Elsevier

The Lancet Oncology

Volume 3, Issue 11, November 2002, Pages 655-664
The Lancet Oncology

Review
Management of malignant gastrointestinal stromal tumours

https://doi.org/10.1016/S1470-2045(02)00899-9Get rights and content

Summary

Gastrointestinal stromal tumours (GISTs) are the most common form of mesenchymal tumour of the gastrointestinal tract. Clinically, they range from small indolent tumours curable with surgery alone to aggressive cancers. Making a distinction between an indolent and a malignant GIST is unreliable with conventional histopathological techniques. The presence of metastases at the time of diagnosis confirms malignancy, but all GISTs should be regarded as having malignant potential. GISTs characteristically express the KIT protein, a transmembrane tyrosine kinase receptor for stem-cell factor. Most GISTs have a mutation in the KIT proto-oncogene that translates into a gain-of-function constitutive activation of the KIT kinase. KIT activation seems to be an early tumour-promoting event in pathogenesis. Commonly, malignant GISTs show high-level primary resistance to conventional chemotherapy. Imatinib mesylate is an orally administered selective inhibitor of certain tyrosine kinases including KIT. Most patients with advanced malignant GISTs achieve clinical benefit and significant antitumour responses with imatinib mesylate. Responses have been durable, and most patients tolerate the drug well at clinically effective doses. Imatinib mesylate is the first effective systemic therapy for advanced GIST.

Section snippets

Clinical features

Most studies of the clinicopathological entity referred to as GIST before the year 2000, are likely to include a group of patients with true GISTs as well as other histological subtypes of spindle-cell sarcoma such as leiomyosarcoma. GISTs occur in both sexes at a similar frequency, but some data show male predominance.2, 6 The median age at diagnosis is about 60. GISTs are occasionally found in young adults, but they are very rare in children.2 Nearly all GISTs arise as a result of a somatic

Histopathology and immunohistochemistry

On histolgical analysis most GISTs look fairly benign, which is surprising in view of the malignant potential of the disease. However, the histological appearance of GISTs can vary greatly among patients, and their malignant potential ranges from clinically benign tumours to aggressive cancers. The spindle-cell variant of malignant GIST (70%) corresponds to tumours previously classified as leiomyosarcoma, and many of the epithelioid or round-cell variants (30%) were previously thought to be

Cell of origin

Kindblom and colleagues suggested in 1998 that GISTs originate from stem cells that differentiate towards the interstitial cells of Cajal (ICCs), and that GISTs should be called gastrointestinal pacemaker-cell tumours.24 ICCs arise from precursor mesenchymal cells and are the pacemaker cells that bring about autonomous movement of the gastrointestinal tract.27 They intercalate between nerve fibres and muscle cells and can be seen in the adult intestine in and around the myenteric plexus.2 Both

Diagnosis

The clinical prediagnostic investigation of GISTs is similar to that of other gastrointestinal malignant disorders. A double-contrast series of radiographs may show a characteristic smooth-lined filling defect with clearly demarcated borders. On endoscopic examination, there may be a smooth protrusion of the bowel wall, lined with mucosa, which can also show signs of bleeding and ulceration.14 Endoscopic ultrasonography may show a hypoechoic mass that is contiguous with the muscularis propria

Prognostic features

Assessment of the malignant potential of a primary GIST lesion is difficult in many cases, and even small GISTs (less than 2 cm in diameter) have uncertain malignant potential.3 The criteria used to predict biological behaviour also vary significantly with tumour location, for example, smooth-muscle tumours arising from the small bowel, colon, rectum, omentum, or mesentery are generally associated with a less favourable outcome than those arising in the stomach.12 Most oesophageal and colonic

Outcome

Before about the year 2000, studies of GISTs included tumours that would not presently be classified as GISTs, and data are therefore contaminated by these cases. However, since GISTs constitute the majority of gastrointestinal sarcomas, the survival data from these studies probably largely reflect the experience of patients with true GISTs. Most recurrences take place within 5 years of the primary diagnosis,12 but in the slowly proliferating subset of GISTs, metastases can appear more than 10

Molecular biology

The fundamental pathogenetic feature of the most common malignant phenotype of GIST seems to be activation of the KIT signalling pathway.44 KIT is a transmembrane tyrosine kinase encoded by the KIT proto-oncogene located on chromosome 4q11-q12.45 It is the cellular homologue of the oncogene v-kit of the Hardy-Zuckerman feline sarcoma virus.46 The natural ligand of KIT is SCF (also known as the mast-cell growth factor, Steel factor, or the KIT ligand). Unbound KIT protein is an enzymatically

Surgery

Surgery remains the standard initial treatment for non-metastatic GISTs. Careful pathological assessment should be done to differentiate GISTs from carcinomas and lymphomas. As with other soft-tissue sarcoma, a true capsule does not exist, and the tumour should be removed en-bloc with its pseudocapsule and, if possible, an adjacent margin of normal soft tissue or bowel. In cases where contiguous organs are involved, en-bloc resection has been recommended wherever feasible.14 Since this process

Radiotherapy

The impact of radiotherapy on outcome is unknown. Many visceral sarcomas are not readily amenable to radiotherapy because of organ motility, and postoperatively contaminated bowel loops may relocate to remote sites. The large target volumes needed and the limited radiation tolerance of the intra-abdominal organs limit the usefulness of radiotherapy. Fixed lesions on the abdominal wall or adjacent organs have been treated with postoperative radiotherapy, but recurrences both within and outside

Chemotherapy

Attempts to treat malignant GISTs with systemic chemotherapy have been almost universally unsuccessful.67 In one study, only 3 of 43 (7%) patients with gastrointestinal soft-tissue sarcomas (most tumours probably GISTs) responded to a combination of doxorubicin and dacarbazine, whereas 22% of patients with uterine leiomyosarcomas and 21% of patients with leiomyosarcmas of other sites responded to this combination (p=0·05), suggesting relative chemoresistance of gastrointestinal soft-tissue

Imatinib mesylate

Imatinib mesylate is a competitive inhibitor of certain tyrosine kinases including the intracellular kinases ABL and BCR-ABL fusion protein present in some leukaemias, KIT, and the platelet-derived growth factor receptors.73 Imatinib mesylate inhibits these tyrosine kinases at submicromolar concentrations, but has little or no effect on many other tyrosine or serine/threonine kinases. It is a small multiringed molecule, which competes with ATP for its kinase-binding site, and prevents the

Effectiveness of imatinib mesylate in advanced GIST

Based on two studies, imatinib mesylate is the first effective drug in the treatment of metastatic GIST. The US-Finland study reported a response rate of 54% among 147 patients with inoperable or metastatic GIST treated with a daily dose of 400 mg or 600 mg with follow-up of at least 6 months.75 In addition, 28% had minor response or stable disease, and only 14% showed primary resistance to the drug. Similar results were reported from a trial by the European Organization for Research and

Tolerability and safety of imatinib mesylate

Tolerability has been acceptable with daily doses of 800 mg or less. The most common adverse effects include periorbital and leg oedema (figure 5), transient nausea associated with drug ingestion, muscle cramps, diarrhoea, headache, dermatitis, fatigue, anaemia, and neutropenia.75 Most of these side-effects are mild to moderate in severity, and grade 3–4 toxic effects occur in less than 30% of patients at a dose of 400–600 mg per day.75, 76 A few patients (5%) have had a tumour-associated

Future directions and unresolved questions

Imatinib mesylate is a major breakthrough in the treatment of advanced GISTs and is the first effective systemic therapy for this disease. However, several important questions remain unanswered: the required duration of imatinib mesylate therapy; the proportion (if any) of the patients with metastatic disease who will achieve long-term disease control, and whether treatment results can be improved with combination therapies. In the treatment of BCR-ABL-expressing leukaemia, resistance to

Search strategy and selection criteria

PubMed was searched for references from 1983 to 2002 with the search terms, “gastrointestinal stromal tumour”, “GIST”, and “gastrointestinal sarcoma”. Only papers published in English were included. Reference lists of review articles were also searched. Recent papers were given emphasis, because GIST is a novel clinical entity, and old published work on gastrointestinal sarcomas is contaminated with other histological tumour types.

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