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Cystic Changes in Hepatic Metastases from Gastrointestinal Stromal Tumors (GISTs) Treated with Gleevec (Imatinib Mesylate)

¹ Department of Radiology, Wake Forest University School of Medicine, Medical Center Blvd., Winston-Salem, NC 27157-1088.
² Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27157-1088.

Received November 20, 2001; accepted after revision March 26, 2002.

 
Address correspondence to M. Y. M. Chen.

Abstract

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OBJECTIVE. The purpose of this article is to illustrate the CT findings in patients with hepatic metastases from a gastrointestinal stromal tumor who were treated with STI-571.

CONCLUSION. Hepatic metastases from gastrointestinal stromal tumors that respond to treatment with STI-571 can appear as near-cystic components with well-defined borders on contrast-enhanced CT. Most metastases became smaller. These metastases resemble simple cysts, but density measurements may differentiate them from one another.

Introduction

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Gastrointestinal stromal tumors (GISTs) are a distinct subset of mesenchymal tumors that arise from the gastrointestinal tract. Gastrointestinal stromal tumors are different from typical leiomyomas, leiomyosarcomas, and schwannomas both histologically and immunohistochemically. Metastases from gastrointestinal stromal tumors are often found in the liver and peritoneum. Surgical resection of a single metastasis is a possibility, but traditional chemotherapy and radiation have little impact on unresectable disease [1]. Recently, a clinical trial of STI-571 (Gleevec [imatinib mesylate]; Novartis, Basel, Switzerland), a first-generation tyrosine kinase inhibitor with high specificity for the c-kit protooncogene, was conducted on patients with unresectable metastases from gastrointestinal stromal tumors [1, 2]. We discuss four patients with hepatic metastases who received STI-571. Follow-up CT showed that all the hepatic metastases resembled cystic lesions after 8 weeks of treatment; in some patients, the overall size of the lesions was larger despite the cystic degeneration. To our knowledge, no report in the radiology literature discusses the effect of STI-571 on the CT appearance of metastatic lesions in the liver. We report these cases to illustrate that hepatic metastases responsive to Gleevec can resemble cysts.

Subjects and Methods

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From April 2001 to September 2001, four patients with unresectable hepatic metastases from gastrointestinal stromal tumors were enrolled in an approved varied-dose trial of STI-571 (4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]-animo]phenyl]benzaide methanesulfonate; Gleevec [imatinib mesylate]; Novartis, Basel, Switzerland). Demographic data are summarized in Table 1. The mean time between diagnosis of gastrointestinal stromal tumors and diagnosis of hepatic metastases was 14 months (range, 1-25 months). The length of treatment before initial followup scans were obtained was 8 weeks. No patients were withdrawn from the study because of unacceptable side effects.

All patients with a diagnosis of unresectable metastatic gastrointestinal stromal tumor who were selected to participate in this clinical trial had to follow a protocol with documented c-kit (CD117) expression. The protocol was approved by our institutional review board. All pathologic slides were reviewed to confirm the diagnosis.

All patients were randomly assigned to STI-571 at a dose of either 400 mg by mouth every day or 400 mg by mouth twice a day. Two patients received the once-daily dose of STI-571, and the other two patients received the twice-daily dose. The dose of 400 mg of STI-571 was administered orally with breakfast daily. The dose of 800 mg of STI-571 was administered orally twice daily, 400 mg with breakfast and 400 mg with dinner. The dose was not escalated, and no other cytoreductive medicine was administered during the study.

Each patient underwent baseline CT before starting the STI-571 trial and the first follow-up CT study after completing 8 weeks of STI-571 treatment. All CT studies, both before and after treatment, were obtained using a LightSpeed Advantage or CT/i scanner (General Electric Medical Systems, Milwaukee, WI). Oral contrast material—700 mL of diatrizoate meglumine (Gastroview; Mallinckrodt, St. Louis, MO)—was administered. A monophasic bolus of 125 mL of ioversol (Optiray 350; Mallinckrodt Medical) at a rate of 2 mL/sec was administered, and scanning was begun 55-70 sec after injection to coincide with the portal venous phase. Images were obtained using 1-sec scans, 5- or 7-mm-thick sections, and either the high-quality mode or a 2:1 pitch, depending on the scanner. The size and attenuation of all hepatic metastases were measured electronically. The trial is ongoing, and patients in this protocol are continuing to take STI-571.

Results

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The original locations of the gastrointestinal stromal tumors were in the stomach in three patients and in the omentum in one. All patients with gastrointestinal stromal tumors underwent laparotomy for surgical resection of the original lesion, but one tumor was found to be unresectable. Hepatic metastases in three patients that were shown on CT were confirmed by biopsy or exploratory laparotomy. A hepatic lesion in one patient was not biopsied.

Hepatic metastases on CT scans obtained before and after treatment were identified and compared. Eight hepatic metastases were measurable and are summarized in Table 1. After 8 weeks of treatment, all eight hepatic lesions and one soft-tissue abdominal mass in the left upper quadrant became cystic in appearance. The density of the hepatic metastases varied from 30 to 60 H (mean ± SD, 43 ± 12) before treatment (measured in six lesions) and from 21 to 29 H (mean, 24 ± 3) after treatment (measured in seven lesions) (p < 0.05, Student's t test), as shown in Table 1 and Figure 1A,1B. The appearance of the metastases was poorly defined and heterogeneous before treatment but became well defined and homogeneous after treatment. Many small hepatic metastases could not be measured. Six of eight hepatic metastases became smaller after treatment (Fig. 2A,2B,2C,2D). Two hepatic metastases remained the same or larger. We did not perform a comparison of radiologic findings between patients with low or high doses of STI-571 because of the limited size of our sample.

View larger version (112K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 1A. —53-year-old woman who had gastrointestinal stromal tumor of omentum 2 years earlier; metastasis was found in liver. Contrast-enhanced CT scan before STI-571 therapy shows 5x7 cm enhancing mass (arrow) at dome of liver. Mass was heterogeneous and peripherally enhanced.

View larger version (117K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 1B. —53-year-old woman who had gastrointestinal stromal tumor of omentum 2 years earlier; metastasis was found in liver. CT scan obtained after 8 weeks of treatment with STI-571 shows mass (arrow) becoming smaller (4.8 x 5.1 cm), with well-defined border, cystlike appearance (24 H), and no contrast enhancement.

View larger version (171K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 2A. —54-year-old man with unresectable gastrointestinal stromal tumor in stomach and hepatic metastases. CT scans before STI-571 therapy show 7.9 x 5.2 cm (33 H) and 4.1 x 4.5 cm (48 H) hypoattenuating metastatic lesions (arrows) at posterior aspect of right lobe of liver. Soft-tissue lesion (M in B) with mixed attenuation measuring 10.6 x 20.6 cm is also seen in left upper quadrant.

View larger version (156K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 2B. —54-year-old man with unresectable gastrointestinal stromal tumor in stomach and hepatic metastases. CT scans before STI-571 therapy show 7.9 x 5.2 cm (33 H) and 4.1 x 4.5 cm (48 H) hypoattenuating metastatic lesions (arrows) at posterior aspect of right lobe of liver. Soft-tissue lesion (M in B) with mixed attenuation measuring 10.6 x 20.6 cm is also seen in left upper quadrant.

View larger version (178K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 2C. —54-year-old man with unresectable gastrointestinal stromal tumor in stomach and hepatic metastases. CT scans obtained after 7 weeks of treatment with STI-571 show two hepatic lesions (arrows) that have decreased in size to 6.1 x 3.1 cm (21 H) and 3.6 x 4.1 cm (23 H). Mass (M in D) in left upper quadrant decreased to 6.6 x 14 cm and is cystlike in appearance.

View larger version (177K): [in this window] [in a new window] [as a PowerPoint slide]   Fig. 2D. —54-year-old man with unresectable gastrointestinal stromal tumor in stomach and hepatic metastases. CT scans obtained after 7 weeks of treatment with STI-571 show two hepatic lesions (arrows) that have decreased in size to 6.1 x 3.1 cm (21 H) and 3.6 x 4.1 cm (23 H). Mass (M in D) in left upper quadrant decreased to 6.6 x 14 cm and is cystlike in appearance.

Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Gastrointestinal stromal tumors are a subset of mesenchymal tumors that are different from neoplasms with neurogenic or smooth muscle origin. Gastrointestinal stromal tumors are located in the stomach (60%), the small bowel (30%), and elsewhere in the gastrointestinal tract (10%) [3]. Gastrointestinal stromal tumors occur predominantly in middle-aged and older persons at a median age of 50-60 years [3]. Gastrointestinal stromal tumors are composed of spindle (70%) and epithelioid (30%) cells. About 10-30% of these tumors are malignant and show intraabdominal spread or liver metastases.

All gastrointestinal stromal tumors express a mutant form of c-kit that is detectable by routine immunohistochemical staining with commercially available kits for CD117 [4]. All our patients were part of a clinical trial that required the presence of c-kit (CD117) using immunostaining antisera (Dako, Carpinteria, CA).

The malignant potential of gastrointestinal stromal tumors depends on their site of origin. Gastric gastrointestinal stromal tumors generally show benign behavior, but duodenal gastrointestinal stromal tumors may infiltrate the pancreas. Gastrointestinal stromal tumors in the small bowel have a high tendency for malignant behavior compared with those in the stomach. Tumor size and mitotic count do not correlate with the prognosis [5]. However, in general, tumors smaller than 2 cm with no mitotic count are at a low risk of metastasis, whereas tumors larger than 5 cm with high mitotic counts are likely to metastasize. The liver is the most common site (49%) of metastases [6]. In our series, three of the original four gastrointestinal stromal tumors arose from the stomach, but all metastasized to the liver. The recorded size of primary gastrointestinal stromal tumors ranges from 7.7 to 12 cm. Large primary gastrointestinal stromal tumor lesions are more likely to be malignant than small primary tumors.

CT is the most common modality used to assess hepatic metastases from gastrointestinal stromal tumors. The overall detection rate of hepatic metastases in all malignancies is 81-94% [7]. The accuracy of CT for detecting metastases depends on the technique used [7]. The CT appearance of metastases after the administration of IV contrast material generally correlates with the degree of tumor vascularity [8, 9]. On unenhanced CT, most lesions appear hypodense or isodense compared with adjacent parenchyma except retained hemorrhage, proteinaceous material, or calcifications. Low attenuation in the center of metastatic lesions often indicates central necrosis of a solid mass or that the lesion is cystic. The cystic component of these lesions may be heterogeneous and marked by an irregular and variable solid periphery. Most cystic metastases come from cystic primary neoplasms such as ovarian or cystic pancreatic malignancies; however, cystic metastases can rarely arise from noncystic primary neoplasms. Cystic hepatic metastases from endometrial carcinoma and leiomyosarcoma of the small bowel after chemotherapy have been reported in two of nine patients [10]. In our series, the density of hepatic metastases decreased to approximately 20-25 H, which is near to, but greater than, that for a true cyst (<15 H). This Hounsfield unit range may be helpful in differentiating true cysts from metastases after treatment with Gleevec. Sonography is an alternative modality for assessing hepatic cysts or cystic lesions, but we have no experience because at our institution we use CT for the routine workup of hepatic metastases.

The mechanism that induces cystic changes after STI-571 treatment is uncertain. Such radiologic changes are not a typical cancer response to conventional cytotoxic chemotherapy or radiation. Histologic examination of tumors treated with STI-571 showed that some tumors undergo myxomatous change, leaving small pyknotic nuclei in an eosinophilic myxoid background [1]. In a case report, the hepatic metastases from a gastrointestinal stromal tumor in a single patient became cystic in appearance on MR imaging after 4 weeks of Gleevec treatment, and the hepatic metastases became smaller after 8 months of treatment [2]. In our series, the borders of all hepatic metastases changed from poorly defined to well defined after 8 weeks of treatment with STI-571. In our experience, most hepatic metastases (from other primary cancers) that respond to therapy become smaller but remain poorly defined. In our study of these eight measurable hepatic metastases, six lesions appeared smaller after treatment and two lesions remained the same size.

In summary, STI-571 is a new therapy for patients with unresectable metastases from gastrointestinal stromal tumors. In our series, after a few weeks of treatment with STI-571, all hepatic metastases, whether hypodense or heterogeneous, exhibited near-cystic components with well-defined borders on contrast-enhanced CT. Most metastases became smaller. These metastases may superficially resemble simple cysts, but meticulous density measurements appear to differentiate the metastases from cysts. A limitation of our study is the small number of patients reviewed. However, a long-term follow-up, which is necessary to refine these observations and determine their histologic basis, is ongoing.

References

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1. Berman J, O'Leary TJ. Gastrointestinal stromal tumor workshop. Hum Pathol 2001;32:578 -582[Medline]
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3. Miettinen M, Sarlomo-Rikala M, Lasota J. Gastrointestinal stromal tumors: recent advances in understanding of their biology. Hum Pathol 1999;30:1213 -1220[Medline]
4. 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[Medline]
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6. Baker ME, Pelley R. Hepatic metastases: basic principles and implications for radiologists. Radiology 1995;197:329 -337[Free Full Text]
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9. Baron RL, Freeny PC, Moss AA. The liver. In: Moss AA, Gamsu G, Genant HK, eds. Computed tomography of the body with magnetic resonance imaging, 2nd ed. Philadelphia: Saunders, 1992: 735-821
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