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Laboratory Investigation of Gastrointestinal Stromal Tumour

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Published: 23rd Sep 2019 in Biology

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Title: Describe the laboratory investigation of GIST.

Gastrointestinal Stromal Tumour (GIST) is one of the most commonly seen mesenchymal neoplasms, a soft tissue sarcoma, present in any area of the gastrointestinal tract (GI tract) and can have extra-gastrointestinal involvement as well. The stomach is the most common site (about 70%). GIST mainly affects middle aged to elderly adults, typically in their 60s with no clear gender preference although some studies demonstrated a slightly greater number of males affected. GISTs are tumours that begin in the smooth muscle cells of the GIT tract wall known as the pace maker interstitial cells of Cajal (ICCs). ICCs are cells that are part of the autonomic nervous system (Joensuu et al., 2002).

Classification of GISTs

Before the late 1990s, any non-epithelial tumours found in the GI tract were classified as GIST. However, with the development of molecular techniques, the molecular basis of GISTs was identified. Histopathologists were now able to distinguish between different types of tumours of the GI tract as either a GIST tumour or another type of tumour based on molecular differences. CD34 and CD117 are identified as markers that can help distinguish between these different types.

Signs and Symptoms of GIST

Symptoms of GIST can include GI tract bleeding, difficulty swallowing or metastasis, particularly the liver. Rarely is intestinal obstruction seen as a result of the outward growth of the tumour. Generally there is a history of vague abdominal pain or discomfort and the tumour is often large when diagnosed.

Pathophysiology of GIST

Unlike other tumours of the GI tract, GIST tumours are non-epithelial tumours, they are connective tissue tumours such as sarcomas. Most GIST tumours occur in the stomach, then small intestine and rarely in the esophagus. Small tumours are generally benign particularly when the mitotic rate is slow, whereas large tumours can metastasize to the liver, omentum or peritoneum. Other abdominal organs, they rarely occur in.

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Almost all GISTs are sporadic, meaning that the mutations are random occurrences affecting single individuals. However, there are rare examples of GIST running in families or due to idiopathic multitumour syndromes. Inheritable germ line mutations, where these tumours are driven by mutations in the genes such as KIT (85%), PDGFRA (10%) or BRAF kinase (rarely). These patients usually have multiple GISTs. GIST rarely occurs along side other syndromes such as neurofibromatosis type I. However, individuals with this syndrome contain a higher chance of GIST development (Steigen and Eide, 2009).

An abnormal c-KIT pathway is associated with about 85% of GISTs. A transmembrane receptor for a growth factor called stem cell factor (scf) is what this c-KIT gene encodes for. Mutation of the gene itself is what causes most of the abnormal c-KIT pathway, however, a small number are due to the constitutive activity of the KIT enzymatic pathway. The product of the c-KIT gene is called CD117, which is found on ICCs, and mainly mast cells, melanocytes and bone marrow cells. However, in the GI tract, a tumour staining positive for CD117 is generally a GIST, originating from ICCs. CD117 is a vital diagnostic marker in diagnosing GIST. The mutations in the c-KIT gene, allow it to function in the absence of the scf, resulting in a high mitotic rate. Other mutations are required for the cell with the c-KIT mutation are required for the cell to progress into a GIST. This mutation is more than likely the first step.

A few GISTs with no mutation in the c-KIT gene, show mutations in the gene for a closely related tyrosine kinase receptor termed Platelet Derived Growth Factor Receptor Alpha (PDGFRA). C-KIT and PDGFRA mutations are mutually exclusive. GISTs with no mutation in either genes, is referred to as wild type tumours (Quek and George, 2009).

Diagnosis of GIST

Often CT scanning is undertaken. However, the definitive diagnosis is made using a biopsy, which is taken by endoscopy, percutaneously using ultrasound or CT or taken during surgery.

Microscopic morphology of GIST

In the histopathology laboratory diagnosis of GIST, microscopically, GISTS have a broad morphological spectrum (Joensuu et al., 2002).

GISTs may be malignant or benign. However, it is now considered that all GIST tumours have malignant potential and that GIST tumours cannot be definitively classified as benign. The benign features are small size, encapsulation (can remove easily with surgery), very low mitotic activity and absence of necrosis. The malignant features are presence of metastases at the time of surgery and may have an invasive margin and high mitotic activity (Steigen and Eide, 2009).

There are three primary histological sub-types of GIST which are spindle cell type (70%), epithelioid type (about 25%) and mixed spindle -epithelioid cell type. Generally, GISTs have a broad variation ranging from hypocellular to hypercellular with higher mitotic activity. Nuclear pleomorphism is uncommon and is found more often in epithelioid type (Katz and DeMatteo, 2008).

Figure 1: Common Haematoxylin and Eosin staining histological features of GIST.

(A) spindle cells with short fascicles and whorls.

(B) ) spindle cells with longer fascicles in bundles.

(C) spindle cells with extensive perinuclear vacuolization.

(D) spindle cells with prominent nuclear palisading.

(E)  epithelioid cells with pleomorphic nuclei and vacuolated cytoplasm.

(F)  epithelioid cells with rhabdoid features (Quek and George, 2009).

The GIST spindle cell type is comprised of cells arranged short fascicles and whorls.They exhibit pale eosinophilic fibrillary cytoplasm, oval nuclei and undefined cell borders. Gastric spindle cells generally exhibit vast perinuclear vacuolization. The distinctive histological patterns found in spindle cells are sclerosing type and palisading vacuolated type. The sclerosing spindle contain slender spindle cells with no nuclear atypia and low mitotic rate and are normally  pauicellular with vast extracellular collagen. The sclerosing spindle cells are generally small and have calcifications. The palisading vacuolated spindle cell type is one of the most occurring gastric GISTs and normally cellular with uniform and plump spindle cells. Nuclear palisading spindle cells with perinuclear vacuolization is typical. There is normally limited atypia with mitotic rate rarely greater than 10/15 high power fields (Heinrich, 2003).

GIST epithelioid cells are typically round cells organised in nests or sheets and have eosinophilic to clear cytoplasm. They also contain spectrums from sclerosing and pauicellular to sarcomatous and mitotically inactive to mitotically highly active. Although the epithelioid cells that have atypia, even with pleomorphism are sometimes found to be benign (Hirota et al., 2003).

Immunohistochemistry of GIST

In the immunohistochemistry aspect of the laboratory, most GISTs (95%) are strongly and diffusely KIT (CD117) positive, which allows KIT to be a very specific and a sensitive immunohistochemistry marker in differentiating GIST diagnostically from other mesenchyma tumours in the GI tract. KIT is a cell membrane spanning signalling molecule (receptor for tyrosine kinase) that triggers cell growth when activated by a specific stem cell ligand. The stain is visible as cytoplasmic, membrane associated or as perinuclear dots. Even though KIT positivity has important treatment implications, the intensity and extent of KIT staining neither correlates with the type mutation in KIT nor the therapeutic importance. A negative result for KIT does not rule out the patient from treatment with tyrosine kinase inhibitor (TKI) (sunitinib or imatinib) as a few wild type GISTs for both PDGFRA and KIT genes respond to TKI treatment (Joensuu et al., 2002).

CD34 is another common immunohistochemistry marker for GIST, but is not as specific or sensitive. CD34 is positive in approximately 80% of gastric GISTs, 50% of small bowel GISTs and in 95% of colorectal and esophageal GISTs (Steigen and Eide, 2009).

Other immunohistochemistry markers which may be expressed by GISTs are SMA, h-caldesmon, desmin, S100, cytokeratins 8 and 18 and Vimentin. Recently other CD markers for GISTs are reported including CD10, CD133 and CD44 (Katz and DeMatteo, 2008).

Figure 2: Immunohistochemical staining features of GIST.

(A) Spindle cell with strong and diffuse cytoplasmic staining of CD117 (c-kit).

(B) Spindle cell with strong and diffuse membrane staining of CD34.

(C) Epithelioid cell with strong cytoplasmic staining of CD117.

(D) Epithelioid cell with patchy and heterogeneous staining of CD34.

(E)  Epithelioid cell with punctate staining of h-Caldesmon

(F)  Epithelioid cell GIST with patchy mambrane staining of h-Caldesmon (Quek and George, 2009).

A small minority of GIST (<5%) are negative for KIT, or minimally, if positive for KIT by immunohistochemistry. These tumours look to have either mutant PDGFRA or KIT wild type, have a preference to stomach or peritoneum and are usually epithelioid or mixed subtype. For this subgroup of GISTs that are negative for KIT, many new antibodies in the diagnosis of GIST have been identified. DOG1, a transmembrane protein, has been found specifically in GISTs. Studies have found that antibodies directed against DOG1 have higher specificity and sensitivity than KIT and CD34 with 75% to 100% sensitivity overall. KIT mutant GISTs highly express DOG1 and DOG1 can also detect about one third of GISTs that are negative for KIT, which generally have the PDGFRA mutation. DOG1, like KIT, is also found in interstitial cells of Cajal (Quek and George, 2009).

Differential diagnosis of GIST

In the differential diagnosis of GISTS, although GISTS are the most common mesenchymal tumour of the GI tract, a variety of other tumours should be included in the differential diagnosis. These are schwannoma, leiomyoma, leiomyosarcoma, inflammatory myofibroblastic tumor, inflammatory fibroid polyp, fibromatosis and melanoma. However, due to the identification of the molecular basis of GIST, histopathologists are able to now distinguish between different types of tumours (Steigen and Eide, 2009).

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Most frequently intramural leiomyomas are present in the esophagus and are rarely in the small intestine and stomach. Leiomyomas are normally less cellular than GISTs, and in opposition to GISTs, they frequently display greater eosinophilic cytoplasm with well-delineated cell borders. Immunohistochemically, leiomyomas are diffusely positive for desmin, smooth muscle actin (SMA) and h-caldesmon and are KIT negative. Even though most GISTs are desmin negative, rare cases express desmin, which can result in misclassification as a smooth muscle tumor. Whats different to leiomyomas, desmin immunoreactivity is focal (Katz and DeMatteo, 2008).

Primary leiomyosarcomas are extremely rare of the GI tract. They generally are present in older adults and most frequently occur in the colon. In contrast to GISTs, leiomyosarcomas are comprised of spindle-shaped cells, with brightly eosinophilic cytoplasm, along with diffuse or focal nuclear pleomorphism and high mitotic rate. KIT positivity is extremely rare in leiomyosarcomas (Katz and DeMatteo, 2008).

Uncommon tumours are gastrointestinal schwannomas that are present in the stomach or colon and are rare in other parts of the GI tract. They display a dense, peripheral cuff of lymphocytes with or without germinal centers and are comprised of cells that exhibit strong immunoreactivity for glial fibrillary acid protein and S100 in the stomach. They are KIT and CD34 negative. They normally lack well-defined nuclear palisading, foamy histocytes, verocay bodies and hyalinized vessels that are characteristic of schwannomas everywhere else. Seen in up to 33% of GISTs is nuclear palisading and perivascular hyalinization. As well as morphological differences, GI schwannomas look to be genetically distinct compared with non-GI schwannomas (Quek and George, 2009).

Mesenteric fibromatosis or intra-abdominal desmoid fibromatosis because of its gross appearance as well as its location can be confused with GIST. It may occur either sporadically or in Gardner syndrome. Microscopically, it is has an infiltrative growth pattern, in contrast to rounded, expansile borders of GISTs. It is comprised of long, sweeping fascicles of spindle to stellate fibroblasts in a collagenous or keloidal stroma. The stroma in GISTs are more myxoid or hyalinized, and keloidal collagen, when present, they surround nests of cells rather than individual cells as is seen in fibromatosis. Another important feature of feature that aids to differentiate these tumours is the vascular pattern. Desmoid tumors display small, muscular arteries and dilated, thin-walled veins in the lesion. Nuclear β-catenin immunoreactivity is present in 75% to 90% of cases of fibromatosis, while it is negative in GIST (Quek and George, 2009).

Inflammatory myofibroblastic tumor are present in paediatrics and young adults and can occur as a mesenteric mass. Histologically, this tumour has greater heterogenous composition with spindle cell areas mixed with a mainly plasma cell-rich inflammatory infiltrate. These tumors are KIT negative. The marker used for diagnosing this tumour is anaplastic lymphoma kinase; but, it is found in less than 50% of cases. (Katz and DeMatteo, 2008).

A submucosa mesenchymal tumour is a inflammatory fibroid polyp that has a preference for the stomach and small intestine. In the morphology aspect, there is a proliferation of spindle and stellate cells that form whorls around blood vessels. The stroma has a granulation tissue like display and enriched with lymphocytes, eosinophils, and plasma cells. Inflammatory fibroid polyps are confused with GISTs as they are positive for CD34 too. Although they are KIT and DOG1 negative. Mutations in PDGFRA of the same type that are in GISTs have been seen in inflammatory fibroid polyps too (Quek and George, 2009).

Epithelioid GISTs have to be separated from carcinoma, melanoma, germ cell tumors, seminoma, clear cell sarcoma and glomus tumor. Melanomas display various of morphologic patterns, such as spindle and epithelioid cell types, and, so, are included in the differential diagnosis of GIST. This is even more complicated as they are KIT positive. Melanoma marker expression such as HMB-45, S100 or Melan-A, aids to solve this differential. The immunoreactivity of KIT in metastatic melanomas can be weaker than it is in primary tumors. Rare are Glomus tumors in the GI tract and are found exclusively in the stomach. They are a uniform cell population with pale eosinophilic staining cytoplasm with round nuclei that display strong immunoreactivity for smooth muscle actin and are negative for S100, desmin and KIT. Clear cell sarcomas of the GI tract are often HMB-45 negative. Apart from the characteristic morphology of large epithelioid cells that have numerous pale eosinophilic staining to nonstaining cytoplasm and stroma that is rich in lymphocytes, seminomas are able to be separated from GISTs using their distinctive immunoreactivity for transcription factor OCT4 and placental alkaline phosphatase. They can, however, exhibit diffuse immunoreactivity with KIT resulting in a potential diagnostic downfall.

Immunohistochemistry plays a vital role in the differential diagnosis. Combining the morphology and the immunohistochemistry results, in the majority of cases enables an accurate diagnosis (Quek and George, 2009).

The risk and staging of GIST

Different GISTs have different risk classifications of their tendency to reoccur or metastasize, dependent on their size, location, mitotic activity, surgical margins and the status of the rupture of the tumour. It is thought that establishing a level of risk for GIST (low, intermediate, or high) is better than calling the tumor as malignant or benign. The most indicators of aggressive behavior are tumor size of 5 cm and 5 mitoses/50 HPF. Risk classification also incorporates the primary site of the tumor as well as the mitotic count and its size. Gastric GISTs have a better prognosis as they have a malignant potential that is lower than other GISTs found in other areas of the gastrointestinal tract. Anatomic site is a parameter in risk assessment for GIST. GISTs that are smaller than 2 cm are considered  benign. Additional factors such as rupture of tumour and non-radical resection, are both linked to an adverse outcome for the patient, that are not affected by any other factors. The presence of a ruptured tumor is regarded as a high risk factor irrespective of its mitotic count or size (Joensuu et al., 2002).

All GISTs, benign or malignant are eligible for staging. In the TNM staging, GIST grading is based on mitotic activity. Mitotic activity lower than 5/50 HPFs (High Power Fields) is low (grade 1) and more than 5/50 HPFs is high (grade 2). However, different staging criteria is used for small intestinal GISTs and gastric GISTs to highlight the more aggressive clinical nature of small intestinal GISTs even with similar parameters of tumor (Steigen and Eide, 2009).


  • Heinrich, M. (2003). PDGFRA Activating Mutations in Gastrointestinal Stromal Tumors. Science, 299(5607), pp.708-710.
  • Hirota, S., Ohashi, A., Nishida, T., Isozaki, K., Kinoshita, K., Shinomura, Y. and Kitamura, Y. (2003). Gain-of-function mutations of platelet-derived growth factor receptor α gene in gastrointestinal stromal tumors. Gastroenterology, 125(3), pp.660-667.
  • Joensuu, H., Fletcher, C., Dimitrijevic, S., Silberman, S., Roberts, P. and Demetri, G. (2002). Management of malignant gastrointestinal stromal tumours. The Lancet Oncology, 3(11), pp.655-664.
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  • Steigen, S. and Eide, T. (2009). Gastrointestinal stromal tumors (GISTs): a review. APMIS, 117(2), pp.73-86.


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