A hidden cause of upper gastrointestinal bleeding

Abstract

Gastrointestinal stromal tumours (GISTs) are a subset of gastrointestinal (GI) mesenchymal tumours of varying differentiation and represent 1–3% of all gastrointestinal malignancies–70% occur in the stomach. Previously, these tumours were classified as GI leiomyomas, leiomyosarcomas, leiomyoblastomas or schwannomas on the basis of histological findings and the fact that these tumours apparently originate in the muscularis propria layer of the intestinal wall. With the advent of immunohistochemical staining techniques and ultrastructural evaluation, GISTs are now recognised as a distinct group of mesenchymal tumours. Most cases are sporadic although some families with hereditary GISTs have been described. We report a coinicidental finding of GIST in an asymptomatic patient and subsequent management.

Background

This is an area of interest as there are often discrepancies in opinion relating to diagnosis, management and subsequent follow-up of these cases.

Case presentation

A 46-year-old man presented with melaena and anaemia. On examination, his vital signs showed a blood pressure of 90/60 and a pulse of 120 bpm with mild epigastric tenderness on palpation.

Investigations

Full blood picture showed a haemoglobin of 7 with a mean corpuscular volume of 65 and biochemistry was normal. Urgent upper gastrointestinal (GI) endoscopy revealed fundal gastric diverticulum, which did not look particularly suspicious (figure 1). However, on advancing the endoscope through the diverticulum, mucosal changes were noted (figure 2). This area was biopsied and histopathology examination revealed gastrointestinal stromal tumours (GISTs) (figure 3).

Figure 1.

Fundal gastric diverticulum.

Figure 2.

Endoscopic view through the diverticulum.

Figure 3.

Histopathology examination with uniform eosinophilic spindle cells arranged in short fascicles.

CT showed a large concentric area of thickening of the gastric fundus with central ulceration (figure 4). At laparotomy, an indurated mass was felt in the gastric fundus. A partial proximal gastrectomy was performed. Macroscopic examination of the resected specimen showed a 8 × 10.5 × 11 cm tumour situated in the submucosa with a cystic cavity within the tumour communicating with the narrowed and compressed gastric lumen (figure 5). Examination revealed it to be strongly C-Kit positive. Along with more than 5 mitotic figures per 50 power fields and size more then 10 cm, this was defined as a high risk category of GIST.

Figure 4.

CT showing large concentric area of thickening of the gastric fundus with central ulceration.

Figure 5.

Macroscopic examination of the resected specimen.

Differential diagnosis

Differential diagnosis would include gastric ulceration, gastric adenocarcinoma or a fistula with the large bowel with malignancy within this.

Outcome and follow-up

The postoperative period was uneventful and the patient was discharged home on the ninth postoperative day. Follow-up with gastroscopy and CT of the abdomen at 4 months later showed no evidence of local recurrence.

Discussion

GISTs are now recognised as a distinct group of mesenchymal tumours^{1 2} and are well-demarcated spherical masses of a few millimetres to over 30 cm that appear to arise from the muscularis propria layer of the GI wall. Intramural in origin, they often project exophytically and/or intraluminally, and they may have overlying mucosal ulceration. Larger GISTs nearly always outgrow their vascular supply leading to extensive areas of necrosis and haemorrhage.^{3 4}

Cytologically, GISTs can be classified into two broad categories: spindle cell GISTs and epithelioid GISTs. Spindle cell GISTs are characterised by nuclear palisading or prominent perinuclear vacuolisation pattern.⁵ Epithelioid GISTs may have either a solid pattern or a myxoid pattern with a possible compartmental pattern.^{3 4 6}

The number of mitotic figures present may be used to histologically grade GISTs. GISTs with less than 1 mitotic figure per 50 high-powered fields (HPFs) are correlated with benign behaviour. A finding of 1–5 mitoses per 10 HPFs suggests potential malignancy. A finding of more than 5 per 10 HPFs indicates malignancy. A finding of more than 10 per 10 HPFs denotes high-grade malignancy.^{3 4 7}

A diagnosis of GIST must be made immunochemically.⁸ Independent of location, most GISTs express the CD34 antigen (70–78%) and the CD117 (72–94%) antigen. Mutations in the CD117 gene have been linked to malignant behaviour in GISTs.^{3 4 9–11} Some GISTS without the KIT mutation have been found to express a mutation in another tyrosine kinase receptor gene—the PDGFRa gene. This gene encodes the platelet-derived growth factor receptor (α receptors) tyrosine kinase protein.^{12 13} Other markers that have been used in the evaluation of GISTs include desmin, actin and S100.³

About 10–30% of GISTs have malignant behaviour.^{3 14} Tumours are more likely to be malignant; however, malignant potential is still seen in all sizes. Malignancy is characterised by local invasion and metastases, particularly to the liver. Increased size or high mitotic rate more then 10 per 50 HPF carry significant risks of recurrence and metastasis.^{15 16} GISTs rarely spread to regional lymph nodes (<10%). Rather, malignancy is manifested by local invasion; distant metastases most commonly involve the liver (50–65%) and peritoneum (21–43%). Only 10% of metastatic lesions occur in the lungs or bones.

Plain radiographs are of little use in diagnosis. Barium images may show intramucosal masses and exophytic elements along with ulcerated areas that fill with barium to give typical ‘target lesions’. CT defines both endoluminal and exophytic extent along with metastatic spread (sensitivity of 87% in detecting GISTS).⁴ MRI is felt to give the best tissue contrast and other modalities include endoscopic ultrasound and angiography. Preoperative diagnosis can be difficult with often inadequate biopsies due to tumour localisation in submucosa;^{17 18} however, ultrasound-guided biopsies carry the risk of seeding.

A benign GIST cannot be conclusively diagnosed because even small, histologically benign-appearing tumours may later demonstrate clinically aggressive behaviour. Factors that are correlated with an improved prognosis include a gastric location, a diameter of less than 2 cm, a low mitotic index and an absence of tumour spillage with complete gross resection. Major negative prognostic factors include large size (>5 cm), high mitotic index and grossly positive resection margins. Other factors with poor prognosis include tumour rupture, distal location, high cellularity, tumour necrosis, the presence of metastases or invasion and mutation in the c-kit gene.^{3 6 11} Findings from two studies show that with microscopic resection, margins are not correlated with improved outcome.^{6 7}

GISTs can present with painless abdominal mass, abdominal pain or discomfort, vomiting, haematemesis, melaena or anaemia.¹⁹ Large tumours grow mainly outward from the bowel wall causing occlusion of their blood supply and necrosis will occur on the inside forming a cavity communicating with the bowel lumen.

Previously, the only proven treatment for GISTs was surgical resection.^{6 20} Excision with a 2 cm margin seems to be most affective treatment;¹⁰ however, local recurrence may occur. Neither radiotherapy nor chemotherapy is successful. Imatinib mesylate (Gleevec; Novartis, Basel, Switzerland), an inhibitor of tyrosine kinases, initially helps control disease in 80% or more of patients.¹² It is effective in early and late-stage disease. Post-treatment, liver lesions become better defined and cyst-like. Five-year survival is about 50% with this figure decreasing to about 35% at 10 years. The median duration of survival is 10–19 months for metastatic or recurrent gastric GISTs.

In some cases, resistance developed following initial responses. Factors thought to be involved include gene amplification and the presence of additional mutations, which may give GISTs an inherent resistance.^21–25

Learning points.

• ▶GISTS represent 1–3% of all GI malignancies.
• ▶Presentation may be a coincidental finding.
• ▶There are varying opinions on the best method of diagnosis.
• ▶Small GISTs may have malignant potential.
• ▶New advances in treatment have improved outcome.