Immunopheotype of Gastrointestinal stromal tumours (GIST)

It has been suggested that GISTs originate from the interstitial cell of Cajal (ICC), or from a primitive stem cell that differentiates towards both the ICC and smooth muscle phenotye.

GISTs occur at every level of the GI tract. Most tumours arise in the stomach (60%) and about
20–30% occur in the small intestine. Colorectal and oesophageal GISTs account for less than 10%. A small proportion of GISTs arise in extra-GI tract sites including the omentum, mesentery and retroperitoneum.

Morphologic patterns:
GISTs show a spectrum of histological features.Morphologically, the cells of GISTs are spindle, epithelioid, mixed pattern and occasionally pleomorphic.Spindle cell type is the predominant pattern, seen in 70% of GIST cases.

The overwhelming majority of GISTs express KIT protein (detected as CD117).The results of KIT immunostaining depend on several technical factors including fixation, tissue preparation, variations in antibody clones in terms of specificity and sensitivity, antibody dilutions and staining techniques. This may account, in part, for the reported immunophenotypic heterogeneity in GISTs. Recently, it has been emphasized that CD117should be performed without epitope retrieval.

Given the potential clinical importance of CD117 immunostaining, optimization of the staining techniques and reproducibility are critical. The pattern of staining is variable Diffuse strong cytoplasmic staining is the predominant pattern. Membranous staining and dot-like ‘golgi pattern’ staining can be identified. It has been suggested that different staining patterns correlate with different types of c-kit mutations. Stromal mast cells and ICC are useful internal positive controls to supplement the normal positive and negative controls.

Immunohistochemical detection of KIT does not necessarily imply c-kit activation. Indeed, CD117 is expressed by other tumour types such as melanoma and soft tissue sarcomas including dermatofibrosarcoma protuberans, synovial sarcoma and angiosarcomas. Therefore, CD117 immunoreactivity should be interpreted in the context of morphology and clinical setting.However, it is increasingly recognized that a high level of KIT expression is not characteristic for tumours with non-mutant KIT isoforms or tumours harbouring PDGFRA mutations.
CD34 is a transmembrane glycoprotein present on human haematopoietic progenitor cells and vascular endothelium. CD34 is detectable in approximately 70% of GISTs. The oesophageal and rectal GISTs have the highest frequency of CD34 positivity, whereas small intestinal tumours are the lowest percentage of CD34 positivity.

Actin expression is reported in approximately 30% of cases.Smooth muscle actin (SMA)expression is often reciprocal with CD34 expression: the SMA-positive tumours are often CD34 negative and vice versa. Some tumours may show a mosaic pattern with actin-positive and CD34-negative areas and vice versa.
Desmin-positive immunostaining is uncommon and, if present, is often limited to scattered tumour cells. Prominent staining is more common in epithelioid neoplasms. GISTs are generally negative for S100. Focal positive staining for cytokeratin markers can be seen especially in malignant epithelioid GISTs.

Proliferation markers (Ki-67, MIB-1 and proliferating cell nuclear antigen (PCNA)) may aid in tumour evaluation. It has been reported that tumours with more than 10% of nuclei that are positive for the KI-67 analogue are associated with metastases and poor survival rate.

In other studies, the MIB-1 index was not superior to mitotic count as a prognostic factor. Alterations of the tumour suppressor gene p16INK4A have been shown to be an independently poor prognostic factor.It has been previously regative p16 immunostaining is associated with malignant behaviour in GISTs.

GISTs with PDGFRA mutations are usually CD117 negative but may respond to STI-571; therefore, KIT detection may not be required for the treatment eligibility for Imatininb.

1)Rubin BP, Fletcher JA, Fletcher CD. Molecular Insights into the histogenesis and pathogenesis of gastrointestinal stromal tumors. Int J Surg Pathol 2000;8:5–10.
2)Kindblom LG, Remotti HE, Aldenborg F, Meis-Kindblom JM.Gastrointestinal pacemaker cell tumor (GIPACT): gastrointestinal stromal tumors show phenotypic characteristics of the
interstitial cells of Cajal. Am J Pathol 1998;152:1259–69.
3) Miettinen M, Lasota J. Gastrointestinal stromal tumors—definition, clinical, histological, immunohistochemical, and molecular genetic features and differential diagnosis.
Virchows Arch 2001;438:1–12.

4)M.Sabah et al.Gastrointestinal stromal tumours: An update.Current Diagnostic Pathology (2005) 11, 400–410

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Interesting Case

Clinical History:

53 years male,History of hypertension and tachycardia,MRI abdomen:-Left adrenal mass:- size 5.8 cm Right renal mass:- size-3.0cm Microscopic examination of the renal mass showed vascular tumor with diffuse sheets of clear cells having Fuhrman grade III nuclei. There was no evidence of necrosis within the tumor. There was no evidence of extraparenchymal invasion.
Gross examination of the left adrenal gland revealed cortically centered, solid and multinodular mass measuring 6.5 x 6.0 x 5.0 cm and weighing 122 grams. The tumor was encapsulated but showed evidence of extraparenchymal penetration. The tumor had golden brown cut surface with areas of hemorrhage and necrosis. The partial nephrectomy showed 3.0cm x 3.0cm x 3.0 cm yellow solid mass which did not invade into the perinephric adipose tissue.
Microscopically, the adrenal mass had predominant diffuse sheets and focal trabecular arrangements. The former pattern was present in about third of tumor. The cells had clear cytoplasm and round to ovoid nuclei with conspicuous nucleoli. Mitotic rate was 9/50 HPF and included atypical forms. Gross necrosis and capsular invasion were documented microscopically. There was no evidence of lymphovascular invasion. Considering the above mentioned features, a Weiss histopathologic score2 of 7/9 was applied.


The differential diagnosis included Renal Cell Carcinoma (RCC) with contralateral adrenal metastasis, Adrenocortical carcinoma (ACC) with contralateral renal metastasis, synchronous RCC and ACC or synchronous RCC and adrenocortical adenoma. A panel of immunohistochemical stains was performed to sort out the diagnosis. Adrenal tumor demonstrated strong Vimentin positivity and is negative for CK7, CK20, E1/AE3, EMA, Synaptophysin and S100.Renal cell carcinoma was positive for CK7, AE1/AE3, EMA (weak) and Vimentin. It was negative for CK20, Synaptophysin and S100. The difference of immunoprofile between the two tumors documented that they originated from two different primaries.

Final Diagnosis:

The diagnosis of synchronous RCC and ACC rather than metastasis influences the prognosis.


The longest disease free interval after removal of contralateral adrenal metastasis was 12.1 years8 and the longest crude survival was 14.3 years. In contrast non metastazing RCC has an excellent prognosis if no metastasis developed.