Published online before print April 15, 2005, 10.1148/radiol.2353040332
(Radiology 2005;235:892-898.)
© RSNA, 2005
Gastrointestinal Stromal Tumor: New Nodule-within-a-Mass Pattern of Recurrence after Partial Response to Imatinib Mesylate1
Sridhar Shankar, MD,
Eric vanSonnenberg, MD,
Jayesh Desai, MD,
Pamela J. DiPiro, MD,
Annick Van Den Abbeele, MD and
George D. Demetri, MD
1 From the Departments of Radiology (S.S., E.v.S., P.J.D., A.V.D.A.) and Adult Oncology (G.D.D.), Dana-Farber Cancer Institute, Harvard Medical School, Boston, Mass; and Department of Radiology, Brigham and Women’s Hospital, Boston, Mass (S.S., E.v.S., P.J.D., A.V.D.A.). From the 2002 RSNA Annual Meeting. Received February 27, 2004; revision requested May 5; revision received August 19; accepted September 8. Address correspondence to S.S., Department of Radiology, University of Massachusetts Medical Center, 55 Lake Ave North, Worcester, MA 01655 (e-mail: shankars@ummhc.org).
 |
ABSTRACT
|
|---|
PURPOSE: To investigate a new pattern of tumor recurrence observed at imaging in patients with metastatic gastrointestinal stromal tumor (GIST) after initial partial reponse to imatinib mesylate.
MATERIALS AND METHODS: Ninety-two patients with metastatic GIST who underwent treatment in a clinical trial with oral imatinib mesylate were followed up for 29 months. An institutional review board–approved protocol was used. The study complied with the Health Insurance Portability and Accountability Act, and written informed consent was obtained from all patients. Images of the chest, abdomen, and pelvis, acquired with computed tomography (CT), positron emission tomography (PET), and, in some cases, magnetic resonance imaging, were evaluated for treatment response and disease recurrence. Thirty-nine patients (29 men, 10 women; age range, 18–84 years; mean, 49.2 years) had recurrent disease after an initial variable period of response (range, 2–24 months; median, 14.4 months). Initial response was determined with findings of decreased uptake of fluorine 18 fluorodeoxyglucose at PET, shrinkage of tumor, and decreased attenuation at CT. Images were evaluated for disease recurrence by two experienced radiologists who were blinded to each other’s interpretation but not to clinical details. Final reading was performed by consensus.
RESULTS: A nodule within a mass was seen in 21 of 39 patients (in intrahepatic tumor [n = 8], extrahepatic tumor [n = 10], or both intra- and extrahepatic tumors [n = 3]) and was the first sign of disease progression in 17 of 21 patients. Other patterns of recurrence included new site of disease (n = 7), regrowth of preexistent lesion (n = 20), and mixed (more than one) pattern (n = 9). Disease progression was verified at needle biopsy (n = 16), follow-up imaging (n = 14), and/or surgical resection (n = 9).
CONCLUSION: A nodule within a mass is an important sign of recurrent GIST, but measurements of overall tumor size may not enable detection of such nodules.
© RSNA, 2005
|
INTRODUCTION
|
|---|
Gastrointestinal stromal tumor (GIST), while relatively rare, is the most common of the mesenchymal malignancies that may affect the gastrointestinal tract and represents approximately 1%–3% of all malignant gastrointestinal tumors (1). While the pathologic features of GIST were first described approximately 2 decades ago, a clear understanding of the pathophysiologic and molecular basis of this disease was achieved only in the past few years. GISTs express the cell-surface transmembrane receptor KIT, which has tyrosine kinase activity and is the protein product of the KIT proto-oncogene. Gain-of-function mutations of KIT are frequent in GIST. These mutations result in the constitutive activation of KIT signaling, which leads to uncontrolled cell proliferation and resistance to apoptosis. It has been reported that KIT activation occurs in all cases of GIST, regardless of the mutational status of KIT (1,2).
Unresectable or metastatic GIST is a fatal disease that resists conventional cytotoxic chemotherapy. In one patient series, the response rate to doxorubicin was less than 5% (3). The effectiveness of radiation therapy for this disease has not been proved. The median duration of survival for patients with a metastatic GIST is approximately 20 months, and that for patients with local recurrence is 9–12 months (2,4).
Technologic advances recently led to the development of a targeted molecular therapeutic agent, the receptor tyrosine kinase inhibitor imatinib mesylate (Gleevec; Novartis, New York, NY), formerly known as STI-571, which has been used as a systemic treatment for GIST (1,2).
In solid tumors, the progression of metastatic disease typically is heralded by the appearance of tumors in other sites and/or an increase in the size of preexistent lesions (5–10). Conversely and most commonly, a positive response to conventional chemotherapeutic agents is signaled by shrinkage of the tumor. When the effectiveness of chemotherapy decreases after an initial positive response, the tumor usually increases in size, and new sites of disease may appear.
Very little information is available in the literature about the appearance of GIST after treatment with imatinib mesylate. The purpose of this study was to investigate a new pattern of tumor recurrence observed at imaging in patients with metastatic GIST after initial partial response to imatinib mesylate.
|
MATERIALS AND METHODS
|
|---|
Study Group
Ninety-two consecutive patients (56 men, 36 women; age range, 18–86 years; median age, 47 years) with biopsy-proved metastatic GIST who were treated at our institution (Dana-Farber Cancer Institute, Harvard Medical School, Boston, Mass) with imatinib mesylate (clinical trial) were followed up prospectively over a period of 29 months. The study was performed by using an institutional review board–approved protocol and complied with the Health Insurance Portability and Accountability Act. Written informed consent was obtained from all patients. Follow-up was performed with clinical examination, routine blood analysis (complete and differential blood cell counts, electrolyte measurements, and liver function tests), and imaging. One of two clinical oncologists (J.D., G.D.D.) and a nurse practitioner performed clinical follow-up. G.D.D. is a consultant with and an occasional invited lecturer for Novartis and received research support from that company.
A total of 39 (42%) of 92 patients showed evidence of disease progression after an initial variable period of response to imatinib mesylate (range, 2–24 months; mean, 13.5 months; median, 14.4 months). This group included 29 men and 10 women with a mean age of 49.2 years (range, 18–84 years; median, 47 years). Of the 39 patients who experienced disease progression, all had purely abdominal disease at baseline (prior to initiation of imatinib mesylate therapy). Five of these patients had only extrahepatic disease, four had only intrahepatic disease, and 30 had both intra- and extrahepatic disease.
Image Acquisition
All patients underwent contrast material–enhanced computed tomography (CT) (Volume Zoom; Siemens, Erlangen, Germany) of the chest, abdomen, and pelvis. Sections with a thickness of 7 mm were acquired with a delay of 70 seconds after intravenous administration of 100 mL of ioxilan (Oxilan 300; Guerbet, Bloomington, Ind). Unenhanced scans were not routinely obtained, but follow-up in six patients included CT without intravenous contrast material for evaluation of intraabdominal bleeding or renal stone or when the creatinine level was elevated. All six patients underwent contrast-enhanced CT either immediately after unenhanced CT (n = 2) or at the next follow-up visit, which was within 6 weeks in all cases. CT scans were obtained approximately every 6 weeks, per the clinical drug trial protocol.
Positron emission tomography (PET) was performed by using a PET imager (ECAT Exact HR+; Siemens/CTI, Knoxville, Tenn). After patients fasted for 4 hours, they received an intravenous injection of 740 MBq (20 mCi) of fluorine 18 fluorodeoxyglucose (FDG). With a 45–60-minute delay after the injection, PET was performed from the base of the skull to the upper thighs by using a multiple-bed whole-body protocol. Standardized values for uptake were not used in this study. PET scans were obtained at 6–12-week intervals.
Magnetic resonance (MR) imaging (Signa; GE Medical Systems, Waukesha, Wis) of the liver was performed in 15 of 39 patients in whom percutaneous interventional therapy (radiofrequency ablation or cryoablation) was contemplated. If the interventional therapy was administered, the patients underwent follow-up MR imaging every 3 months afterward, in addition to the standard follow-up examination for monitoring of response. MR imaging included transverse T1-weighted spin-echo (repetition time msec/echo time msec, 600/14; section thickness, 4 mm; field of view, 34 cm), transverse T2-weighted fast spin-echo (5100/100; echo train length, 12; section thickness, 4 mm; field of view, 30 cm), and transverse fat-suppressed fast multiplanar spoiled gradient-echo (285/1.6; flip angle, 75°; section thickness, 5 mm; field of view, 34 cm) sequences applied before and after intravenous injection of 20 mL gadopentetate dimeglumine (Magnevist; Berlex Laboratories, Wayne, NJ).
Image Review and Evaluation
Two experienced radiologists (S.S. and E.v.S., with 10 and 28 years of experience, respectively, in cross-sectional imaging, and 3 and more than 10 years of experience, respectively, in cancer imaging) performed the measurements on CT scans by using electronic calipers at a picture archiving and communication system workstation (IMPAX; Agfa, Ridgefield Park, NJ). We ensured that the same lesion was evaluated on pretreatment and follow-up scans and that the measurement technique was uniform with respect to section selection and anatomic level. The radiologists were blinded to each other’s reading but were aware of both the underlying disease and the therapy. The final data compilation was performed by consensus. The radiologists specifically looked for enlargement or decrease in the size of lesions, changes in lesion attenuation, the presence of new lesions and/or new sites of involvement, and the appearance of nodules within preexistent lesions (a new pattern that we had observed).
Criteria.—A change of more than 25% in the bidimensional measurement (sum of length and width) of the tumor was classified as an increase or a decrease in size. A change of more than 20 HU in attenuation values, with assessment based on a mean of three different matched measurements, was considered substantial enough to be classified as decreased or increased attenuation, similar to observations by Chen et al (11). The presence of a lesion in a location where none was present on the previous CT scan was considered to indicate a new site of disease.
The presence of a new nodule within the preexistent mass was a new finding that we observed initially in some patients. We therefore reevaluated the images from all patients then enrolled in the study, to make sure that we had not missed this finding in any of them during the prospective evaluation of the images. After confirming that we had not missed the finding in any, we continued to prospectively seek this new pattern on images obtained in subsequent patients. The composition of the nodules was not specifically studied, but a subjective observation was made about the morphologic characteristics of the nodule (ie, whether the nodule was uniformly enhanced or showed a ringlike pattern of enhancement).
Images from all patients were evaluated for evidence of response to treatment and/or eventual progression of disease. Response to therapy was assessed for all lesions by using bidimensional tumor measurement (ie, the sum of the largest diameter and its orthogonal perpendicular) on contrast-enhanced CT scans. Initial response was defined as shrinkage of the tumor on CT scans, with a marked decrease (>20 HU) in CT attenuation values in the treated tumor (12). When available, MR images were also evaluated (for tumor location, appearance, and morphologic change) by the same two radiologists who reviewed the CT scans.
The PET scans were reviewed by a nuclear medicine physician (A.V.D.A.) with more than 10 years of experience in cancer imaging and PET and approximately 20 years of experience in nuclear medicine. Follow-up scans were reviewed qualitatively for interval changes in FDG uptake in comparison with that at baseline and on prior FDG PET scans.
A nodule within a mass on CT scans was defined as a new contrast-enhanced nodule within a nonenhanced tumor mass that previously had responded to treatment. These nodules were considered recurrent disease, not residual disease, because they were not present previously and appeared during the follow-up period within treated masses that had decreased in size and attenuation after therapy with imatinib mesylate. CT and PET images were analyzed for the presence of such nodules and to determine whether nodules were mural (ie, originated from the wall of the preexistent mass) or originated within the matrix (intramatrix), or central portion, of the preexistent tumor mass, as well as to evaluate the morphologic characteristics of nodules. Images were also analyzed for more conventional patterns of progression, including enlargement of preexistent lesions and presence of new lesions. For each CT examination, the images were reviewed independently by at least two of three radiologists (S.S., E.v.S., P.J.D.), and the final results were documented by consensus. Findings on PET images were correlated with CT findings by the nuclear medicine physician (A.V.D.A.) in collaboration with at least one of the three radiologists.
Documentation of nodules.—Verification of recurrent tumor in patients who exhibited the imaging pattern of a nodule within a mass was accomplished with percutaneous CT or ultrasonographic (US) image-guided fine-needle and/or core-needle biopsy, surgical resection, and/or concomitant or follow-up imaging with CT, MR, or PET.
Image comparisons.—The images from the six unenhanced CT studies were retrospectively compared (S.S., E.v.S., A.V.D.A.) with the contrast-enhanced scans obtained either at the same time or at the next follow-up session, for completeness. FDG PET images were subsequently compared with the CT scans by using a side-by-side display at the picture archiving and communication system workstation.
|
RESULTS
|
|---|
Patterns of Recurrence
The pattern of a nodule within a mass was present at imaging in 21 (54%) of 39 patients and was verified by means of fine-needle and/or core-needle biopsy in eight of 21, surgical excision in six of 21, and follow-up imaging in seven of 21. The appearance of such a nodule on CT and/or PET scans was the first sign of disease progression in 17 (81%) of 21 patients in whom such nodules were seen (17 [44%] of 39 patients with disease recurrence). Other patterns of recurrence included a new site of disease (seven [18%] of 39), regrowth of a preexistent lesion (20 [51%] of 39), and mixed pattern (more than one pattern of disease progression) (nine [23%] of 39) (Table).
Detection of a Nodule within a Mass
With regard to the pattern of a nodule within a mass, both radiologists identified the largest nodule on the CT scans, with a difference of opinion occurring only with regard to the presence of additional nodules. The nodules identified on CT scans were also identified on PET scans in 18 of 21 patients and on MR images in nine of 21 patients.
Distribution of Nodules
Among the 21 patients, a nodule within a mass was seen in intrahepatic tumors in eight (38%), in extrahepatic tumors in 10 (48%), and in both extra- and intrahepatic tumors in three (14%) patients (Fig 1). Mural nodules were seen in 12 of these 21 patients, and both intramatrix and mural nodules were seen in the other nine of 21 patients (Fig 2). No patient had clear evidence of an intramatrix nodule alone (without an accompanying mural nodule).
View larger version (134K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 1a. Patient 35. Metastatic GIST in 53-year-old man. (a) Transverse contrast-enhanced CT scan obtained prior to initiation of imatinib mesylate therapy shows three lesions (arrows) in the liver and a large mass in the left upper abdominal quadrant intimately associated with the stomach, with small areas of internal calcification. All lesions are heterogeneously enhanced. (b) PET projection image obtained prior to therapy shows large FDG-avid mass (straight arrow) in left upper quadrant of abdomen and smaller masses (curved arrow) in liver that correspond to lesions in a. (c) Transverse contrast-enhanced CT scan obtained 3 months after start of therapy shows shrinkage of tumors and decreased CT attenuation values in all lesions. (d) PET projection image obtained 2 months after start of therapy shows no discernible uptake of FDG in the left upper quadrant, a finding that signifies decreased metabolic activity. Metabolic activity in the hepatic masses also appears to have ceased. Normal uptake of FDG is seen in both renal collecting systems and the urinary bladder. (e) Transverse contrast-enhanced CT scan obtained 17 months after start of therapy demonstrates recurrent nodule (arrow) in extrahepatic mass after initial good response. (f) PET projection image obtained at the same time as e demonstrates new focal area of abnormal FDG uptake (straight arrow) that corresponds to nodule in e. A few smaller nodules (curved arrows) also are visible.
|
|
View larger version (61K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 1b. Patient 35. Metastatic GIST in 53-year-old man. (a) Transverse contrast-enhanced CT scan obtained prior to initiation of imatinib mesylate therapy shows three lesions (arrows) in the liver and a large mass in the left upper abdominal quadrant intimately associated with the stomach, with small areas of internal calcification. All lesions are heterogeneously enhanced. (b) PET projection image obtained prior to therapy shows large FDG-avid mass (straight arrow) in left upper quadrant of abdomen and smaller masses (curved arrow) in liver that correspond to lesions in a. (c) Transverse contrast-enhanced CT scan obtained 3 months after start of therapy shows shrinkage of tumors and decreased CT attenuation values in all lesions. (d) PET projection image obtained 2 months after start of therapy shows no discernible uptake of FDG in the left upper quadrant, a finding that signifies decreased metabolic activity. Metabolic activity in the hepatic masses also appears to have ceased. Normal uptake of FDG is seen in both renal collecting systems and the urinary bladder. (e) Transverse contrast-enhanced CT scan obtained 17 months after start of therapy demonstrates recurrent nodule (arrow) in extrahepatic mass after initial good response. (f) PET projection image obtained at the same time as e demonstrates new focal area of abnormal FDG uptake (straight arrow) that corresponds to nodule in e. A few smaller nodules (curved arrows) also are visible.
|
|
View larger version (139K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 1c. Patient 35. Metastatic GIST in 53-year-old man. (a) Transverse contrast-enhanced CT scan obtained prior to initiation of imatinib mesylate therapy shows three lesions (arrows) in the liver and a large mass in the left upper abdominal quadrant intimately associated with the stomach, with small areas of internal calcification. All lesions are heterogeneously enhanced. (b) PET projection image obtained prior to therapy shows large FDG-avid mass (straight arrow) in left upper quadrant of abdomen and smaller masses (curved arrow) in liver that correspond to lesions in a. (c) Transverse contrast-enhanced CT scan obtained 3 months after start of therapy shows shrinkage of tumors and decreased CT attenuation values in all lesions. (d) PET projection image obtained 2 months after start of therapy shows no discernible uptake of FDG in the left upper quadrant, a finding that signifies decreased metabolic activity. Metabolic activity in the hepatic masses also appears to have ceased. Normal uptake of FDG is seen in both renal collecting systems and the urinary bladder. (e) Transverse contrast-enhanced CT scan obtained 17 months after start of therapy demonstrates recurrent nodule (arrow) in extrahepatic mass after initial good response. (f) PET projection image obtained at the same time as e demonstrates new focal area of abnormal FDG uptake (straight arrow) that corresponds to nodule in e. A few smaller nodules (curved arrows) also are visible.
|
|
View larger version (73K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 1d. Patient 35. Metastatic GIST in 53-year-old man. (a) Transverse contrast-enhanced CT scan obtained prior to initiation of imatinib mesylate therapy shows three lesions (arrows) in the liver and a large mass in the left upper abdominal quadrant intimately associated with the stomach, with small areas of internal calcification. All lesions are heterogeneously enhanced. (b) PET projection image obtained prior to therapy shows large FDG-avid mass (straight arrow) in left upper quadrant of abdomen and smaller masses (curved arrow) in liver that correspond to lesions in a. (c) Transverse contrast-enhanced CT scan obtained 3 months after start of therapy shows shrinkage of tumors and decreased CT attenuation values in all lesions. (d) PET projection image obtained 2 months after start of therapy shows no discernible uptake of FDG in the left upper quadrant, a finding that signifies decreased metabolic activity. Metabolic activity in the hepatic masses also appears to have ceased. Normal uptake of FDG is seen in both renal collecting systems and the urinary bladder. (e) Transverse contrast-enhanced CT scan obtained 17 months after start of therapy demonstrates recurrent nodule (arrow) in extrahepatic mass after initial good response. (f) PET projection image obtained at the same time as e demonstrates new focal area of abnormal FDG uptake (straight arrow) that corresponds to nodule in e. A few smaller nodules (curved arrows) also are visible.
|
|
View larger version (139K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 1e. Patient 35. Metastatic GIST in 53-year-old man. (a) Transverse contrast-enhanced CT scan obtained prior to initiation of imatinib mesylate therapy shows three lesions (arrows) in the liver and a large mass in the left upper abdominal quadrant intimately associated with the stomach, with small areas of internal calcification. All lesions are heterogeneously enhanced. (b) PET projection image obtained prior to therapy shows large FDG-avid mass (straight arrow) in left upper quadrant of abdomen and smaller masses (curved arrow) in liver that correspond to lesions in a. (c) Transverse contrast-enhanced CT scan obtained 3 months after start of therapy shows shrinkage of tumors and decreased CT attenuation values in all lesions. (d) PET projection image obtained 2 months after start of therapy shows no discernible uptake of FDG in the left upper quadrant, a finding that signifies decreased metabolic activity. Metabolic activity in the hepatic masses also appears to have ceased. Normal uptake of FDG is seen in both renal collecting systems and the urinary bladder. (e) Transverse contrast-enhanced CT scan obtained 17 months after start of therapy demonstrates recurrent nodule (arrow) in extrahepatic mass after initial good response. (f) PET projection image obtained at the same time as e demonstrates new focal area of abnormal FDG uptake (straight arrow) that corresponds to nodule in e. A few smaller nodules (curved arrows) also are visible.
|
|
View larger version (78K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 1f. Patient 35. Metastatic GIST in 53-year-old man. (a) Transverse contrast-enhanced CT scan obtained prior to initiation of imatinib mesylate therapy shows three lesions (arrows) in the liver and a large mass in the left upper abdominal quadrant intimately associated with the stomach, with small areas of internal calcification. All lesions are heterogeneously enhanced. (b) PET projection image obtained prior to therapy shows large FDG-avid mass (straight arrow) in left upper quadrant of abdomen and smaller masses (curved arrow) in liver that correspond to lesions in a. (c) Transverse contrast-enhanced CT scan obtained 3 months after start of therapy shows shrinkage of tumors and decreased CT attenuation values in all lesions. (d) PET projection image obtained 2 months after start of therapy shows no discernible uptake of FDG in the left upper quadrant, a finding that signifies decreased metabolic activity. Metabolic activity in the hepatic masses also appears to have ceased. Normal uptake of FDG is seen in both renal collecting systems and the urinary bladder. (e) Transverse contrast-enhanced CT scan obtained 17 months after start of therapy demonstrates recurrent nodule (arrow) in extrahepatic mass after initial good response. (f) PET projection image obtained at the same time as e demonstrates new focal area of abnormal FDG uptake (straight arrow) that corresponds to nodule in e. A few smaller nodules (curved arrows) also are visible.
|
|
View larger version (137K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 2a. Metastatic GIST in patients with initial positive response to imatinib mesylate therapy. (a) Patient 38. Transverse contrast-enhanced CT scan obtained in 48-year-old woman 14 months after start of therapy shows a small enhanced mural nodule (arrow) within a larger low-attenuation mass. (b) Patient 17. Transverse contrast-enhanced CT scan obtained in 62-year-old man 8 months after start of therapy shows a small contrast-enhanced nodule (white arrow) within the matrix of a larger low-attenuation mass, as well as two metastatic lesions (curved black arrows) and an adjacent hemangioma (straight black arrow). (c) Patient 4. Transverse contrast-enhanced CT scan obtained in 42-year-old man 18 months after start of therapy shows a homogeneously enhanced nodule (arrow) within the matrix of a low-attenuation mass, as well as mural nodules in new sites.
|
|
View larger version (145K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 2b. Metastatic GIST in patients with initial positive response to imatinib mesylate therapy. (a) Patient 38. Transverse contrast-enhanced CT scan obtained in 48-year-old woman 14 months after start of therapy shows a small enhanced mural nodule (arrow) within a larger low-attenuation mass. (b) Patient 17. Transverse contrast-enhanced CT scan obtained in 62-year-old man 8 months after start of therapy shows a small contrast-enhanced nodule (white arrow) within the matrix of a larger low-attenuation mass, as well as two metastatic lesions (curved black arrows) and an adjacent hemangioma (straight black arrow). (c) Patient 4. Transverse contrast-enhanced CT scan obtained in 42-year-old man 18 months after start of therapy shows a homogeneously enhanced nodule (arrow) within the matrix of a low-attenuation mass, as well as mural nodules in new sites.
|
|
View larger version (113K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 2c. Metastatic GIST in patients with initial positive response to imatinib mesylate therapy. (a) Patient 38. Transverse contrast-enhanced CT scan obtained in 48-year-old woman 14 months after start of therapy shows a small enhanced mural nodule (arrow) within a larger low-attenuation mass. (b) Patient 17. Transverse contrast-enhanced CT scan obtained in 62-year-old man 8 months after start of therapy shows a small contrast-enhanced nodule (white arrow) within the matrix of a larger low-attenuation mass, as well as two metastatic lesions (curved black arrows) and an adjacent hemangioma (straight black arrow). (c) Patient 4. Transverse contrast-enhanced CT scan obtained in 42-year-old man 18 months after start of therapy shows a homogeneously enhanced nodule (arrow) within the matrix of a low-attenuation mass, as well as mural nodules in new sites.
|
|
Verification of Tumor Recurrence
When the nodules were initially identified on CT or PET scans, they were 2 mm to 1.4 cm in diameter. Tissue specimens obtained with percutaneous CT- or US-guided fine-needle and/or core-needle biopsy in eight of 21 patients and surgical excision in six of 21 patients showed evidence of tumor recurrence at histopathologic examination. Follow-up imaging with CT, MR, or PET demonstrated either interval enlargement of nodules within preexistent masses that were presumed to be dormant (on the basis of absence of metabolic activity on prior FDG PET scans or stability in size) and/or increased metabolic activity evidenced by new abnormal foci of uptake on FDG PET scans.
Size of Nodules
When nodules were initially identified, they were 2 mm to 1.4 cm in diameter. During the period of data collection, all nodules demonstrated growth, and some even enlarged to the size of the preexistent mass or engulfed it. All patients in whom initial images showed a nodule within a mass developed multiple nodules that increased in size over the period of data collection.
Imaging Appearance of Nodules
Nodules were not well visualized on unenhanced CT scans but were seen to enhance on the immediate postcontrast scan (n = 2) or the next follow-up postcontrast scan (n = 4), on which they demonstrated attenuation equal to that of the surrounding normal liver parenchyma. The enhancement of nodules was similar to that of the original tumor on the baseline scan (subjective observation) prior to the initiation of imatinib mesylate therapy.
MR images (obtained in nine of 21 patients) showed isointense to mildly hyperintense signal in the lesions, compared with signal intensity in normal liver parenchyma on T2-weighted images. The masses within which the nodules originated appeared hyperintense, with signal intensity similar to that of fluid. The signal in the nodules appeared isointense compared with signal intensity in liver parenchyma on unenhanced T1-weighted images, and the nodules demonstrated enhancement similar to that seen on postcontrast CT scans (Fig 3). The FDG PET images depicted new foci of increased FDG uptake in 18 of 21 patients; all of these lesions corresponded to nodules seen at CT. One of the patients did not undergo PET, and two of 21 patients had a negative PET scan. The diameters of the latter two lesions were 7 and 9 mm, respectively, on CT scans when the lesions were first seen.
View larger version (107K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 3a. Patient 33. MR images obtained 20 months after start of imatinib mesylate therapy in 46-year-old woman with initial positive response to therapy. (a) Transverse T2-weighted image (5100/100; echo train length, 12; section thickness, 4 mm; field of view, 30 cm) shows nodules (straight arrows) with signal intensity higher than that of liver, located within a larger mass (curved arrow) that has very high signal intensity similar to that of cerebrospinal fluid. (b) Transverse contrast-enhanced fat-suppressed spoiled gradient-echo image (285/1.6; flip angle, 75°; section thickness, 5 mm; field of view, 34 cm) demonstrates enhanced nodules (arrows) with signal intensity similar to, or slightly greater than, that of liver.
|
|
View larger version (107K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 3b. Patient 33. MR images obtained 20 months after start of imatinib mesylate therapy in 46-year-old woman with initial positive response to therapy. (a) Transverse T2-weighted image (5100/100; echo train length, 12; section thickness, 4 mm; field of view, 30 cm) shows nodules (straight arrows) with signal intensity higher than that of liver, located within a larger mass (curved arrow) that has very high signal intensity similar to that of cerebrospinal fluid. (b) Transverse contrast-enhanced fat-suppressed spoiled gradient-echo image (285/1.6; flip angle, 75°; section thickness, 5 mm; field of view, 34 cm) demonstrates enhanced nodules (arrows) with signal intensity similar to, or slightly greater than, that of liver.
|
|
There were subjectively noted morphologic differences on CT and MR images between nodules that originated in intrahepatic lesions and nodules that originated in extrahepatic lesions. The former appeared solid, with relatively homogeneous enhancement, while the latter tended to have a more ringlike enhancement pattern (Fig 4).
View larger version (111K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 4a. Morphologic change in extrahepatic nodules. (a) Patient 2. Transverse contrast-enhanced CT scan in 60-year-old man with nodular recurrence in left perinephric region shows nodule (straight arrow) with ringlike enhancement, in contradistinction to the uniform enhancement typically seen in intrahepatic nodules, and internal fluid-fluid level (curved arrow) suggestive of hemorrhage. (b) Patient 12. Transverse contrast-enhanced CT scan in 58-year-old woman shows recurrent nodules (arrows) with similar ringlike enhancement within perihepatic GIST.
|
|
View larger version (124K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 4b. Morphologic change in extrahepatic nodules. (a) Patient 2. Transverse contrast-enhanced CT scan in 60-year-old man with nodular recurrence in left perinephric region shows nodule (straight arrow) with ringlike enhancement, in contradistinction to the uniform enhancement typically seen in intrahepatic nodules, and internal fluid-fluid level (curved arrow) suggestive of hemorrhage. (b) Patient 12. Transverse contrast-enhanced CT scan in 58-year-old woman shows recurrent nodules (arrows) with similar ringlike enhancement within perihepatic GIST.
|
|
|
DISCUSSION
|
|---|
The pattern of tumor recurrence described here, the nodule within a mass, is a new imaging appearance that, to our knowledge, has not been reported previously. Our study results demonstrate that this finding indicates progression of disease. According to commonly accepted criteria, masses that are stable in size indicate no progression of disease. However, this new finding of enhancing nodules within stable masses was the first sign of disease progression in 17 of 21 patients with GIST that was treated successfully, at least initially, with imatinib mesylate. It is important to note that although the clinical protocol did not specify that the presence of a nodule indicated tumor progression, Southwest Oncology Group criteria were used in the study design, and the radiologists and clinicians therefore considered this finding a sign of recurrence.
Tumor measurement protocols used to assess response to therapy typically are based on the measurement of one dimension (as in the protocol developed by the Response Evaluation Criteria in Solid Tumors Group [12]) or two dimensions (as in the standard Southwest Oncology Group criteria [13]) on transverse CT images or involve the calculation of volume by using computer-assisted modeling (6,8,9,14,15). Because these techniques are predicated on external measurements of the lesion, the presence of a nodule within the mass would go undetected.
The development of imatinib mesylate represents one of the early and important innovations in molecular targeting of cancer with chemotherapy (1). Imatinib mesylate appears to selectively target cells that produce the mutant form of c-KIT. Experience with the imaging characteristics of tumor response to this class of drugs, many of which are in early stages of clinical development, is limited (1). The criteria for response to therapy have largely been modeled on previous experience with conventional cytotoxic chemotherapeutic agents. According to the results of our study, indicators of progression of disease during imatinib mesylate therapy may be tumor enlargement, new sites, and/or a new nodule within the mass.
It is interesting to compare findings at follow-up imaging after radiofrequency ablation of hepatic tumors with the findings after chemotherapy in GIST. After successful treatment with radiofrequency ablation, tumors do not shrink rapidly or disappear, as they do after treatment with cytotoxic chemotherapeutic agents; rather, they demonstrate a well-defined area that lacks contrast enhancement on CT scans or MR images (10), an appearance reminiscent of that in GIST after treatment with imatinib mesylate. Patterns of tumor recurrence after treatment have been extensively studied in the radiofrequency ablation literature (10,16–20); according to accepted criteria, a recurrent tumor is defined as a new focal area with contrast enhancement on CT or MR images and/or hyperintense signal on T2-weighted MR images and with nodularity or irregular thickening of the boundaries of the treated area (10). Recurrence after radiofrequency ablation is found only at the margins of the treated area and increases the overall size of the treated lesion (10,17,18), while the pattern of a nodule within a mass that we have seen in GIST does not increase the overall size of the mass because the recurrence lies completely within the measured area or volume.
Twenty patients (21%) with progressive disease in our series demonstrated an apparent global increase in size and enhancement of preexistent nonenhanced or hypoenhanced lesions without development of intratumoral nodules. While it is possible that this pattern may differ from that of the nodule within a mass, it is also possible that this global increase might represent a particularly aggressive variant of the nodule within a mass, one that grows rapidly, fills, and then expands the original tumor. Further studies with sequential and detailed imaging may better evaluate this speculation.
The appearance of a nodule within a mass on CT scans or of a new focal area of increased FDG uptake on PET scans is suggestive of disease recurrence even after a relatively long period of apparent quiescence characterized by no growth and low attenuation at CT and by lack of FDG uptake in the treated lesions after initial response to imatinib mesylate. New focal FDG uptake was seen in the majority (86%) of our patients and correlated with new nodules in masses on CT scans. The two patients who had negative PET scans may have had lesions with a size below the threshold for detection, as the nodules on the corresponding CT scans were smaller than 1 cm.
We speculate that the origin of this pattern of a nodule within a mass is due to the localized cloning of mutant tumor cells, followed by the development of resistance to c-KIT inhibition with imatinib mesylate. This impression is further strengthened by the appearance of some nodules as enlargements of a clone of mutated cells within the nonenhancing (and PET-negative) tumor matrix, in contradistinction to the appearance of mural nodules at the edge of the lesion, where, arguably, residual tumor cells might be expected to exist. Imatinib mesylate is a selective inhibitor of certain tyrosine kinases, among them the constitutively active tyrosine kinase in the cells of GISTs (1,2,21). Our speculation has been supported by experiments in human tumor-cell lines that are dependent on the KIT pathway. Exposure of these cells to imatinib mesylate blocked the kinase activity of KIT, arrested proliferation, and caused apoptotic cell death (22,23). Further studies to assess the mutations in these nodules are required to prove this point.
In several other studies (1,2,21) in which biopsy was performed in low-attenuation masses that appeared quiescent on images, reduced numbers of tumor cells were found at the baseline biopsy, and a hypocellular myxohyaline stroma with small numbers of scattered atypical nuclei and, frequently, prominent stromal hemorrhage were demonstrated. Frank necrosis of the tumor rarely was seen (2) even though the imaging appearance was suggestive of necrosis, with a marked decrease in contrast enhancement on CT scans and MR images and decreased uptake of the radiotracer on PET scans. The appearance of clonal nodules, therefore, is in keeping with the apparent mechanism of action of imatinib mesylate, in that the therapeutic agent does not induce substantial necrosis in the tumor.
Limitations of the study include the fact that pathologic proof was not available for every patient or for every lesion. In addition, the time intervals between imaging examinations slightly differed for some of the patients, and MR images were available only in a subset of patients with the finding of a nodule within a mass. Since nodules were detected initially only on CT scans, we do not believe that any bias was introduced because of the analysis of MR images.
In conclusion, several patterns of disease recurrence can be identified at imaging in patients with GIST after an initial positive response to imatinib mesylate treatment, and we report the pattern of a nodule within a mass, a finding that is important for the diagnosis of progressive disease because commonly accepted unidimensional, bidimensional, or volume measurements of tumor mass do not enable the detection of nodular recurrence.
|
ACKNOWLEDGMENTS
|
|---|
The authors are grateful to Amy Potter and Kristin Rancourt for assistance with the manuscript.
|
FOOTNOTES
|
|---|
Abbreviations: FDG = fluorine 18 fluorodeoxyglucose,
GIST = gastrointestinal stromal tumor
See Materials and Methods for pertinent disclosures.
Author contributions: Guarantors of integrity of entire study, S.S., E.v.S., G.D.D., A.V.D.A.; study concepts, S.S., E.v.S., J.D.; study design, S.S., J.D., E.v.S., G.D.D., P.J.D.; literature research, S.S., J.D., A.V.D.A., G.D.D.; clinical studies, all authors; data acquisition, S.S., J.D., E.v.S., P.J.D.; data analysis/interpretation, S.S., J.D., G.D.D., A.V.D.A., E.v.S.; statistical analysis, S.S., J.D.; manuscript preparation, definition of intellectual content, editing, revision/review, and final version approval, all authors
|
REFERENCES
|
|---|
- George S, Desai J. Management of gastrointestinal stromal tumors in the era of tyrosine kinase inhibitors. Curr Treat Options Oncol 2002; 3(6):489-496.[Medline]
- Demetri GD, von Mehren M, Blanke CD, et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. N Engl J Med 2002; 347:472-480.[Abstract/Free Full Text]
- Goss GA, Merriam P, Manola J, Singer S, Fletcher CD, Demetri GD. Clinical and pathological characteristics of gastrointestinal stromal tumors (GIST) (abstr) In: American Society of Clinical Oncology Program/Proceedings. Vol 19. Alexandria, Va: American Society of Clinical Oncology, 2000; 599a.
- DeMatteo RP, Lewis JJ, Leung D, Mudan SS, Woodruff JM, Brennan MF. Two hundred gastrointestinal stromal tumors: recurrence patterns and prognostic factors for survival. Ann Surg 2000; 231:51-58.[CrossRef][Medline]
- Hopper KD, Singapuri K, Finkel A. Body CT and oncologic imaging. Radiology 2000; 215:27-40.[Abstract/Free Full Text]
- Prasad SR, Jhaveri KS, Saini S, Hahn PF, Halpern EF, Sumner JE. CT tumor measurement for therapeutic response assessment: comparison of unidimensional, bidimensional, and volumetric techniques—initial observations. Radiology 2002; 225:416-419.[Abstract/Free Full Text]
- Saini S. Radiologic measurement of tumor size in clinical trials: past, present, and future. AJR Am J Roentgenol 2001; 176:333-334.[Free Full Text]
- Sohaib SA, Turner B, Hanson JA, Farquharson M, Oliver RT, Reznek RH. CT assessment of tumour response to treatment: comparison of linear, cross-sectional and volumetric measures of tumour size. Br J Radiol 2000; 73:1178-1184.[Abstract]
- Schwartz LH, Ginsberg MS, DeCorato D, et al. Evaluation of tumor measurements in oncology: use of film-based and electronic techniques. J Clin Oncol 2000; 18:2179-2184.[Abstract/Free Full Text]
- Dromain C, de Baere T, Elias D, et al. Hepatic tumors treated with percutaneous radio-frequency ablation: CT and MR imaging follow-up. Radiology 2002; 223:255-262.[Abstract/Free Full Text]
- Chen MY, Bechtold RE, Savage PD. Cystic changes in hepatic metastases from gastrointestinal stromal tumors (GISTs) treated with Gleevec (imatinib mesylate). AJR Am J Roentgenol 2002; 179:1059-1062.[Abstract/Free Full Text]
- Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 2000; 92:205-216.
- Green S, Weiss GR. Southwest Oncology Group standard response criteria, endpoint definitions and toxicity criteria. Invest New Drugs 1992; 10:239-253.[CrossRef][Medline]
- Dachman AH, MacEneaney PM, Adedipe A, Carlin M, Schumm LP. Tumor size on computed tomography scans: is one measurement enough? Cancer 2001; 91:555-560.[CrossRef][Medline]
- Miller AB, Hoogstraten B, Staquet M, Winkler A. Reporting results of cancer treatment. Cancer 1981; 47:207-214.[CrossRef][Medline]
- Solbiati L, Goldberg SN, Ierace T, et al. Hepatic metastases: percutaneous radio-frequency ablation with cooled-tip electrodes. Radiology 1997; 205:367-373.[Abstract/Free Full Text]
- Solbiati L, Ierace T, Goldberg SN, et al. Percutaneous US-guided radio-frequency tissue ablation of liver metastases: treatment and follow-up in 16 patients. Radiology 1997; 202:195-203.[Abstract/Free Full Text]
- Goldberg SN, Gazelle GS, Solbiati L, et al. Ablation of liver tumors using percutaneous RF therapy. AJR Am J Roentgenol 1998; 170:1023-1028.[Free Full Text]
- Gazelle GS, Goldberg SN, Solbiati L, Livraghi T. Tumor ablation with radio-frequency energy. Radiology 2000; 217:633-646.[Abstract/Free Full Text]
- McGahan JP, Dodd GD, 3rd. Radiofrequency ablation of the liver: current status. AJR Am J Roentgenol 2001; 176:3-16.[Free Full Text]
- George S, Desai J. Management of gastrointestinal stromal tumors in the era of tyrosine kinase inhibitors. Curr Treat Options Oncol 2002; 3:489-496.
- Heinrich MC, Griffith DJ, Druker BJ, Wait CL, Ott KA, Zigler AJ. Inhibition of c-kit receptor tyrosine kinase activity by STI 571, a selective tyrosine kinase inhibitor. Blood 2000; 96:925-932.[Abstract/Free Full Text]
- Tuveson DA, Willis NA, Jacks T, et al. STI571 inactivation of the gastrointestinal stromal tumor c-KIT oncoprotein: biological and clinical implications. Oncogene 2001; 20:5054-5058.[CrossRef][Medline]
This article has been cited by other articles:
|
|
|
|
 
C. Suzuki, H. Jacobsson, T. Hatschek, M. R. Torkzad, K. Boden, Y. Eriksson-Alm, E. Berg, H. Fujii, A. Kubo, and L. Blomqvist
Radiologic Measurements of Tumor Response to Treatment: Practical Approaches and Limitations
RadioGraphics,
March 1, 2008;
28(2):
329 - 344.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Desai, S. Shankar, M. C. Heinrich, J. A. Fletcher, C. D. Fletcher, J. Manola, J. A. Morgan, C. L. Corless, S. George, K. Tuncali, et al.
Clonal Evolution of Resistance to Imatinib in Patients with Metastatic Gastrointestinal Stromal Tumors
Clin. Cancer Res.,
September 15, 2007;
13(18):
5398 - 5405.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. H. I. Andtbacka, C. S. Ng, C. L. Scaife, J. N. Cormier, K. K. Hunt, P. W. T. Pisters, R. E. Pollock, R. S. Benjamin, M. A. Burgess, L. L. Chen, et al.
Surgical Resection of Gastrointestinal Stromal Tumors After Treatment with Imatinib
Ann. Surg. Oncol.,
January 1, 2007;
14(1):
14 - 24.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Kuehl, P. Veit, S. J. Rosenbaum, A. Bockisch, and G. Antoch
Can PET/CT Replace Separate Diagnostic CT for Cancer Imaging? Optimizing CT Protocols for Imaging Cancers of the Chest and Abdomen
J. Nucl. Med.,
January 1, 2007;
48(1_suppl):
45S - 57S.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. Wardelmann, S. Merkelbach-Bruse, K. Pauls, N. Thomas, H.-U. Schildhaus, T. Heinicke, N. Speidel, T. Pietsch, R. Buettner, D. Pink, et al.
Polyclonal Evolution of Multiple Secondary KIT Mutations in Gastrointestinal Stromal Tumors under Treatment with Imatinib Mesylate.
Clin. Cancer Res.,
March 15, 2006;
12(6):
1743 - 1749.
[Abstract]
[Full Text]
[PDF]
|
|
|
TOP
ABSTRACT
INTRODUCTION
