Indian Journal of Pathology and Microbiology

: 2016  |  Volume : 59  |  Issue : 4  |  Page : 441--443

Talking KIT of the gastrointestinal stromal tumors

Kim Vaiphei 
 Department of Histopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India

Correspondence Address:
Kim Vaiphei
Department of Histopathology, Postgraduate Institute of Medical Education and Research, Chandigarh

How to cite this article:
Vaiphei K. Talking KIT of the gastrointestinal stromal tumors.Indian J Pathol Microbiol 2016;59:441-443

How to cite this URL:
Vaiphei K. Talking KIT of the gastrointestinal stromal tumors. Indian J Pathol Microbiol [serial online] 2016 [cited 2021 Oct 28 ];59:441-443
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Dear Readers,

To make a brief comment on a rare syndromic presentation of the case in the reference entitled "Combined presence of multiple gastrointestinal stromal tumors (GISTs) along with duodenal submucosal somatostatinoma in a patient with neurofibromatosis type 1 (NF1) [1]" may be tough and challenging. Importantly, understanding the molecular pathways will definitely have a significant impact in the interpretation of the tumors which may exhibit a seemingly innocuous morphology (obviously not in all) but with a complex molecular genetics.

In the following paragraphs, an attempt has been made to discuss the various aspects of a few select pathways (known, unknown, and hypothetical) in context to GIST. GIST is a mesenchymal neoplasm which may be of low-, intermediate-, or high-risk malignant potential. [2] GISTs are generally seen in older individuals, and only 2% of the cases are observed in children. [3] Immunohistochemistry (IHC) and ultrastructural studies have suggested it to be related to interstitial cells of Cajal (ICC). [4],[5],[6] ICC and 95% of GISTs express type III receptor tyrosine kinase (RTK) KIT (CD117) and variably exhibit myoid or neural features. Majority of GISTs exhibit activated mutations in KIT or in the related receptor platelet-derived growth factor receptor α (PDGFRA), and mutations in these two genes are mutually exclusive. [6],[7] About 15% of adult and all pediatric GIST cases lack mutation in these two genes, [8] which are labeled as "wild-type" (WT) GIST. WT GIST may occur in Carney-Stratakis Syndrome (CSS) and Carney's triad (CT). Clinical manifestations of CSS and CT include gastric GIST and paraganglioma, neural crest-derived tumors. The spectrum of neoplasms in CT may be pulmonary chondroma and several other types. [9] CSS is associated with loss of function mutations in succinate dehydrogenase (SDH) enzyme complex subunits (SDHB, SDHC, and SDHD). [10] CT cases are SDH-deficient and associated with epigenetic silencing of SDHC gene [11] and are similar to pediatric GIST, i.e. gets manifested in early age, multifocal in nature, gastric location, and female predominance. [12] Characterizing the SDH-deficient genotype (type 2) helps in distinguishing KIT and PDGFRA mutant types (type 1). Some WT GIST with intact SDH may be associated with a mutation in serine-threonine kinase gene BRAF constituting 5%-15% of sporadic cases and are KIT-positive spindle cell or mixed morphology located primarily in the adult small intestine. [13] The molecular pathogenesis of GISTs lacking kinase mutations remains unknown and is the subject of intense investigations. From the standpoints of light microscopy and IHC, these tumors are indistinguishable from the ones having kinase mutations. [14]

Approximately, 1%-2% of GISTs occur in the context of NF1. [2] NF is due to a mutation in neurofibromin 1 which is an RAS-GAP protein and is a negative regulator for RAS signaling. Germline NF1 mutation accompanied by the somatic event has been identified in NF1 GIST cases. [14] GIST in NF1 is multifocal and involves the small intestine with spindle cell tumor morphology observed in younger age group than the KIT and PDGFRA mutant GISTs. [13] Hence, some of these tumors appear to be driven by an alternative mechanism. KIT or PDGFRA mutation if present may be a late event during the tumor development. Factors causing GIST in NF1 have yet not been identified. However, there are many hypothetical suggestions by various groups based on their observations although none of the studies has made any definite claim still so far. Andersson et al. discussed the possibility of NF1 inactivation resulting in constitutive activation of RAS and increased MAP kinase signaling. [15] Maertens et al. showed that inactivation of neurofibromin 1 was sufficient to hyperactivate MAPK pathway. [14] Yamamoto et al. documented 92% of GISTs of NF1 patients and the precursor hyperplasia of ICC exhibiting activated MAPK p44/42 pathway, and loss of heterozygosity for chromosomes 14q in 87% and 22q in 42% of the cases. Their group had suggested the probable role of tumor suppressor genes in the development of GIST in NF1 patients. [16] Stewart et al. observed GISTs from NF1 patients having homozygosity for mutant NF1 allele and losing the normal WT allele. They have thereby hypothesized that loss of heterozygosity through mitotic recombination could be the initiating mechanism in GIST development. [17] Belinsky et al. studied in detail the results of the whole exome sequencing of the SDH intact WT GIST cases and they could identify a somatic inactivation of NF1 outside the context of NF1 syndrome along with the somatic loss of function mutation in MYC-associated factor X (MAX) gene. [18] NF1 gene changes may be inherited from a parent or in some it occurs before birth without being inherited. NF1 diagnosis is usually made clinically based on first-degree family history and a triad of symptoms, i.e., café-au-lait spots, cutaneous neurofibromas and tumors in central or peripheral nervous system, [19] and 3%-15% of the patients may have associated malignancy. [19] Gastrointestinal tract (GIT) involvement may be observed in one-quarter of the cases in three forms, i.e., hyperplasia of submucosal and myenteric nerve plexuses, GIST and periampullary carcinoid that may be associated with pheochromocytoma, [21],[22] and GIST constitutes 34% of all GIT tumors. [23]

The purpose of the review will be incomplete if one fails to mention the role of Discovered on GIST-1 (DOG1) in the diagnosis of GIST. DOG1 is a calcium-dependent chloride channel protein that regulates the cholinergic activity of gastrointestinal smooth muscle encoded by ANO1/TMEM16A on chromosome 11q13. Its expression by GIST shows high sensitivity and specificity. [24] Other functions of Anoctamin 1 (ANO1) include regulation of cell viability and proliferation. In DOG1+ cells, ANO1 activates alternative signals downstream of RAS/RAF/MEK/ERK and insulin-like growth factor-dependent pathways [25] supporting the role of DOG1 in GIST development, regardless of KIT and PDGFRA status. In KIT-negative PDGFRA-positive GISTs, DOG1 appears to be a promising tool in the diagnosis of rare variants of GISTs including the gastric spindle and epithelioid cell types. [26] Recently, Rizzo et al. had studied DOG1 expression in GISTs and correlated with an aggressive malignant phenotype. [27] Thus, the measurement of DOG1 expression may be helpful in predicting and stratifying recurrence risk.

To summarize, the categorical KIT mutation profiles that may be observed in GIST can be in one or more of the following subgroups:

In KIT mutation, ~80%-95% of GISTs have mutations in KIT RTK, resulting in constitutive activation of the protein. KIT gene is mapped to 4q12-13 in close vicinity of the genes encoding RTK, PDGFRA, and vascular endothelial growth factor receptor 2. Mutations in five different KIT exons observed are exon 11 (67%), exon 9 (10%), and exons 8, 13, and 17 (3%). GISTs may be heterozygous for a particular mutation with loss of WT allele in 8%-15% of the tumors. Variants of KIT mutations exhibit distinct anatomic distributions, i.e., exon 8 (small bowel), exon 9 (small bowel, colon), and exons 11, 13, and 17 (all sites)PDGFRA mutation is observed in 5%-8% of cases and has predilection for stomach with epithelioid morphology, myxoid stroma, nuclear pleomorphism, and variable CD117 expressionWT GIST refers to a group with no detectable mutation either in KIT or PDGFRA though KIT gets phosphorylated and constitutes 12%-15%. This group does not have any peculiar association with anatomic location or clinical outcomeKIT-negative cases refer to the group with negative or uncertain IHC for CD117 in about 5% of the GISTs and about 30% of them harbor PDGFRA gene mutation, and more than half have KIT mutationsSyndromic presentations of GISTs have been associated with NF1 and CT. NF1-associated GISTs tend to be multicentric with spindle cell morphology and no KIT or PDGFRA gene mutations that exhibits CD117 antigen in IHC. CT syndrome-associated GIST has epithelioid morphology in antrum with no KIT and PDGRFA gene mutations and has indolent courseFamilial GIST: Less than a hundred cases have been documented till date with heritable mutations in KIT or PFGFRA genes. Affected individuals develop one or more GISTs by middle age, majority with a benign clinical courseMultiple GIST: Besides the multiple GISTs present in syndromic and familial cases, multiple tumors may also be observed in sporadic, synchronous, and metachronous patients without identifiable germline risk factors, thereby suggesting existence of other genes or factors in the development of GISTSecondary mutation in GISTs may take place during imatinib therapy especially in the setting of a metastatic disease as the result of a secondary imatinib-resistant mutation in KIT or PDGFRA tyrosine kinase domains I and II.


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