Metastatic gastrointestinal stromal tumours of the stomach: A report on two cases and literature review

Introduction 

Gastrointestinal stromal tumours are mesenchymal tumours of the gastrointestinal tract, accounting for approximately 0.2–1% [1], [2] of gastric malignancies. Primary GISTs can originate from all regions of the gastrointestinal tract most commonly being found in the stomach (40–70%), small bowel (20–40%), colorectum (5–15%) and oesophagus (5%) [10]. We report on two cases of large malignant irresectable stromal tumours of the stomach with presence of concomitant distant metastases, treated palliatively, and followed by adjuvant imatinib therapy.

Case report 

Case 1: a 48year old male presented to the surgery department of our hospital with vague abdominal pain and a large lump occupying the entire left abdomen. Clinically, a large lobulated lesion was palpable in the upper abdomen, about 22×19×15cm, predominantly involving the left upper half, and appearing to extend up to the pelvic inlet. Ultrasonography showed a heterogeneous mass with a size of 16×14×12cm, with cystic necrotic components interspersed. A CT scan confirmed the presence of a 11×6cm mass occupying the left upper abdomen (Fig. 1, Fig. 2). Upper gastrointestinal endoscopy revealed a large globular ulcerated lesion with central umbilication at the posterior wall of the body of the stomach. Ultrasound guided biopsy was done and a gastrointestinal stromal tumour was diagnosed.

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Fig. 1. Sagittal view of the abdominal CT scan showing the mass occupying the left upper abdomen.

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Fig. 2. Coronal section of the CT scan with the dimensions of the mass clearly stated.

An exploratory laparotomy was done. Intraoperatively, a large cystic lesion 25×18cm in size, occupying the lesser sac, densely adherent to the posterior wall of the stomach and transverse colon and extending downward up to pelvic inlet was present (Fig. 3). Furthermore, perigastric lymph nodes were also found to be involved. Intratumoural evacuation of haemorrhagic, necrotic material with intralesional drain placement in the lesser sac as well as lymph node biopsy was done and specimen sent for histopathology.

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Fig. 3. Intraoperative photograph with the marker showing the mass at the posterior stomach wall.

Microscopy showed elongated spindle like cells with hyperchromatic nuclei and areas with a whorled pattern, while the cyst wall showed fibrofatty tissue with smooth muscle bundles infiltrated with dense round cells. GIST of the stomach was diagnosed based on these findings. Postoperative period was uneventful and patient was started imatinab mesylate therapy.

Case 2: a 36year female presented to us with anaemia and a lump in her left upper abdomen. Ultrasound was done and it showed a heterogenous mass 10×8×8cm in size with cystic necrotic components interspersed. Upper gastrointestinal endoscopy revealed an antral tumour confined to the submucosa. CT scan was further done and showed a 10cm intramural mass and multiple liver metastases. A concomitant CT guided biopsy was done and it astoundingly diagnosed a GIST of the stomach.

The patient was managed conservatively and subsequently discharged on lifelong therapy of imatinib mesylate.

Discussion 

Gastrointestinal stromal tumours (GISTs) are the most common sarcomas of the gastrointestinal tract, accounting for 0.2% of all gastrointestinal tumours [1], [2]. The term GIST was first used by Mazur and Clarke in 1983 to describe the nonepithelial tumours of the gastrointestinal tract lacking the ultrastructural feature of smooth muscle cells as well as the immunohistochemical characteristics of schwann’s cells [3]. Based on their histologic and immunohistochemical features, GIST are presumed to originate from the interstitial cells of Cajal (ICC), which are components of the intestinal autonomic nervous system and act as pacemakers, regulating intestinal peristalsis [4].

In 1998, Hirota et al. demonstrated the involvement of a functional mutation of the kit proto-oncogene [5]. Kit is a tyrosine kinase receptor that gets activated when bound to a ligand known as ‘steel factor’ [6]. Oncogenic mutations of kit have been found in neoplasms associated with mast cell tumours, myelofibrosis, germ cell tumours, GIST, etc. [7]. GISTs are identified by the universal expression of the CD 117 antigen (95%) [7]. They have been found to be associated with functional mutations in the PDGFRA tyrosine kinase receptor [8]. Furthermore, transition from ICC hyperplasia to low risk GIST is associated with 14q deletion, while loss of 22q is found in high risk or metastatic GIST [9]. The broad morphological spectrum exhibited by GISTs at a light microscopic and ultrastructural level has generated much debate and controversy concerning tumour histogenesis. Although this will probably remain for the foreseeable future, Kindblom et al. [4] and more recently Sircar et al. [10] have elegantly provided considerable support for a possible histogenetic origin from the ICCs encountered in the gastrointestinal tract, which are thought to play a role in coordinating intestinal motility [11], [12]. The ICCs appear to be modified smooth muscle cells occurring at various intramural sites within the intestinal tract, primarily in the muscularis propria and in association with the myenteric plexus.

Sites outside gastrointestinal tract that express CD 117/c-kit are melanocytes, basal cells of epidermis, immature Langerhans cells in the epidermis, variety of epithelial cells (breast/salivary gland/sweat gland/renal tubule), cells present in the reproductive system, a subset of glial cells and osteoclast precursor.

Although CD 117 is a diagnostically useful antigen expressed by the ICC (and in most GISTs), it is important to be aware of the expression of this antigen in a variety of other cells.

Primary GIST can originate from all regions of the gastrointestinal tract but are most commonly found in the stomach (40–70%), small intestine (20–40%), colorectum (5–15%) and oesophagus (5%) [13]. They are equally common in men and women and usually present in the 40–60 age group [14]. Association of paragangliomas, pulmonary chondromas, and gastric lesions, known as ‘Carney’s triad’, was initially classified as leiomyosarcoma [15]. Many GISTs are asymptomatic discovered incidentally during imaging and laparotomy for other reasons. In advanced diseases, patient may present with a mass lesion or with vague abdominal discomfort, although the tumour can grow to a very large size before producing any symptoms. GISTs can be highly vascular and bleeding is one of the most common symptoms. These tumours are typically soft and friable and can cause life threatening haemorrhage. Tumour rupture along with intraperitoneal bleeding can occur, leading to a high risk of dissemination by peritoneal seeding of the tumour. Obstruction of the gastrointestinal tract is occasionally a condition at presentation and can lead to perforation. GISTs with overt metastatic diseases account for 5–15% of all cases [13], [16]. The most common metastatic sites are the liver and peritoneum. Diffuse peritoneal spread is not uncommon and may involve innumerable small tumour nodules replacing the omentum, studding the diaphragmatic surface or covering the serosal surface of the bowel.

GISTs, gastrointestinal leiomyoma or leiomyosarcoma, schwannoma, local extension by a primary retroperitoneal dedifferentiated liposarcoma, benign and malignant vascular tumours, intra-abdominal fibromatosis (desmoid tumour), carcinoid with a spindle cell morphology ST and metastatic disease (spindle cell melanoma/spindle cell carcinoma) are the predominant tumours that may need to be considered in the differential diagnosis. Most of these tumours can be characterised accurately on the basis of precise clinical data and diligent microscopy, supplemented by appropriate immunohistochemical, ultrastructural, and molecular biological analyses. Differentiating GISTs from true smooth muscle tumours is clinically relevant because of differences in biological behaviour and can sometimes be difficult.

They cannot be easily differentiated from other GI tumours of smooth muscle origin (Fig. 4, Fig. 5), however, because of their submucosal location. Fine needle aspiration or core biopsy with endoscopic ultrasound guidance is commonly required to obtain tissue for diagnosis [17]. CT scans are used to determine the anatomic extent of the GIST and to assist with operative planning. Unfortunately, CT is unable to differentiate between inflammatory adhesions and malignant involvement of an adjoining organ, and is unlikely to identify any peritoneal metastasis smaller than 2cm in diameter. PET scan is useful along with CT for evaluating GIST in totality as well as for assessing response to chemotherapy. Sequential scans prior to and after imatinib mesylate reliably and rapidly indicate the responsiveness or resistance of the tumour to therapy [18].

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Fig. 4. Epitheloid variety of GIST on histopathology.

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Fig. 5. Spindle cell variety of GIST on histopathology.

GIST exhibits a wide spectrum of clinical behaviour. It may remain stable for years. Primary tumours more than 5cm and those with increased mitotic activity are associated with poor prognosis. Location of the tumour in the small bowel further worsens the outcome [1], [19].

Surgery remains the gold standard therapy for all resectable tumours. The importance of clear resection of margins should be emphasized. Tumour rupture or any trauma to the pseudocapsule is associated with an enormously increased risk of recurrence, including a risk of dissemination of tumour throughout the peritoneum. If lesions involve adjacent organs, en bloc resection must be done in order to avoid further spillage. Overall 5year survival rates after complete resection of localised GIST are 40–55% [20], [21], [22], [23]. Lymph node metastases are extremely rare so that regional lymphadenectomy is not recommended routinely. Lymph node dissection should be undertaken for patients with any evidence or suspicion of nodal metastasis.

The typical site of tumour recurrence following resection of GIST is the liver and peritoneum. Pulmonary metastases are rare. Mostly abdominal/pelvic CT scans are used for post treatment follow up.

Although it is not well documented which group of patients will benefit most from imatinib treatment as well as the duration of treatment, its success as an orally administered inhibitor of the kit receptor tyrosine kinase in managing metastatic disease has lead to an improvement of resectability, especially in cases of technically inoperable primary tumours. Responses to imatinib are evident in 30–40% of patients after 7months and 50–60% after 9months of treatment [24]. Surgery is performed when tumour size has decreased to the point at which resection is technically possible or when successive CT scans show no further evidence of tumour shrinkage.

In conclusion, GISTs are the most common mesenchymal neoplasms of the stomach and small intestine and are relatively less frequent at other gastrointestinal sites. A lack of awareness of their broad morphological spectrum can complicate diagnosis. Nevertheless, an increasing awareness of their immunophenotypic, ultrastructural, and genotypic features coupled with an evolving understanding of their histogenesis is facilitating our ability to identify these tumours. Surgery remains the gold standard for treatment of patients with resectable, localised gastrointestinal stromal tumours. On the contrary, palliation along with imatinib forms the mainstay in managing the converse. Due to the rarity of lymph node metastases, lymph node dissection should be undertaken only in case of evidence or suspicion of nodal involvement. A guarded approach is, thus, vital in the appropriate as well as timely management and satisfactory outcome of such patients.