Other oesophageal and gastric neoplasms

Pathophysiology

GISTs are soft-tissue sarcomas of mesenchymal origin that arise in the gastrointestinal (GI) tract; they are rare, representing 0.1–3% of all gut tumours and 5% of all soft-tissue sarcomas. Historically, these tumours were considered to be of smooth muscle origin and were generally regarded as leiomyomas (benign) or leiomyosarcomas (malignant). Electron microscopy and immunohistochemical studies indicated, however, that only a minority of stromal tumours have the typical features of smooth muscle, with some having a more neural appearance and others appearing undifferentiated. ‘Gastrointestinal stromal tumour’ was subsequently introduced as being a more appropriate term for these neoplasms, with the variable histological features (smooth muscle, neural, or undifferentiated) considered to be of little clinical relevance. GI autonomic nerve tumour (GANT) was also introduced to describe sarcomas with ultrastructural evidence of autonomic nervous system differentiation ; these tumours are now recognised as a variant of GIST. The discovery of CD34 expression in many GISTs suggested that they were a specific entity, distinct from smooth muscle tumours. It was also observed that GISTs and the interstitial cells of Cajal (ICCs) express the receptor tyrosine kinase KIT (CD117). This has led to the now widely accepted classification of mesenchymal tumours of the GI tract into GISTs, true smooth muscle tumours, and, far less frequently, true Schwann cell tumours. A pathologist experienced in GI mesenchymal cancers should make the histopathological diagnosis of GISTs. Tumours may have a spindle cell, epithelioid, or mixed histological appearance. An immunohistochemical panel should include CD117, DOG-1, desmin, CD34, and smooth muscle antigen (SMA). Typically GISTs are positive for CD117 and DOG-1 and negative for desmin. Around 85% of GISTs have activating mutations in either the KIT or PDGFRA genes, which are situated on the same chromosome. The most common KIT mutations are found in exons 11 and 9. GISTs with PDGFRA exon 18 D842V mutations are exclusively gastric in location and are resistant to the currently used tyrosine kinase inhibitors. About 15% of the GISTs are designated as ‘wild type’ with no mutations in KIT or PDGFRA genes and have distinctive clinical, biological, and molecular phenotypes. succinate dehydrogenase-deficient GISTs occur in young women and are almost exclusively gastric in their location.

Incidence and malignant potential

The estimated annual incidence of GISTs is around 15 per million, which equates to approximately 900 new cases per year in the UK. Incidental microscopic gastric GISTs are commonly found in gastrectomy specimens but not in other intestinal resections. The size of the tumour, the symptoms at diagnosis, the organ of origin (small bowel GISTs have the worst prognosis), and mitotic count seem to be the most important factors when assessing prognosis. An analysis of 1765 gastric GISTs showed that tumours <10 cm diameter or with a mitotic count <5/50 high-power fields (HPFs) had a 2–3% risk of having metastasised, whereas those >10 cm diameter or mitotic count >5/50 HPFs had an 86% risk of metastatic spread. For non-gastric intestinal GISTs the risk of aggressive behaviour is highest for tumours >5 cm diameter and mitotic count >5/50 HPFs.

Patient demographics and anatomical distribution

No marked sex difference is apparent for GISTs. Two larger series of malignant GI sarcomas did, however, demonstrate a slight male predominance. ^, The age distribution appears to be unimodal with a median age at presentation of 58 years (range 16–94). The peak incidence in men occurs in the fifth decade, slightly before that in women, where it peaks in the sixth decade. Only 1–2% of GISTs present in patients before 30 years of age.

Most GISTs arise in the stomach or small intestine, and infrequently in the oesophagus, mesentery, omentum, colon, or rectum ^, ( Table 10.3 ). Approximately 10–30% of GISTs are overtly malignant at presentation ; the principal sites of metastasis are the liver and the peritoneal cavity, and spread to lymph nodes is very rare.

Presentation

The symptoms of GISTs are non-specific and depend on the size and location of the lesion. Small GISTs (2 cm or less) are usually asymptomatic and are detected during investigations or surgical procedures for unrelated disease. The vast majority of these are of low risk for malignancy. In many cases the mucosa is normal so that endoscopic biopsies are unremarkable. Incidental discovery accounts for approximately one-third of cases.

The most common symptom is GI bleeding which is present in approximately 50% of patients ( Table 10.4 ). Patients with larger tumours may experience abdominal discomfort or develop a palpable mass. GISTs are often clinically silent until they reach a large size, bleed, or rupture. Most duodenal GISTs occur in the second part of the duodenum where they can cause obstructive symptoms or infiltrate into the pancreas.

Investigation

Approximately 60% of GISTs are submucosal and grow towards the lumen where, if in the proximal GI tract, they may be visualised endoscopically as smooth submucosal projections. If a small submucosal mass is seen as an incidental finding at the time of endoscopy, EUS should be the first investigation as a proportion will be due to extrinsic impression from normal adjacent structures, e.g. gallbladder, spleen, or loaded colon. If this is the case, no further investigation is required. Other differentials to consider for submucosal lesions other than GISTs are gastric cancer, leiomyoma, soft tissue sarcoma, inflammatory fibrous polyps, pancreatic rest, and schwannoma. For larger palpable masses, or where the patients present with haemorrhage, abdominal pain, or obstruction, computed tomography (CT) is usually the first investigation after endoscopy both to assess the primary and to look for metastases.

Endoscopic ultrasound

The classical features are of a hypoechoic mass contiguous with the fourth (muscularis propria) or second (muscularis mucosae) layers of the normal gut wall, both of which are hypoechoic ( Fig. 10.1 ).

The accuracy of EUS in predicting GIST behaviour is controversial. EUS features most predictive of ‘benign’ tumours are regular margins, tumour size ≤30 mm, and a homogeneous echo pattern. Larger tumours with irregular extraluminal margins and cystic spaces may behave more aggressively.

To further aid diagnostic accuracy it is possible to use a linear EUS scope through which needle aspirates and core biopsies can be taken without breaching surgical resection planes. EUS–fine-needle aspiration (FNA) in experienced hands has a diagnostic accuracy of up to 97% for GIST lesions, is becoming more widely available, and should be considered in the diagnostic work-up of a possible GIST lesion if the result could change clinical management.

Computed tomography

GIST imaging by CT scanning typically shows an extraluminal mass, often with central necrosis, arising from the digestive tract wall. Small tumours typically appear as sharply margined, smooth-walled, homogeneous, soft-tissue masses with moderate contrast enhancement. Large tumours tend to have mucosal ulceration, central necrosis and cavitation, and heterogeneous enhancement following intravenous (IV) contrast. As well as defining the presence and nature of a mass, if possible, the likely organ of origin should be defined. Multiplanar reconstruction can assist this, particularly with large masses. Negative oral contrast (e.g. tap water) and IV contrast for the assessment of gastric GISTs are recommended ( Fig. 10.2 ). CT of the chest, abdomen and pelvis is recommended for staging of GIST, with the exception of small incidental tumours or when a patient presents as an emergency requiring urgent surgery. With regards to assessing treatment response, traditional CT criteria (Response Evaluation Criteria in Solid Tumours [RECIST] criteria) have been shown to be inaccurate for measuring GIST response to imatinib and the Choi criteria are recommended (10% reduction in size and 15% reduction in density).

GIST syndromes

Families have been reported with single-base ‘gain of function’ mutation in the kinase domain of KIT. The resultant effect is the development of multiple GISTs in the small bowel. Diffuse hyperplasia of spindle-shaped cells within the myenteric plexus at sites unaffected by GIST formation was also noted. ^, The association of three uncommon neoplasms – gastric GIST, functioning extra-adrenal paraganglionoma and pulmonary chondroma – was first reported in 1977 and has been recognised as ‘Carney’s triad’ since ( Fig. 10.3 ). A subsequent review of 79 cases demonstrated that unlike isolated sporadic GIST, where no significant sex difference was noted, 85% were female. Twenty-two per cent of the patients had all three tumours; the remainder had two of the three, usually the gastric and pulmonary lesions. Adrenocortical adenoma has since been identified as a new constituent of the disorder. The presence of two of the three main tumours is considered sufficient for the syndrome. GISTs may also occur in neurofibromatosis-1 patients, when they are often multicentric and found in the small intestine.