Gastrointestinal Stromal Tumor: An Ultrastructural Investigation on Regional Differences with Considerations on Their Histogenesis

Abstract

Gastrointestinal stromal tumor (GIST) is the most frequent spindle cell tumor in the gastrointestinal tract and may arise from esophagus to rectum. The stomach is the most frequent site, followed by small intestine, rectum, and esophagus. There have been some regional differences reported in their histopathologic and clinical presentations. The purpose of this study is to compare ultrastructural features of GIST, according to its anatomic site, in order to provide additional data to support the current concept of its histogenesis. Fifty-four GISTs (27 from stomach, 23 from small intestine, and 4 from rectum) were included in the study. Histopathologically, gastric GISTs tended to be more frequently epithelioid, particularly those in children, while small intestinal GISTs (SISTs) were mostly spindly in all but three cases. All four of the rectal GISTs were spindly. Ultrastructurally, there seem to be considerable regional differences. In the majority of gastric GISTs, in both epithelioid and spindle types, tumor cells exhibited focal features of myoid differentiation evidenced by the presence of incomplete external lamina (EL) and/or focal accumulations of thin fibers with interrupted electron densities consistent with actin filaments. However, features of myoid differentiation were exceptional for SISTs and rectal GISTs, being present in only one example in each. Some gastric GISTs, particularly those having an epithelioid appearance, showed cell borders luxuriously decorated by long filopods (anemone cell features). Anemone cell features were also present in spindle cell types of gastric GISTs as well as SISTs, albeit it was simpler and less luxuriant. Skeinoid fibers were present in the majority of SISTs and rectal GISTs, but absent in all gastric GISTs except one. These differences appeared to be too significant to propose a uniform histogenesis for all GISTs. Nevertheless, on closer analysis, certain features could be identified to explain a line of differentiation in all GISTs ranging from (1) polygonal uncommitted epithelioid mesenchymal cells with cell borders decorated by luxuriant fimbria, to (2) spindly tumor cells with less prominent fimbria, or (3) cells with or without features of minimum myoid differentiation characterized by the focal presence of cytoplasmic actin fibers or incomplete EL or skeinoid fibers, which might represent an altered product of EL protein. These findings led the author to speculate that the probable primordial cells of GIST may be the primitive mesenchymal cells, which have the potential to differentiate into myoid cells. In this regard, it is important to note that the putative primordial cell of GIST, interstitial cells of Cajal (ICC), and intestinal smooth muscle cells have been shown to develop from the common progenitor cells of the primitive gut, and c-Kit plays a crucial role in the determination of their fate to differentiate to muscle cells or ICC. The author concludes that all GISTs derive from stem cells in the gut retaining some of the differentiation potential se...

Succinate Dehydrogenase Mutation Underlies Global Epigenomic Divergence in Gastrointestinal Stromal Tumor

“…13, 14). GIST is postulated to derive from the lineage of interstitial cell of Cajal (ICC), a mesodermal cell resident of the gastrointestinal tract involved in peristalsis and with both neuronal and mesenchymal characteristics ( 15, 16 ). Thus, neuronal cells and gut muscularis ( Fig.…”

Rectal adenocarcinoma coexisting with gastro-intestinal stromal tumor: A case report and literature review

“…These cells have been shown to express CD117, express insulin-like growth factor and CD34, indicating their stem cell nature. [6] Of late, the occurrence of a second primary malignancy in patients has received much attention as well as the syndromic association of GIST has been described. Syndromes with autosomal dominant hereditary GIST with germ line KIT or PDGFRA mutations have been reported.…”

“…Activating mutations in KIT (75-80%) or platelet-derived growth factor receptor alpha (PDGFRA) (<10%) are the most common oncogenic events in GIST. [4][5][6] The coexistence of GISTs with other epithelial cancers of different histological types is well known and the second tumor can develop synchronously or metachronously. [7] Of special interest are those cases in which one or more tumors were located within the same organ.…”

Frequency, phenotype, and genotype of minute gastrointestinal stromal tumors in the stomach: an autopsy study

“…GISTs are defined as gastrointestinal mesenchymal tumors that, along with a characteristic histomorphologic appearance, express CD117, the receptor tyrosine kinase KIT [2]. Originally thought to arise from the interstitial cells of Cajal (ICC), GISTs are currently believed to originate from multipotential mesenchymal stem cells [3]. Recognition of KIT protein expression in GISTs in 1998 as well as identification of gain-of-function mutations in the c-KIT proto-oncogene in up to 85% of GISTs [4] resulted in the introduction of imatinib mesylate (Gleevec) as the first effective systemic therapy for patients with advanced GISTs [5].…”