with this therapy; in addition, at least 20% have shown stabilized disease, and 90% report relief of obstructive symptoms. (10) The ideal dose and duration of treatment are still under investigation and are being studied in randomized clinical trials. Positron emission tomography/ CT is reported to be a reliable tool for assessment of GIST response to therapy. (10)

The prognosis of these tumors is determined by the size and the mitotic count per 50 high-power fields (HPF) examined. In 2001, Fletcher et al (5) reported that tumors <5 cm with <5 mitoses/HPF have a very low risk of recurrence; tumors between 2 to 5 cm in size with <5 mitoses/ HPF have a low risk; those <10 cm with <5 mitoses/HPF have an intermediate risk; and tumors >10 cm or those with >10 mitoses/HPF are at high risk of recurrence (malignant).

Studies in Sweden have shown that <1% of patients with very-low-, low-, and intermediate-risk tumors die from GIST-related complications, while up to 80% of patients with high-risk tumors die from GIST-related conditions. When present, most recurrences appear within 3 years of surgical treatment. (2)

CONCLUSION

Gastrointestinal stromal tumors are rare neoplasms that arise from precursor GI cells that differentiate into the interstitial cells of Cajal. The most common site of origin is the stomach, followed by the small bowel. Different gene mutations have been associated, but the most frequent one occurs in the Kit proto-oncogene, resulting in a constantly stimulated CD 117 receptor. The clinical presentation varies depending on the site of origin and the size of the tumor. Surgical resection is the treatment choice for localized tumors. Imatinib mesylate has proven to be the first effective systemic therapy in cases of unresectable tumors or metastatic disease. Anatomic and functional imaging has proven to be helpful and complementary in the diagnosis and follow-up of patients with these tumors.

REFERENCES

(1.) Licht J, Weissmann L, Antman K. Gastrointestinal sarcomas. Surg Oncol. 1988;15:181-188.

(2.) Miettinen M, Lasota J. Gastrointestinal stromal tumor--Definition, clinical, histological, immunohistochemical and molecular genetic features and differential diagnosis. Virchows Arch. 2001;438(1):1-12.

(3.) Heinrich MC, Blanke CD, Druker BJ, Corless CL. Inhibition of KIT tyrosine kinase activity: A novel molecular approach to the treatment of KIT-positive malignancies. J Clin Oncol. 2002;20:1692-1703.

(4.) Joensuu H, Kindblom LG. Gastrointestinal stromal tumors-A review. Acta Orthop Scand Suppl. 2004;75:62-71.

(5.) Miettinen M, Sarlomo-Rikala M, Lasota J. Gastrointestinal stromal tumors: Recent advances in understanding of their biology. Human Pathol. 1999;30:1213-1220.

(6.) Lau S, Tam KF, Kam CK, et al. Imaging of gastrointestinal stromal tumor (GIST). Clin Radiol. 2004;59:487-498.

(7.) Levy AD, Remotti HE, Thompson WM, et al. Gastrointestinal stromal tumors: Radiologic features with pathologic correlation. Radio-Graphics. 2003;23:283-304, 456; quiz 532.

(8.) Antoch G, Kanja J, Bauer S, et al. Comparison of PET, CT and dual-modality PET/CT imaging for monitoring of imatinib (STI571) therapy in patients with gastrointestinal stromal tumors. J Nuc Med. 2004;45:357-365.

(9.) Hasegawa S, Semelka RC, Noone TC, et al. Gastric stromal sarcomas: Correlation of MR imaging and histopathological findings in nine patients. Radiology. 1998;208:591-595.

(10.) Demetri GD, von Mehern M, Blanke CD, et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med. 2002;347:472-480.

Prepared by Felipe Martinez, MD, Joseph A. Gagliardi, MD, and Thomas D. Olsavsky, MD, Department of Radiology, St. Vincent's Medical Center, Bridgeport, CT.
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Author:Martinez, Felipe; Gagliardi, Joseph A.; Olsavsky, Thomas D.
Publication:Applied Radiology
Date:Jul 1, 2006
Words:2096
Previous Article:Radiological case of the month: Douglas P. Beall, MD; Robert L. Emery, MD; Justin Q. Ly, MD; Thomas P. Jones, MD.
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