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Imaging in gastrointestinal stromal tumours: current status and future directions
Clinical Radiology 65 (2010) 584–592
Contents lists available at ScienceDirect
Clinical Radiology journal homepage: www.elsevierhealth.com/journals/crad
Review
Imaging in gastrointestinal stromal tumours: current status and future directions R. Kochhar a, *, P. Manoharan a, M. Leahy b, M.B. Taylor a a b
Department of Radiology, The Christie NHS Foundation Trust, Manchester, UK Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK
article in formation Article history: Received 5 January 2010 Received in revised form 27 January 2010 Accepted 3 February 2010
Gastrointestinal stromal tumours (GISTs) have distinct biological and treatment-related features posing challenges for imaging. In this review the importance of imaging in different stages of patient management is discussed, emphasizing the unique characteristics of GISTs. Potential pitfalls of using the standard response criteria on conventional imaging have been highlighted. These include size measurements, which may not adequately reflect response rates, pseudoprogression, and spurious new lesions. Furthermore, the role of positron emission tomography/computed tomography (PET/CT) in early response evaluation and in the detection of both primary and acquired resistance is explored. The current role and future directions of use of both conventional and metabolic imaging in the management of GISTs are discussed. Ó 2010 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
Introduction Gastrointestinal stromal tumours (GISTs) are rare, softtissue sarcomas representing around 0.1–3% of all gastrointestinal (GI) cancers and 5.7% of sarcomas.1,2 GISTs are, however, the most common mesenchymal tumours of the GI tract1 with an estimated annual incidence of around 15 per million or approximately 900 new cases per year in the UK. Historically, GISTs were considered to be of smooth muscle origin and were classified as leiomyomas (benign) or leiomyosarcomas (malignant); however, they are now recognized as a biologically distinct tumour type. GISTs differ from the other mesenchymal neoplasms histopathologically as nearly all (90%) display a strong immunohistochemical staining for KIT (a tyrosinase kinase growth factor receptor).3 GISTs have a peak age incidence at 50–60 years of age, with a slight male predominance.4 These can arise anywhere in the gastrointestinal tract (from the oesophagus to the * Guarantor and correspondent: Department of Radiology, The Christie NHS Foundation Trust, Wilmslow Road, Manchester M20 4BX, UK. Tel.: þ44 161 4463053; fax: þ44 161 4463827. E-mail address: [email protected] (R. Kochhar).
rectum), with the majority arising in the stomach (60–70%) or small intestine (20–30%), and infrequently in the oesophagus, mesentery, omentum, colon, or rectum (5%).5 Surgery is the preferred primary treatment for the organconfined GISTs. The management of GISTs in recent years has been revolutionized by molecularly targeted therapeutic agents, such as imatinib mesylate (a selective tyrosinase kinase inhibitor). Prior to the introduction of imatinib, there was no effective treatment for unresectable and metastatic GISTs. Imatinib is an established effective and well-tolerated oral treatment for GISTs and should be considered the standard of care in non-surgical patients with nearly 84% of patients deriving clinical benefit from therapy.6 Imaging plays a major role in the detection, characterization, staging, and postoperative surveillance of GISTs, and has a key role in assessing response to treatment. For optimum treatment of this tumour type, a multidisciplinary team (MDT) with an experience with GISTs should oversee the management. The Christie NHS Foundation Trust is a tertiary referral centre for GISTs, treating about 50 new patients each year and with this review we share our experience of the role of imaging in the management of GISTs.
0009-9260/$ – see front matter Ó 2010 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.crad.2010.02.006
R. Kochhar et al. / Clinical Radiology 65 (2010) 584–592
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Imaging for detection, diagnosis, and characterization Imaging of GISTs depends on the mode of presentation and the local availability. Endoscopic ultrasound (EUS) and computed tomography (CT) are the most widely used imaging methods. EUS, if available, is a valuable imaging technique for diagnosing small (<2 cm), incidentally detected submucosal GISTs which are often difficult to identify on endoscopy alone, as the overlying mucosa is often normal. The high frequencies used in EUS clearly delineate the gut wall layers and also allow for biopsy confirmation, where appropriate. However, due to a small field of view, EUS has limited use in larger masses as it may underestimate the disease extent. For larger tumours (>5 cm) and where the patient presents with haemorrhage, abdominal pain, or obstruction, CT is the investigation of choice. GISTs have a wide spectrum of radiological appearances depending on tumour size and site of origin, but can be broadly fitted into one of three patterns; intraluminal, extraluminal, and dumbbell type. Small GISTs appear on CT as sharply margined, smooth walled, homogeneous, softtissue masses with moderate contrast enhancement. More typically, GISTs are seen as large, well-demarcated, extraluminal tumours, arising from the digestive tract wall, and show certain key radiological features, such as heterogeneous enhancement with central necrosis, cavitation, and fistula formation, seen as gas in the tumour.5 Focal areas of low attenuation on CT in small GISTs represent varying pathological conditions including solid tumour, haemorrhage, haemorrhage with necrosis, cystic degeneration, fluid in ulcers, and fibrous septae, and do not predict malignant potential.7 Large tumours can also have a ‘‘dumbbell-like’’ appearance, with masses protruding both into the lumen and growing exophytically from the serosa of the bowel wall (Fig. 1). In addition to defining the presence and nature of a mass, the likely organ of origin should be defined, which is facilitated by multiplanar reconstruction on multidetector CT.8
Figure 1 Primary GIST with dumbbell-type morphology. Axial, contrast-enhanced CT demonstrates a large, solid, lobulate mass with both intraluminal and exophytic components related to the stomach with central low attenuation (arrow), consistent with a typical morphology for gastric GIST.
Although the risk of metastases is highest in large tumours with a high mitotic index, small tumours with low mitotic activity may still metastasize, making it difficult to predict malignant potential.13 The criteria for postoperative risk assessment of relapse of GISTs were proposed by consensus at a National Institute of Health workshop, and are based on tumour size and the mitotic count; the two most important predictors of progression.3 However, tumour location is also an independent predictor of risk and its inclusion as a predictor of progression is helpful to optimize the management of GISTs.14,15 Tumours that arise in the stomach tend to have a less aggressive behaviour compared with other GISTs, but approximately 50% will have metastasized by the time of presentation.16 The
Imaging for pre-operative staging and post-operative surveillance of GISTs All GISTs have malignant potential, with up to 30% being frankly malignant, and accurate preoperative CT assessment is essential to identify resectable disease. The clinical diagnosis is based on imaging, as biopsy runs the risk of tumour rupture or seeding of the biopsy tract, in an otherwise resectable disease.9 CT is used to assess the primary tumour extension, local invasion, and the presence of metastases.10 Tumour size is a factor in predicting the metastatic risk, but the heterogeneity of large tumours does not reliably predict the behaviour or malignant potential of GISTs.11 The main sites of metastasis are the liver2 and the peritoneal cavity, including the omentum and the mesentery (Fig. 2). Rarely, GISTs metastasize to the lymph nodes, bones, lungs, or to the subcutaneous tissues.12
Figure 2 Metastatic GIST with complicated hepatic metastases. Axial, contrast-enhanced CT demonstrates multiple hepatic metastases in both lobes of the liver, several of these demonstrate a fluid–fluid level (arrow heads) likely due to internal haemorrhage, a known complication of GISTs. Note also the primary gastric GIST (arrow) showing internal calcific areas likely secondary to treatment.
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postoperative risk assessment criteria and the follow-up schedule for organ-confined operable GISTs used at our institute are detailed in Figs. 3 and 4. In all cases, if the patient develops new symptoms, an early CT examination may be appropriate, and in intermediate and high-risk patients, the follow-up should be prolonged, as these tumours may even recur several years after an apparently curative resection. In patients with an unresectable primary tumour or metastatic disease at presentation, biopsy confirmation is essential before starting therapy with imatinib. Histopathologically, the diagnosis of GISTs is supported by positive CD117 (KIT) staining as part of an immunohistochemical panel in a spindle cell tumour of the GI tract when morphological and clinical features of the tumour are consistent with GISTs.
Imaging for response assessment of treated GISTs Figure 3 Postoperative assessment of risk of relapse. M, mitotic figures; hpf, high power field; int, intermediate; V, very.
Targeted molecular therapy using imatinib (a selective tyrosinase kinase inhibitor) is now established as the standard of care for treating KIT-positive, inoperable, and metastatic GISTs. A recent trial has shown that after the
Figure 4 Follow-up schedule in organ-confined operable GISTs.
R. Kochhar et al. / Clinical Radiology 65 (2010) 584–592
Figure 5 Histopathologic appearances (haematoxylin and eosin stain, 400) of primary and post-treatment GISTs. A pre-treatment biopsy specimen (a) reveals a cellular lesion with frequent mitotic figures. After 6 weeks of imatinib treatment histopathological examination now demonstrates large areas of predominant myxoid degeneration (b).
resection of primary GISTs, adjuvant imatinib therapy is safe and improves recurrence-free survival as compared with the placebo.17 Following treatment with imatinib, extensive fibrosis, myxoid degeneration, and a few scattered, nonproliferating CD117-positive cells replace the abundant, frequently mitotic, GIST cells, indicative of a good response to treatment (Fig. 5).18 This mode of response is unique to GISTs and has to be borne in mind when imaging is used for the response assessment.
Response assessment on CT CT is still the most commonly used imaging method for response assessment. Response to therapy on CT has been traditionally assessed by RECIST (Response Evaluation Criteria in Solid Tumours) criteria and is classified as stable disease, disease progression, partial response or complete response, based on the changes in size of the marker and non-marker lesions.19,20 It is important to note that the RECIST criteria may not apply to GISTs or may only apply after many months of
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treatment.21 This is because the initial response after treatment with imatinib is often seen as a cystic change due to myxoid degeneration, which causes tumour liquefaction corresponding to a change in density on CT (measured using Hounsfield units) rather than a change in the size.22 The RECIST criteria are solely based on size, and therefore, substantially underestimate the effect of imatinib on metastatic GISTs, especially at the early stage of treatment. Modified CT response assessment criteria, known as the Choi criteria, have been proposed. These use a combination of the tumour density (>15% reduction) and the modified tumour size (>10% reduction).23 The Choi criteria correlate well with a good response by positron emission tomography (PET) and are more sensitive and precise than the RECIST criteria in assessing the response of GISTs to imatinib and time to tumour progression.21 Potential pitfalls on the post-treatment follow-up CT in the presence of a clinically documented response include cystic change with an increase in the size of lesions (Fig. 6) and the development of spurious new lesions (Fig. 7). On pre-treatment portal venous-phase CT, the metastatic hepatic lesions may be isodense to the surrounding liver parenchyma and thus, difficult to visualize. These lesions may become hypodense and clearly visible on follow-up CT when undergoing myxoid degeneration in response to treatment, and should not be misinterpreted as new lesions or disease progression.22,24 The CT technique can be critical and a combination of unenhanced and enhanced CT, possibly using a triphasic dynamic technique may be necessary on baseline and follow-up CT, for accurate evaluation of the tumour response.25 Stable disease implies no significant change in tumour size or density.26 Disease progression is further classified into limited and generalized progression. Limited progression is described as the development of enhancing tumour nodules within the treated hypoattenuating tumour, regardless of changes in tumour size, and is consistent with GIST recurrence (Fig. 8).27 Identifying an intratumoural nodule within the treated GIST is a unique and important imaging finding in recurrent GISTs. General progression includes an increase in the tumour size and density in two or more masses or development of new lesions.28 The timing of CT examinations after initiating treatment is variable. We advocate an initial CT as early as 6 weeks, followed by examinations performed at 3 monthly intervals. Early detection of the tumour response ensures effective therapy, whilst stable disease or even tumour progression may require an increase in the dosage of imatinib.26 Stable disease with symptomatic benefit is as important clinically as traditionally measured response. Treatment with imatinib should be continued until there is radiological and/or symptomatic progression. The role of surgery in patients who have responded to imatinib is contentious, but it should be considered in patients who have previously been viewed as inoperable, but have shown a good response to imatinib and are now suitable for potentially curative total surgical resection.
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Response assessment on 2- [18F]-fluoro-2-deoxy-Dglucose (FDG)-PET/CT There are several potential advantages of monitoring tumour response in GISTs using FDG-PET/CT; both the anatomic and the functional tumour evaluation are performed in the same sitting. The metabolic response detected by FDG-PET/CT precedes the anatomic response in GISTs treated with molecularly targeted drugs, such as imatinib mesylate. The metabolic response can be observed as early as 24 h following the administration of a single dose of imatinib, whereas conventional objective response criteria
Figure 6 Pitfalls of response assessment showing increase in size but with cystic change. Axial, contrast-enhanced CT (a) demonstrates an exophytic gastric GIST with soft-tissue elements (short arrow) and multiple hepatic metastases. The largest hepatic lesion demonstrates a fluid–fluid level (long arrow). (b) Follow-up CT 3 months posttreatment with imatinib demonstrates that both the primary GIST (short arrow) and the hepatic metastases (long arrow) have increased in size suggesting disease progression on conventional RECIST criteria. The lesions, however, now show predominant cystic attenuation and this is in keeping with treatment response despite the slight increase in size. (c) Follow-up CT at 6 months post-treatment demonstrates that the cystic change is maintained and now there is a decrease in size of both the gastric GIST (short arrow) and the hepatic metastases (long arrow) in keeping with continued response to treatment. Decrease in size can occur several months after cystic change limiting early response assessment by standard RECIST criteria.
Figure 7 Pitfalls of response assessment with development of spurious new liver lesions. Axial, contrast-enhanced CT (a) in the portal venous phase demonstrates an exophytic gastric GIST and unremarkable appearances of the liver. Follow-up post-imatinib treatment CT at 3 months (b) demonstrates multiple apparently new hypodense hepatic lesions (arrow heads) and a decrease in size of the primary gastric GIST (arrow). Findings are in keeping with a partial response to treatment despite the spurious new hepatic lesions. This should not be misinterpreted as disease progression as these appearances are due to post-treatment cystic change, which makes the hepatic lesions visible on the portal venous phase images; the lesions were previously isodense and apparently not seen.
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based on tumour size measured by CT, lag weeks or months behind.29,30 FDG-PET/CT is most useful for evaluating early response. A baseline examination should always be obtained prior to initiating treatment, as approximately 20% of the lesions shown on CT do not display appreciable glucose uptake on the pre-treatment FDG-PET/CT, and in such cases, FDG-PET/ CT cannot be used to evaluate treatment response. Response on FDG-PET/CT is characterized by a dramatic decrease in the glycolytic metabolism of GISTs. The degree of FDG uptake can be quantified using the maximal standardized uptake value for a particular region of interest (SUVmax). The European organization for research and treatment of cancer (EORTC) guidelines suggest that a 25% reduction in SUVmax should be
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considered as the threshold for partial metabolic response.31 Patients who achieve an absolute value for SUVmax of 2.5 in their tumours 1 month after starting treatment have a better tumour-free survival.32 FDG-PET/CT should also be performed when CT findings are inconclusive or are inconsistent with the clinical presentation.22 FDG-PET/CT is helpful in resolving ambiguous findings on CT when CT findings may suggest tumour growth, when the increase in size is actually related to intratumoural bleeding or to tumour swelling unrelated to progressive disease. In both cases, FDG-PET/CT will be negative, whereas the viable tumour will be FDG-avid.32 In addition to detecting early response, FDG-PET/CT performed soon after treatment may identify patients with a primary resistance to the drug who will not benefit from this therapy, and for whom alternative treatment should be considered. FDG-PET/CT is useful in clinical trials for the assessment of patients treated with new drugs (Fig. 9), and in selection of optimal dose for therapy.33 FDG-PET/CT can also aid in the identification of secondary or acquired resistance demonstrated by a re-emergence of metabolic activity within tumour sites after a period of an initial therapeutic response. Termination of imatinib therapy in patients with progressive disease (imatinib refractory GISTs), may also result in a ‘‘flare’’ phenomenon, suggesting that some progressing tumours may still have cell populations sensitive to imatinib.32 Imaging with combined FDG-PET/CT now has an increasing role for the optimal management of this group of malignancies.
Detection of tumour and treatment-related complications
Figure 8 Limited disease progression in GISTs with a nodule-withina mass pattern. Axial, contrast-enhanced CT (a) demonstrates a predominantly low-density mass in the left supracolic omental region (arrow) with focal calcific areas in a patient taking imatinib for metastatic GIST. Follow-up CT (b) after 3 months demonstrates the development of a new, enhancing, solid nodule in the inferior portion of the previously noted supracolic omental mass (arrow), which otherwise has shown no significant change in size, in keeping with limited disease progression.
GISTs, especially in their early stages are usually asymptomatic, and they often go unrecognized until severe symptoms ensue, which can create surgical emergencies. These symptoms mainly depend on the size and the location of the tumour, with lesions distal to the ligament of Treitz having a tendency to present with either bleeding or obstruction. GISTs tend to grow in an extraluminal fashion; however, they can also erode into the lumen of the gastrointestinal tract inducing significant haemorrhage or anaemia from occult bleeding. They can also rupture into the peritoneal cavity causing significant haemorrhage. In addition to symptoms from mass effect or bleeding, GISTs can cause intussusception or rarely, intestinal obstruction.34 Imatinib mesylate is generally well tolerated; the more common toxicities include oedema, nausea, diarrhoea, myalgia, fatigue, skin rash, haemorrhage, and occasionally neutropenia.35 We have encountered a case of imatinibinduced neutropenia presenting with typhlitis, which resolved on cessation of imatinib with normalization of the neutrophil count. Less common toxicities include respiratory complications, mainly in the form of dyspnoea and cough, documented in approximately 10% of patients and mostly attributed to pulmonary oedema.36 In addition, interstitial lung disease is now recognized as a distinct toxic effect of imatinib mesylate treatment.37 Timely cessation of drug results in resolution of changes. As the use of targeted
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therapy becomes more prevalent, treatment-related complications will be more commonly encountered and the radiologist needs to be aware of them to avoid misinterpretation of imaging findings.
Future directions CT is currently the most commonly used technique in the diagnosis, response assessment, and monitoring of
GISTs. The limitations of using standard RECIST criteria for monitoring response on CT to targeted molecular therapies must be kept in mind. The Choi criteria are objective criteria that are promising in early response evaluation and have an excellent prognostic value; the potential limitations being the high observer variations in placing regions of interest to assess density changes, and these criteria still need further validation in larger populations.
Figure 9 Response assessment on PET/CT. Baseline PET/CT image (a) performed in a patient with a metastatic GIST to assess response to a clinical trial drug after second-line treatment failed to show response. High-grade FDG uptake is seen in a primary small bowel GIST (short arrows) and also in the hepatic metastases. Four-week follow-up PET/CT (b) demonstrates persistent high-grade uptake in the primary tumour (short arrows) and in several new hepatic lesions (long arrows). Findings are in keeping with progressive disease.
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Studies have also shown potential advantages of using volumetric analysis for early response assessment.38 The potential of using dual-energy CT with virtual unenhanced and iodine only images and overlay CT numbers as a marker for monitoring therapy in patients with advanced GISTs is another exciting development.39 Although semi-automatic tumour volumetry and dualenergy CT for response assessment are exciting tools, they are still being evaluated and are not in routine clinical use. Subjective evaluation using a combination of changes in tumour size, number, density, presence of enhancing nodules and tumour vessels, is currently the best way to assess response by CT.40 FDG-PET/CT does have advantages over conventional CT imaging alone for the diagnostic and therapeutic management of patients with GISTs, and there is an argument in favour of its introduction as a routine diagnostic tool.41 However, in our experience, in the majority of patients, response assessment can be accurately performed with clinical evaluation and routine CT imaging. Although the use of PET/CT is certain to increase, currently, its main value is in early response assessment, for problem-solving in cases with equivocal CT and clinical findings, and in clinical trials to evaluate new drugs in patients with primary or secondary resistance to imatinib.
Conclusion A correct histological diagnosis, careful staging, accurate post-operative assessment, and detection of tumour response to treatment, are all crucial in the management of patients with GISTs. Imaging plays an integral role in all these stages and optimized criteria must be defined to assess response to therapy for both anatomic and functional imaging methods.
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10. Joensuu H, Fletcher C, Dimitrijevic S, et al. Management of malignant gastrointestinal stromal tumours. Lancet Oncol 2002;3:655–64. 11. Levy AD, Remotti HE, Thompson WM, et al. Gastrointestinal stromal tumors: radiologic features with pathologic correlation. RadioGraphics 2003;23:283–304. 456; quiz 532. 12. DeMatteo RP, Lewis JJ, Leung D, et al. Two hundred gastrointestinal stromal tumors: recurrence patterns and prognostic factors for survival. Ann Surg 2000;231:51–8. 13. Dematteo RP, Heinrich MC, El-Rifai WM, et al. Clinical management of gastrointestinal stromal tumors: before and after STI-571. Hum Pathol 2002;33:466–77. 14. Dematteo RP, Gold JS, Saran L, et al. Tumor mitotic rate, size, and location independently predict recurrence after resection of primary gastrointestinal stromal tumor (GIST). Cancer 2008;112:608–15. 15. Miettinen M, Lasota J. Gastrointestinal stromal tumors: pathology and prognosis at different sites. Semin Diagn Pathol 2006;23:70–83. 16. King DM. The radiology of gastrointestinal stromal tumours (GIST). Cancer Imaging 2005;5:150–6. 17. Dematteo RP, Ballman KV, Antonescu CR, et al. Adjuvant imatinib mesylate after resection of localised, primary gastrointestinal stromal tumour: a randomised, double-blind, placebo-controlled trial. Lancet 2009;373:1097–104. 18. Joensuu H, Roberts PJ, Sarlomo-Rikala M, et al. Effect of the tyrosine kinase inhibitor STI571 in a patient with a metastatic gastrointestinal stromal tumor. N Engl J Med 2001;344:1052–6. 19. 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;92:205–16. 20. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228–47. 21. Benjamin RS, Choi H, Macapinlac HA, et al. We should desist using RECIST, at least in GIST. J Clin Oncol 2007;25:1760–4. 22. Hong X, Choi H, Loyer EM, et al. Gastrointestinal stromal tumor: role of CT in diagnosis and in response evaluation and surveillance after treatment with imatinib. RadioGraphics 2006;26:481–95. 23. Choi H, Charnsangavej C, Faria SC, et al. Correlation of computed tomography and positron emission tomography in patients with metastatic gastrointestinal stromal tumor treated at a single institution with imatinib mesylate: proposal of new computed tomography response criteria. J Clin Oncol 2007;25:1753–9. 24. Linton KM, Taylor MB, Radford JA. Response evaluation in gastrointestinal stromal tumours treated with imatinib: misdiagnosis of disease progression on CT due to cystic change in liver metastases. Br J Radiol 2006;79:e40–e44. 25. Blay JY, Bonvalot S, Casali P, et al. Consensus meeting for the management of gastrointestinal stromal tumors. Report of the GIST Consensus Conference of 20-21 March 2004, under the auspices of ESMO. Ann Oncol 2005;16:566–78. 26. 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 Nucl Med 2004;45:357–65. 27. Shankar S, vanSonnenberg E, Desai J, et al. Gastrointestinal stromal tumor: new nodule-within-a-mass pattern of recurrence after partial response to imatinib mesylate. Radiology 2005;235:892–8. 28. Ryu MH, Lee JL, Chang HM, et al. Patterns of progression in gastrointestinal stromal tumor treated with imatinib mesylate. Jpn J Clin Oncol 2006;36:17–24. 29. Shinto A, Nair N, Dutt A, et al. Early response assessment in gastrointestinal stromal tumors with FDG PET scan 24 hours after a single dose of imatinib. Clin Nucl Med 2008;33:486–7. 30. Gayed I, Vu T, Iyer R, et al. The role of 18F-FDG PET in staging and early prediction of response to therapy of recurrent gastrointestinal stromal tumors. J Nucl Med 2004;45:17–21. 31. Young H, Baum R, Cremerius U, et al. Measurement of clinical and subclinical tumour response using [18F]-fluorodeoxyglucose and positron emission tomography: review and 1999 EORTC recommendations. European Organization for Research and Treatment of Cancer (EORTC) PET Study Group. Eur J Cancer 1999;35:1773–82.
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32. Van den Abbeele AD. The lessons of GIST–PET and PET/CT: a new paradigm for imaging. Oncologist 2008;13(Suppl. 2):8–13. 33. Basu S, Mohandas KM, Peshwe H, et al. FDG-PET and PET/CT in the clinical management of gastrointestinal stromal tumor. Nucl Med Commun 2008;29:1026–39. 34. Vasiliadis K, Kogopoulos E, Katsamakas M, et al. Ileoileal intussusception induced by a gastrointestinal stromal tumor. World J Surg Oncol 2008; 6:133. 35. van Oosterom AT, Judson I, Verweij J, et al. Safety and efficacy of imatinib (STI571) in metastatic gastrointestinal stromal tumours: a phase I study. Lancet 2001;358:1421–3. 36. Kantarjian H, Sawyers C, Hochhaus A, et al. Hematologic and cytogenetic responses to imatinib mesylate in chronic myelogenous leukemia. N Engl J Med 2002;346:645–52.
37. Ohnishi K, Sakai F, Kudoh S, et al. Twenty-seven cases of drug-induced interstitial lung disease associated with imatinib mesylate. Leukemia 2006;20:1162–4. 38. Hashiba T, Oda K, Koda K, et al. A gastrointestinal stromal tumor in the stomach: usefulness of computed tomographic volumetry. Gastric Cancer 2004;7:260–5. 39. Yeh BM, Shepherd JA, Wang ZJ, et al. Dual-energy and low-kVp CT in the abdomen. AJR Am J Roentgenol 2009;193:47–54. 40. Choi H. Response evaluation of gastrointestinal stromal tumors. Oncologist 2008;13(Suppl. 2):4–7. 41. Kaneta T, Takahashi S, Fukuda H, et al. Clinical significance of performing (18)F-FDG PET on patients with gastrointestinal stromal tumors: a summary of a Japanese multicenter study. Ann Nucl Med 2009;23: 459–64.
Contents lists available at ScienceDirect
Clinical Radiology journal homepage: www.elsevierhealth.com/journals/crad
Review
Imaging in gastrointestinal stromal tumours: current status and future directions R. Kochhar a, *, P. Manoharan a, M. Leahy b, M.B. Taylor a a b
Department of Radiology, The Christie NHS Foundation Trust, Manchester, UK Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, UK
article in formation Article history: Received 5 January 2010 Received in revised form 27 January 2010 Accepted 3 February 2010
Gastrointestinal stromal tumours (GISTs) have distinct biological and treatment-related features posing challenges for imaging. In this review the importance of imaging in different stages of patient management is discussed, emphasizing the unique characteristics of GISTs. Potential pitfalls of using the standard response criteria on conventional imaging have been highlighted. These include size measurements, which may not adequately reflect response rates, pseudoprogression, and spurious new lesions. Furthermore, the role of positron emission tomography/computed tomography (PET/CT) in early response evaluation and in the detection of both primary and acquired resistance is explored. The current role and future directions of use of both conventional and metabolic imaging in the management of GISTs are discussed. Ó 2010 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
Introduction Gastrointestinal stromal tumours (GISTs) are rare, softtissue sarcomas representing around 0.1–3% of all gastrointestinal (GI) cancers and 5.7% of sarcomas.1,2 GISTs are, however, the most common mesenchymal tumours of the GI tract1 with an estimated annual incidence of around 15 per million or approximately 900 new cases per year in the UK. Historically, GISTs were considered to be of smooth muscle origin and were classified as leiomyomas (benign) or leiomyosarcomas (malignant); however, they are now recognized as a biologically distinct tumour type. GISTs differ from the other mesenchymal neoplasms histopathologically as nearly all (90%) display a strong immunohistochemical staining for KIT (a tyrosinase kinase growth factor receptor).3 GISTs have a peak age incidence at 50–60 years of age, with a slight male predominance.4 These can arise anywhere in the gastrointestinal tract (from the oesophagus to the * Guarantor and correspondent: Department of Radiology, The Christie NHS Foundation Trust, Wilmslow Road, Manchester M20 4BX, UK. Tel.: þ44 161 4463053; fax: þ44 161 4463827. E-mail address: [email protected] (R. Kochhar).
rectum), with the majority arising in the stomach (60–70%) or small intestine (20–30%), and infrequently in the oesophagus, mesentery, omentum, colon, or rectum (5%).5 Surgery is the preferred primary treatment for the organconfined GISTs. The management of GISTs in recent years has been revolutionized by molecularly targeted therapeutic agents, such as imatinib mesylate (a selective tyrosinase kinase inhibitor). Prior to the introduction of imatinib, there was no effective treatment for unresectable and metastatic GISTs. Imatinib is an established effective and well-tolerated oral treatment for GISTs and should be considered the standard of care in non-surgical patients with nearly 84% of patients deriving clinical benefit from therapy.6 Imaging plays a major role in the detection, characterization, staging, and postoperative surveillance of GISTs, and has a key role in assessing response to treatment. For optimum treatment of this tumour type, a multidisciplinary team (MDT) with an experience with GISTs should oversee the management. The Christie NHS Foundation Trust is a tertiary referral centre for GISTs, treating about 50 new patients each year and with this review we share our experience of the role of imaging in the management of GISTs.
0009-9260/$ – see front matter Ó 2010 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.crad.2010.02.006
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Imaging for detection, diagnosis, and characterization Imaging of GISTs depends on the mode of presentation and the local availability. Endoscopic ultrasound (EUS) and computed tomography (CT) are the most widely used imaging methods. EUS, if available, is a valuable imaging technique for diagnosing small (<2 cm), incidentally detected submucosal GISTs which are often difficult to identify on endoscopy alone, as the overlying mucosa is often normal. The high frequencies used in EUS clearly delineate the gut wall layers and also allow for biopsy confirmation, where appropriate. However, due to a small field of view, EUS has limited use in larger masses as it may underestimate the disease extent. For larger tumours (>5 cm) and where the patient presents with haemorrhage, abdominal pain, or obstruction, CT is the investigation of choice. GISTs have a wide spectrum of radiological appearances depending on tumour size and site of origin, but can be broadly fitted into one of three patterns; intraluminal, extraluminal, and dumbbell type. Small GISTs appear on CT as sharply margined, smooth walled, homogeneous, softtissue masses with moderate contrast enhancement. More typically, GISTs are seen as large, well-demarcated, extraluminal tumours, arising from the digestive tract wall, and show certain key radiological features, such as heterogeneous enhancement with central necrosis, cavitation, and fistula formation, seen as gas in the tumour.5 Focal areas of low attenuation on CT in small GISTs represent varying pathological conditions including solid tumour, haemorrhage, haemorrhage with necrosis, cystic degeneration, fluid in ulcers, and fibrous septae, and do not predict malignant potential.7 Large tumours can also have a ‘‘dumbbell-like’’ appearance, with masses protruding both into the lumen and growing exophytically from the serosa of the bowel wall (Fig. 1). In addition to defining the presence and nature of a mass, the likely organ of origin should be defined, which is facilitated by multiplanar reconstruction on multidetector CT.8
Figure 1 Primary GIST with dumbbell-type morphology. Axial, contrast-enhanced CT demonstrates a large, solid, lobulate mass with both intraluminal and exophytic components related to the stomach with central low attenuation (arrow), consistent with a typical morphology for gastric GIST.
Although the risk of metastases is highest in large tumours with a high mitotic index, small tumours with low mitotic activity may still metastasize, making it difficult to predict malignant potential.13 The criteria for postoperative risk assessment of relapse of GISTs were proposed by consensus at a National Institute of Health workshop, and are based on tumour size and the mitotic count; the two most important predictors of progression.3 However, tumour location is also an independent predictor of risk and its inclusion as a predictor of progression is helpful to optimize the management of GISTs.14,15 Tumours that arise in the stomach tend to have a less aggressive behaviour compared with other GISTs, but approximately 50% will have metastasized by the time of presentation.16 The
Imaging for pre-operative staging and post-operative surveillance of GISTs All GISTs have malignant potential, with up to 30% being frankly malignant, and accurate preoperative CT assessment is essential to identify resectable disease. The clinical diagnosis is based on imaging, as biopsy runs the risk of tumour rupture or seeding of the biopsy tract, in an otherwise resectable disease.9 CT is used to assess the primary tumour extension, local invasion, and the presence of metastases.10 Tumour size is a factor in predicting the metastatic risk, but the heterogeneity of large tumours does not reliably predict the behaviour or malignant potential of GISTs.11 The main sites of metastasis are the liver2 and the peritoneal cavity, including the omentum and the mesentery (Fig. 2). Rarely, GISTs metastasize to the lymph nodes, bones, lungs, or to the subcutaneous tissues.12
Figure 2 Metastatic GIST with complicated hepatic metastases. Axial, contrast-enhanced CT demonstrates multiple hepatic metastases in both lobes of the liver, several of these demonstrate a fluid–fluid level (arrow heads) likely due to internal haemorrhage, a known complication of GISTs. Note also the primary gastric GIST (arrow) showing internal calcific areas likely secondary to treatment.
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postoperative risk assessment criteria and the follow-up schedule for organ-confined operable GISTs used at our institute are detailed in Figs. 3 and 4. In all cases, if the patient develops new symptoms, an early CT examination may be appropriate, and in intermediate and high-risk patients, the follow-up should be prolonged, as these tumours may even recur several years after an apparently curative resection. In patients with an unresectable primary tumour or metastatic disease at presentation, biopsy confirmation is essential before starting therapy with imatinib. Histopathologically, the diagnosis of GISTs is supported by positive CD117 (KIT) staining as part of an immunohistochemical panel in a spindle cell tumour of the GI tract when morphological and clinical features of the tumour are consistent with GISTs.
Imaging for response assessment of treated GISTs Figure 3 Postoperative assessment of risk of relapse. M, mitotic figures; hpf, high power field; int, intermediate; V, very.
Targeted molecular therapy using imatinib (a selective tyrosinase kinase inhibitor) is now established as the standard of care for treating KIT-positive, inoperable, and metastatic GISTs. A recent trial has shown that after the
Figure 4 Follow-up schedule in organ-confined operable GISTs.
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Figure 5 Histopathologic appearances (haematoxylin and eosin stain, 400) of primary and post-treatment GISTs. A pre-treatment biopsy specimen (a) reveals a cellular lesion with frequent mitotic figures. After 6 weeks of imatinib treatment histopathological examination now demonstrates large areas of predominant myxoid degeneration (b).
resection of primary GISTs, adjuvant imatinib therapy is safe and improves recurrence-free survival as compared with the placebo.17 Following treatment with imatinib, extensive fibrosis, myxoid degeneration, and a few scattered, nonproliferating CD117-positive cells replace the abundant, frequently mitotic, GIST cells, indicative of a good response to treatment (Fig. 5).18 This mode of response is unique to GISTs and has to be borne in mind when imaging is used for the response assessment.
Response assessment on CT CT is still the most commonly used imaging method for response assessment. Response to therapy on CT has been traditionally assessed by RECIST (Response Evaluation Criteria in Solid Tumours) criteria and is classified as stable disease, disease progression, partial response or complete response, based on the changes in size of the marker and non-marker lesions.19,20 It is important to note that the RECIST criteria may not apply to GISTs or may only apply after many months of
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treatment.21 This is because the initial response after treatment with imatinib is often seen as a cystic change due to myxoid degeneration, which causes tumour liquefaction corresponding to a change in density on CT (measured using Hounsfield units) rather than a change in the size.22 The RECIST criteria are solely based on size, and therefore, substantially underestimate the effect of imatinib on metastatic GISTs, especially at the early stage of treatment. Modified CT response assessment criteria, known as the Choi criteria, have been proposed. These use a combination of the tumour density (>15% reduction) and the modified tumour size (>10% reduction).23 The Choi criteria correlate well with a good response by positron emission tomography (PET) and are more sensitive and precise than the RECIST criteria in assessing the response of GISTs to imatinib and time to tumour progression.21 Potential pitfalls on the post-treatment follow-up CT in the presence of a clinically documented response include cystic change with an increase in the size of lesions (Fig. 6) and the development of spurious new lesions (Fig. 7). On pre-treatment portal venous-phase CT, the metastatic hepatic lesions may be isodense to the surrounding liver parenchyma and thus, difficult to visualize. These lesions may become hypodense and clearly visible on follow-up CT when undergoing myxoid degeneration in response to treatment, and should not be misinterpreted as new lesions or disease progression.22,24 The CT technique can be critical and a combination of unenhanced and enhanced CT, possibly using a triphasic dynamic technique may be necessary on baseline and follow-up CT, for accurate evaluation of the tumour response.25 Stable disease implies no significant change in tumour size or density.26 Disease progression is further classified into limited and generalized progression. Limited progression is described as the development of enhancing tumour nodules within the treated hypoattenuating tumour, regardless of changes in tumour size, and is consistent with GIST recurrence (Fig. 8).27 Identifying an intratumoural nodule within the treated GIST is a unique and important imaging finding in recurrent GISTs. General progression includes an increase in the tumour size and density in two or more masses or development of new lesions.28 The timing of CT examinations after initiating treatment is variable. We advocate an initial CT as early as 6 weeks, followed by examinations performed at 3 monthly intervals. Early detection of the tumour response ensures effective therapy, whilst stable disease or even tumour progression may require an increase in the dosage of imatinib.26 Stable disease with symptomatic benefit is as important clinically as traditionally measured response. Treatment with imatinib should be continued until there is radiological and/or symptomatic progression. The role of surgery in patients who have responded to imatinib is contentious, but it should be considered in patients who have previously been viewed as inoperable, but have shown a good response to imatinib and are now suitable for potentially curative total surgical resection.
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Response assessment on 2- [18F]-fluoro-2-deoxy-Dglucose (FDG)-PET/CT There are several potential advantages of monitoring tumour response in GISTs using FDG-PET/CT; both the anatomic and the functional tumour evaluation are performed in the same sitting. The metabolic response detected by FDG-PET/CT precedes the anatomic response in GISTs treated with molecularly targeted drugs, such as imatinib mesylate. The metabolic response can be observed as early as 24 h following the administration of a single dose of imatinib, whereas conventional objective response criteria
Figure 6 Pitfalls of response assessment showing increase in size but with cystic change. Axial, contrast-enhanced CT (a) demonstrates an exophytic gastric GIST with soft-tissue elements (short arrow) and multiple hepatic metastases. The largest hepatic lesion demonstrates a fluid–fluid level (long arrow). (b) Follow-up CT 3 months posttreatment with imatinib demonstrates that both the primary GIST (short arrow) and the hepatic metastases (long arrow) have increased in size suggesting disease progression on conventional RECIST criteria. The lesions, however, now show predominant cystic attenuation and this is in keeping with treatment response despite the slight increase in size. (c) Follow-up CT at 6 months post-treatment demonstrates that the cystic change is maintained and now there is a decrease in size of both the gastric GIST (short arrow) and the hepatic metastases (long arrow) in keeping with continued response to treatment. Decrease in size can occur several months after cystic change limiting early response assessment by standard RECIST criteria.
Figure 7 Pitfalls of response assessment with development of spurious new liver lesions. Axial, contrast-enhanced CT (a) in the portal venous phase demonstrates an exophytic gastric GIST and unremarkable appearances of the liver. Follow-up post-imatinib treatment CT at 3 months (b) demonstrates multiple apparently new hypodense hepatic lesions (arrow heads) and a decrease in size of the primary gastric GIST (arrow). Findings are in keeping with a partial response to treatment despite the spurious new hepatic lesions. This should not be misinterpreted as disease progression as these appearances are due to post-treatment cystic change, which makes the hepatic lesions visible on the portal venous phase images; the lesions were previously isodense and apparently not seen.
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based on tumour size measured by CT, lag weeks or months behind.29,30 FDG-PET/CT is most useful for evaluating early response. A baseline examination should always be obtained prior to initiating treatment, as approximately 20% of the lesions shown on CT do not display appreciable glucose uptake on the pre-treatment FDG-PET/CT, and in such cases, FDG-PET/ CT cannot be used to evaluate treatment response. Response on FDG-PET/CT is characterized by a dramatic decrease in the glycolytic metabolism of GISTs. The degree of FDG uptake can be quantified using the maximal standardized uptake value for a particular region of interest (SUVmax). The European organization for research and treatment of cancer (EORTC) guidelines suggest that a 25% reduction in SUVmax should be
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considered as the threshold for partial metabolic response.31 Patients who achieve an absolute value for SUVmax of 2.5 in their tumours 1 month after starting treatment have a better tumour-free survival.32 FDG-PET/CT should also be performed when CT findings are inconclusive or are inconsistent with the clinical presentation.22 FDG-PET/CT is helpful in resolving ambiguous findings on CT when CT findings may suggest tumour growth, when the increase in size is actually related to intratumoural bleeding or to tumour swelling unrelated to progressive disease. In both cases, FDG-PET/CT will be negative, whereas the viable tumour will be FDG-avid.32 In addition to detecting early response, FDG-PET/CT performed soon after treatment may identify patients with a primary resistance to the drug who will not benefit from this therapy, and for whom alternative treatment should be considered. FDG-PET/CT is useful in clinical trials for the assessment of patients treated with new drugs (Fig. 9), and in selection of optimal dose for therapy.33 FDG-PET/CT can also aid in the identification of secondary or acquired resistance demonstrated by a re-emergence of metabolic activity within tumour sites after a period of an initial therapeutic response. Termination of imatinib therapy in patients with progressive disease (imatinib refractory GISTs), may also result in a ‘‘flare’’ phenomenon, suggesting that some progressing tumours may still have cell populations sensitive to imatinib.32 Imaging with combined FDG-PET/CT now has an increasing role for the optimal management of this group of malignancies.
Detection of tumour and treatment-related complications
Figure 8 Limited disease progression in GISTs with a nodule-withina mass pattern. Axial, contrast-enhanced CT (a) demonstrates a predominantly low-density mass in the left supracolic omental region (arrow) with focal calcific areas in a patient taking imatinib for metastatic GIST. Follow-up CT (b) after 3 months demonstrates the development of a new, enhancing, solid nodule in the inferior portion of the previously noted supracolic omental mass (arrow), which otherwise has shown no significant change in size, in keeping with limited disease progression.
GISTs, especially in their early stages are usually asymptomatic, and they often go unrecognized until severe symptoms ensue, which can create surgical emergencies. These symptoms mainly depend on the size and the location of the tumour, with lesions distal to the ligament of Treitz having a tendency to present with either bleeding or obstruction. GISTs tend to grow in an extraluminal fashion; however, they can also erode into the lumen of the gastrointestinal tract inducing significant haemorrhage or anaemia from occult bleeding. They can also rupture into the peritoneal cavity causing significant haemorrhage. In addition to symptoms from mass effect or bleeding, GISTs can cause intussusception or rarely, intestinal obstruction.34 Imatinib mesylate is generally well tolerated; the more common toxicities include oedema, nausea, diarrhoea, myalgia, fatigue, skin rash, haemorrhage, and occasionally neutropenia.35 We have encountered a case of imatinibinduced neutropenia presenting with typhlitis, which resolved on cessation of imatinib with normalization of the neutrophil count. Less common toxicities include respiratory complications, mainly in the form of dyspnoea and cough, documented in approximately 10% of patients and mostly attributed to pulmonary oedema.36 In addition, interstitial lung disease is now recognized as a distinct toxic effect of imatinib mesylate treatment.37 Timely cessation of drug results in resolution of changes. As the use of targeted
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therapy becomes more prevalent, treatment-related complications will be more commonly encountered and the radiologist needs to be aware of them to avoid misinterpretation of imaging findings.
Future directions CT is currently the most commonly used technique in the diagnosis, response assessment, and monitoring of
GISTs. The limitations of using standard RECIST criteria for monitoring response on CT to targeted molecular therapies must be kept in mind. The Choi criteria are objective criteria that are promising in early response evaluation and have an excellent prognostic value; the potential limitations being the high observer variations in placing regions of interest to assess density changes, and these criteria still need further validation in larger populations.
Figure 9 Response assessment on PET/CT. Baseline PET/CT image (a) performed in a patient with a metastatic GIST to assess response to a clinical trial drug after second-line treatment failed to show response. High-grade FDG uptake is seen in a primary small bowel GIST (short arrows) and also in the hepatic metastases. Four-week follow-up PET/CT (b) demonstrates persistent high-grade uptake in the primary tumour (short arrows) and in several new hepatic lesions (long arrows). Findings are in keeping with progressive disease.
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Studies have also shown potential advantages of using volumetric analysis for early response assessment.38 The potential of using dual-energy CT with virtual unenhanced and iodine only images and overlay CT numbers as a marker for monitoring therapy in patients with advanced GISTs is another exciting development.39 Although semi-automatic tumour volumetry and dualenergy CT for response assessment are exciting tools, they are still being evaluated and are not in routine clinical use. Subjective evaluation using a combination of changes in tumour size, number, density, presence of enhancing nodules and tumour vessels, is currently the best way to assess response by CT.40 FDG-PET/CT does have advantages over conventional CT imaging alone for the diagnostic and therapeutic management of patients with GISTs, and there is an argument in favour of its introduction as a routine diagnostic tool.41 However, in our experience, in the majority of patients, response assessment can be accurately performed with clinical evaluation and routine CT imaging. Although the use of PET/CT is certain to increase, currently, its main value is in early response assessment, for problem-solving in cases with equivocal CT and clinical findings, and in clinical trials to evaluate new drugs in patients with primary or secondary resistance to imatinib.
Conclusion A correct histological diagnosis, careful staging, accurate post-operative assessment, and detection of tumour response to treatment, are all crucial in the management of patients with GISTs. Imaging plays an integral role in all these stages and optimized criteria must be defined to assess response to therapy for both anatomic and functional imaging methods.
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