Gastrointestinal stromal tumour (GIST)
Gastrointestinal stromal tumour is the commonest mesenchymal tumour of the digestive tract, and the stomach is its commonest site. It is worth understanding two things about it from the outset. First, GIST is not simply benign or malignant — every GIST sits somewhere on a spectrum of risk, determined by its size, its site and how fast its cells divide. Second, GIST is the condition in which targeted drug treatment first transformed the outlook of a solid tumour, and it remains one of the clearest examples in cancer medicine of treatment aimed precisely at the molecular fault that causes the disease.
How they form
GISTs arise from the interstitial cells of Cajal — the pacemaker cells that lie between the muscle layers of the gut wall and generate the rhythmic electrical activity driving peristalsis. This origin explains the behaviour of the tumour: it grows within the wall, not from the lining, so the mucosa over it is normal and an ordinary biopsy usually returns nothing.
The molecular cause is well defined. Most GISTs carry an activating mutation in the KIT gene, which encodes a receptor tyrosine kinase. Normally this receptor signals cell growth only when bound by its ligand; the mutation locks it permanently switched on, so the cell receives a continuous growth signal that does not depend on any external stimulus. A further group carry mutations in PDGFRA, a closely related receptor, with the same effect.
Because the tumour depends on one continuously active signalling pathway, blocking that pathway is remarkably effective — this is precisely what imatinib does, and it is why the treatment works as well as it does.
A minority of GISTs have neither mutation. These wild-type GISTs often involve loss of the succinate dehydrogenase complex, occur in younger patients, arise in the stomach, spread to lymph nodes (which conventional GIST rarely does), and respond poorly to imatinib. They may occur within the Carney triad or Carney-Stratakis syndrome, and they need a different treatment approach — which is why mutation testing is not an academic exercise.
GIST may also occur in neurofibromatosis type 1, typically multiple and in the small bowel, and in rare familial KIT mutation syndromes.
Crucially, GIST spreads by blood and by direct seeding, not usually through lymph nodes — the liver and the peritoneum are the sites of metastasis. This determines both the extent of the operation and where follow-up imaging is directed.
Symptoms
Many GISTs are found incidentally, at endoscopy or on a scan, or during an operation for something else. When symptomatic, the features are:
- Bleeding — the commonest presentation. The tumour outgrows its blood supply, the overlying mucosa ulcerates, and bleeding follows — either chronic, causing iron-deficiency anaemia and fatigue, or acute, with vomiting of blood or black stools.
- vague abdominal discomfort or fullness
- a palpable mass, sometimes large before it causes anything else
- early satiety
- obstruction, uncommon in the stomach, more typical of small bowel GIST
- acute abdomen from rupture into the peritoneal cavity — uncommon, serious, and significant because rupture seeds the peritoneum and worsens prognosis
How the diagnosis is made
- Endoscopy shows a smooth submucosal bulge covered by normal mucosa, sometimes with a central ulcer — the classical appearance.
- Endoscopic ultrasound establishes the layer of origin (typically the muscularis propria), the size, the margins and internal features, and distinguishes GIST from leiomyoma, lipoma, cyst and other subepithelial lesions. Fine-needle aspiration or core biopsy can be taken through it where the result would change management.
- CT of abdomen and pelvis with contrast defines the tumour and assesses the liver and peritoneum for metastases. Large GISTs are often heterogeneous with necrosis and may appear alarming without being unresectable.
- Histology and immunohistochemistry make the diagnosis: spindle or epithelioid cells positive for CD117 (KIT) and DOG1, which separates GIST from leiomyoma (desmin and smooth muscle actin positive) and schwannoma (S100 positive).
- Mutation analysis of KIT and PDGFRA. This predicts response to imatinib and should be performed in all patients being considered for drug treatment — the PDGFRA D842V mutation, for instance, is resistant to imatinib and requires a different agent.
A note on biopsy: a resectable tumour with typical appearances does not require biopsy before surgery, and percutaneous biopsy of an intact GIST is avoided because of the risk of rupture and peritoneal seeding. Biopsy is indicated where drug treatment is planned first, where the diagnosis is uncertain, or where disease is metastatic.
Assessing risk
Every resected GIST is assigned a risk of recurrence, and this determines follow-up and whether adjuvant treatment is given. Three factors drive it:
- Size of the tumour
- Mitotic rate — the number of dividing cells per defined area, the strongest single predictor
- Site — gastric GISTs behave considerably better than small bowel, colonic or rectal GISTs of the same size and mitotic rate
Tumour rupture, whether spontaneous or during surgery, is treated as an independent high-risk feature, because it seeds the peritoneum.
Very small gastric GISTs, under 2cm, without high-risk features, are common and frequently indolent, and surveillance rather than removal is a reasonable option for some patients.
Treatment
Surgery
Complete removal with an intact pseudocapsule and microscopically clear margins is the treatment for localised disease. The principles differ from adenocarcinoma surgery in ways worth stating:
- A wide margin is unnecessary. A clear margin of a few millimetres suffices, so a wedge resection of the stomach is usually adequate and total gastrectomy is rarely required.
- Lymphadenectomy is not performed routinely, because GIST does not typically spread to nodes. The exception is succinate dehydrogenase-deficient GIST, which does.
- Avoiding rupture is paramount. The tumour is handled minimally and gently. Spillage converts a curable tumour into peritoneal disease.
Laparoscopic and robotic resection is standard for most gastric GISTs and gives equivalent results with faster recovery. Endoscopic resection techniques are used in selected small lesions in specialist centres.
Drug treatment
- Neoadjuvant imatinib — given before surgery for large tumours or those in awkward positions, such as near the gastro-oesophageal junction, where shrinkage over several months converts an extensive operation into a limited one. This is one of the most useful applications of the drug and is often under-considered.
- Adjuvant imatinib — given for at least three years after surgery in high-risk tumours, and significantly reduces recurrence. Mutation status guides whether it will work.
- Advanced or metastatic disease — imatinib is first-line and controls disease for years in many patients. On progression, sunitinib, regorafenib and ripretinib follow in sequence; avapritinib is used for the PDGFRA D842V mutation. Surgery retains a role for limited residual disease in patients responding well.
Imatinib is generally well tolerated. Common effects include fluid retention and periorbital swelling, nausea, muscle cramps, rash and fatigue, and most are manageable. Continuing it — rather than stopping when scans look clear — matters, since disease frequently progresses on interruption.
Recovery
After laparoscopic wedge resection of a gastric GIST, hospital stay is typically two to four days and return to normal activity two to four weeks. Diet returns to normal in most patients, since only a small part of the stomach is removed. Larger resections involve a longer recovery and dietary adjustment.
Follow-up
Determined by risk category. Low-risk gastric GISTs require limited follow-up; intermediate and high-risk tumours are followed with CT at intervals for several years, with attention to the liver and peritoneum, since these are the sites of recurrence. Follow-up continues longer than for many tumours, because GIST can recur late.
When to seek an opinion
Unexplained iron-deficiency anaemia, black stools, or a subepithelial lesion found at endoscopy and described as "a lump in the wall" without a clear plan for characterising it. A GIST diagnosis should be managed with access to a sarcoma or upper gastrointestinal multidisciplinary team, mutation testing, and a surgeon who resects these regularly.
Common questions
Is a GIST cancer?
It is best described as a tumour with a range of behaviour rather than as simply cancer or not cancer. Some are effectively harmless and never cause trouble; others can spread, usually to the liver or the lining of the abdomen. Where yours sits on that range is judged from its size, its position, and how rapidly its cells are dividing under the microscope.
Why was no biopsy taken before my operation?
Because these tumours sit under normal lining, so ordinary biopsies usually miss them, and because putting a needle into an intact tumour risks rupturing it and spreading cells within the abdomen. When the appearances are typical and the tumour is removable, it is generally safer to remove it whole and examine it then.
Does the whole stomach have to come out?
Almost never. Unlike stomach cancer, a GIST does not need a wide margin of normal tissue or removal of the surrounding lymph glands. A wedge of stomach containing the tumour is usually enough, and this is normally done through keyhole surgery.
What is imatinib and will I need it?
It is a tablet that blocks the specific faulty signal driving the tumour to grow. It is not conventional chemotherapy and is usually well tolerated. It is used before surgery to shrink large tumours, after surgery for those assessed as higher risk, and as the main treatment when disease has spread. Whether you need it depends on the risk assessment of your tumour and on the genetic result from it.
Why is my tumour being tested genetically?
Because the particular mutation predicts which drug will work. Most respond well to imatinib; one specific mutation does not and needs a different tablet; and a group with no mutation at all behave differently again and are managed in another way. Testing avoids months of ineffective treatment.
Will it come back?
Most low-risk tumours, completely removed, do not. Higher-risk tumours can recur, usually in the liver or the lining of the abdomen, and sometimes several years later — which is why scans continue for longer than you might expect. Tablet treatment after surgery substantially reduces that risk in the higher-risk group.
Is it inherited?
Almost always no. The mutation occurs in the tumour itself, not in the rest of your body, so it is not passed on. Rare inherited forms exist, and are suspected when GISTs are multiple, occur at a young age, or run in a family — in which case genetic assessment is offered.
Related conditions
Other conditions of the stomach covered on this site:
- Peptic ulcer disease
- Perforated and bleeding peptic ulcer
- Gastric outlet obstruction
- Gastric polyps
- Gastric neuroendocrine tumours (gastric carcinoids)
- Stomach cancer (gastric cancer)
This page provides general information and does not replace an individual medical consultation. Assessment and treatment are decided for each patient after review of their history, examination, investigations and discussion in a multidisciplinary meeting.