Gastrointestinal stromal tumors – definition, clinical, histological, immunohistochemical, and molecular genetic features and differential diagnosis

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal (GI) tract. They are defined here as KIT (CD117, stem cell factor receptor)-positive mesenchymal spindle cell or epithelioid neoplasms primary in the GI tract, omentum, and mesentery. GISTs typically present in older individuals and are most common in the stomach (60–70%), followed by small intestine (20–25%), colon and rectum (5%), and esophagus (<5%). Benign tumors outnumber the malignant ones by a wide margin. Approximately 70% of GISTs are positive for CD34, 20–30% are positive for smooth muscle actin (SMA), 10% are positive for S100 protein and <5% are positive for desmin. The expression of CD34 and SMA is often reciprocal. GISTs commonly have activating mutations in exon 11 (or rarely exon 9 and exon 13) of the KIT gene that encodes a tyrosine kinase receptor for the growth factor named stem cell factor or mast cell growth factor. Ligand-independent activation of KIT appears to be a strong candidate for molecular pathogenesis of GISTs, and it may be a target for future treatment for such tumors. Other genetic changes in GISTs discovered using comparative genomic hybridization include losses in 14q and 22q in both benign and malignant GISTs and occurrence in various gains predominantly in malignant GISTs. GISTs have phenotypic similarities with the interstitial cells of Cajal and, therefore, a histogenetic origin from these cells has been suggested. An alternative possibility, origin of pluripotential stem cells, is also possible; this is supported by the same origin of Cajal cells and smooth muscle and by the common SMA expression in GISTs. GISTs differ clinically and pathogenetically from true leiomyosarcomas (very rare in the GI tract) and leiomyomas. The latter occur in the GI tract, predominantly in the esophagus (intramural tumors) and the colon and rectum (muscularis mucosae tumors). They also differ from schwannomas that are benign S100-positive spindle cell tumors usually presenting in the stomach. GI autonomic nerve tumors (GANTs) are probably a subset of GIST. Other mesenchymal tumors that have to be separated from GISTs include inflammatory myofibroblastic tumors in children, desmoid, and dedifferentiated liposarcoma. Angiosarcomas and metastatic melanomas, both of which are often KIT-positive, should not be confused with GISTs.


Introduction
Gastrointestinal stromal tumors (GISTs) are specific mesenchymal tumors of the GI tract that may occur in the entire length of the GI tract, from the esophagus to the anus and, sometimes, even in the omentum and mesentery adjacent to but separate from the stomach and intestines. These tumors have a wide clinical spectrum from benign, small, incidentally detected nodules to frankly malignant tumors. The recent understanding on their molecular pathogenesis, namely common presence of activating mutations in the gene encoding KIT, may have significant clinical importance, making it necessary to accurately define and clinically diagnose these tumors and separate them from other mesenchymal tumors of the abdomen.
In the earlier literature, GISTs were designated as smooth muscle tumors: leiomyomas, cellular leiomyomas, leiomyoblastomas, and leiomyosarcomas [2]. However, electron microscopic studies in the 1960s demonstrated a lack of typical smooth muscle differentiation in The opinions and assertions contained herein are the expressed views of the authors and are not to be construed as official or reflecting the views of the Departments of the Army or Defense.

Markku Miettinen · Jerzy Lasota
Gastrointestinal stromal tumors -definition, clinical, histological, immunohistochemical, and molecular genetic features and differential diagnosis gastric leiomyoma [78]. Mazur and Clark [35] found that the GI mesenchymal tumors of the stomach, formerly defined as leiomyomas, lacked immunohistochemical features of Schwann cells (S100 protein negative) and did not have ultrasturctural characteristics of smooth muscle cells. Therefore, these authors used the histogenetically neutral designation "gastric stromal tumors", which subsequently has become applied to other, similar tumors in the intestines, and GIST has become the widely applied term now used on the specific mesenchymal tumors of the GI tract.
Because the majority of all mesenchymal tumors of the GI tract (except esophagus) are GISTs, older data on gastric and intestinal smooth muscle tumors [1,17,53,67] largely reflect GISTs. This review will discuss the definition, clinical behavior and prognostic factors, and histological and immunohistochemical spectrum of GIST, pathogenesis and genetics, and the relationship between GISTs and smooth muscle tumors and GISTs and GANTs. The differential diagnosis of GISTs from other mesenchymal tumors of the GI tract will also be discussed.

Definition of gastrointestinal stromal tumors
Gastrointestinal stromal tumors (GISTs) are defined here as cellular spindle cell, epithelioid, or occasionally pleomorphic mesenchymal tumors of the gastrointestinal (GI) tract that express the KIT (CD117, stem cell factor receptor) protein, as detected using immunohistochemistry. The majority of GI mesenchymal tumors are GISTs and are strongly and nearly uniformly KIT positive. Relatively few other tumors may also be KIT positive, but these tumors, metastatic melanoma, angiosarcoma, pulmonary small cell carcinoma, Ewing sarcoma, some other carcinomas, mastocytoma, and seminoma, only rarely enter in the differential diagnosis of GISTs [3,42,44,48,72].
This definition specifically excludes gastrointestinal true smooth muscle tumors (leiomyomas and leiomyosarcomas) and schwannomas and neurofibromas. There is a small, somewhat problematic group of tumors that are in the histological range but do not express KIT. These undifferentiated mesenchymal tumors typically lack all other cell-type markers employed in the differential diagnosis of GIST [CD34, smooth muscle actin (SMA), desmin and S100-protein]. The classification of such tumors with a "null-phenotype" is open. Some investigators may include them among GISTs (when applied in a broad sense), whereas others may exclude them. Correlated morphologic and molecular genetic studies are necessary to determine whether or not these tumors biologically belong to the GIST group.

Epidemiology
According to a population-based sample, we estimate the incidence of GISTs as 10-20/million. Of these, 20-30% are malignant tumors. GISTs typically occur in older individuals over 50 years of age [40]. The median ages in the largest series of GISTs of different locations have ranged between 55 years and 65 years. Some series show a male predominance, and others show equal gender distribution [32,40,43,75]. GISTs are rare before the age of 40 years, and they are very rare in children; we have found that many tumors earlier classified as gastrointestinal smooth muscle tumors in children actually are inflammatory myofibroblastic tumors.
GISTs are most common in the stomach (60-70%), followed by small intestine (20-30%), colon and rectum (5%), and esophagus (<5%). Occasional GISTs primary in the omentum and mesentery have also been reported [38]. The primary site for a malignant GIST extensively involving the abdominal cavity may be impossible to determine.

Clinical presentation
Small GISTs are often incidentally detected on gastric or small intestinal serosa during surgery for other conditions, for example, during gall bladder or gynecologic surgery. GISTs may also be detected during a gastroscopy as submucous nodules or occasionally as incidental radiologic findings. For example, some esophageal GISTs analyzed by us were seen as esophageal masses in routine chest X-ray [41]. Small rectal GISTs may be palpated during routine physical examination (in men during prostate cancer screening and in women during gynecologic examination).
The symptomatic GISTs of the esophagus typically present with dysphagia or occasionally as a mediastinal tumor that at surgery is found to be connected with the esophagus [41]. Gastric and small intestinal GISTs often present with vague symptoms leading to their gastroscopic or radiologic detection, but sometimes they cause upper gastrointestinal bleeding [53,67,75]. Colorectal GISTs may manifest with lower GI bleeding, colonic perforation, pain, obstruction, or combination thereof [43]. A minority of GISTs, usually malignant tumors, may be externally palpable.

Tumor behavior and prognostic factors
Study of larger series of GISTs, defined as KIT-positive tumors, reveals that these tumors have a spectrum of clinical behavior at all sites of their occurrence. In the stomach, the most common site of GIST benign tumors outnumber the malignant ones by a wide margin (3-5:1), whereas most esophageal and colonic GISTs are malignant.
The incidental small GISTs have an invariably benign clinical behavior, probably contributed by the fact that their complete excision is easy. Tumors that show low mitotic frequency (five or fewer mitoses per 50 HPF) usually have a benign behavior. However, there is a defi-