GISTs originate from the interstitial cell of Cajal or its precursor, within the submucosa or muscularis propria, but may extend toward the serosa (extraluminal or exophytic type) or lumen (endoluminal type). Clinical symptoms typically vary depending on the tumor size, growth type, and location. Most patients presenting with symptoms have tumors that exceed 5 cm in maximum dimension, and some tumors are as large as 30–40 cm at presentation. The most frequent symptoms include early satiety, gastrointestinal or intraperitoneal hemorrhage, and abdominal mass or pain. Intestinal obstruction and intestinal perforation can also occur. Associated symptoms may include nausea, vomiting, anorexia, and weight loss. Other patients with GISTs are asymptomatic and are incidentally diagnosed by abdominal imaging or endoscopy. No laboratory test can confirm or exclude the diagnosis of a GIST [7].

Radiologic exams are often essential in determining the size, location, extent of local invasion, and operative strategy for the treatment of GISTs. Imaging is also critical in restaging, monitoring the response to therapy, and performing follow-up surveillance for recurrence. Contrast-enhanced computed topography (CT) is preferred for initial screening and staging because of its superior ability to provide a comprehensive evaluation of the abdomen (Fig. 28.3). Magnetic resonance imaging (MRI) may be preferred for the evaluation of GISTs in certain anatomic sites such as the rectum or liver. Tumors that are greater than 5 cm, lobulated, enhance heterogeneously, and have mesenteric fat infiltration, ulceration, or an exophytic growth pattern are more likely to demonstrate metastatic or recurrent behavior. Conversely, smaller GISTs, those with an endoluminal growth pattern, and those with a homogeneous pattern of enhancement tend to demonstrate less aggressive behavior.

While positron emission tomography (PET) imaging of GISTs is rarely required for the evaluation of localized disease, PET is capable of detecting sub-centimeter lesions and may therefore be useful for detecting an unknown primary site or monitoring the response to systemic therapy. PET can also help differentiate active tumor from necrotic or inactive scar tissue, malignant from benign tissue, and recurrence from nondescript postsurgical changes.

On upper gastrointestinal endoscopy, a smooth, mucosa-lined protrusion of the bowel wall may be present, with or without signs of ulceration (Fig. 28.1). Standard endoscopic biopsies usually do not obtain sufficient tissue for a definite diagnosis. Endoscopic ultrasound (EUS)-guided fine-needle aspiration (FNA) or forceps biopsies have a higher yield and may also be useful for excluding the diagnosis of other submucosal lesions (Fig. 28.2). Definitive tissue diagnosis is not required for a resectable lesion in which there is a high suspicion for a GIST, but biopsy should be performed to confirm the diagnosis when metastatic disease is present or suspected. A biopsy is also required for patients with a locally advanced GIST who are being considered for neoadjuvant therapy. EUS-FNA of the primary site is preferred over percutaneous biopsy due to the risk of tumor hemorrhage and dissemination.

The gross pattern of GISTs is diverse but most are well-circumscribed nodular masses. However, they can also be multinodular and exhibit foci of cystic degeneration, hemorrhage, and necrosis. Microscopically, most GISTs can be divided into histologic subgroups including both spindle cell type, epithelioid type, and mixed variants. Intestinal variants are histologically more homogenous group of tumors. Differentiation between GISTs and other spindle cell tumors is typically based upon morphology, immunohistochemistry staining, and molecular analysis. Approximately 85–90 % of GISTs has gain-of-function mutations of KIT and PDGFRA genes and characteristically stain positive for either KIT (CD117), CD34, or DOG1. The level of expression can vary from diffuse and strong to focal and weakly positive. CD34, however, is not a sensitive or specific marker, staining only 50–80 % of gastric and small intestinal GIST. The morphologic identification of KIT negative remains a diagnostic challenge, but a newly discovered antigen known as DOG1 (discovered on GIST-1) can help to identify certain KIT-negative GISTs. DOG1 is a calcium-dependent, receptor-activated chloride channel protein, and it is expressed in GISTs independent of mutation type. In view of the cross-reactivity and expression of these antibodies in a variety of other spindle cell mesenchymal tumors considered in the differential diagnosis of GIST, a panel of antibodies is recommended and include CD117, DOG1, CD34, S10, desmin, smooth muscle actin, and keratin as indicated.

Several factors have been identified as contributing to clinical outcomes in patients with GISTs. The most reliable prognostic factors for GISTs are tumor size, location of the primary tumor, and the mitotic index [8]. Gastric tumors have a more favorable prognosis than the intestinal ones with similar characteristics [9]. Risk of metastatic disease or recurrence is higher for tumors greater than 5 cm and those demonstrating high cellularity, prominent nuclear pleomorphism, necrosis, greater than 5 mitoses per 50 high-power field (HPF), and invasion into adjacent structures. Historically, some GISTs were classified as “benign” based on a size less than 2 cm and favorable histologic features, but with long-term follow-up, it is becoming increasingly clear that virtually all GISTs have the potential for malignant behavior and recurrence.

The American Joint Commission on Cancer (AJCC) and International Union Against Cancer (UICC) first included a TNM (tumor/node/metastasis) classification and staging system for GISTs in the 2010 7th edition of the cancer staging manual (Table 28.1) [10]. The T-categories are based on tumor size and then combined with mitotic rate and tumor site to define a clinical stage. Given the rarity of nodal metastasis with GISTs, any patient without examined regional nodes is considered to be N0. The presence of either nodal or distant disease is classified as stage IV. There remains some controversy as to whether or not the TNM system applies well to GISTs since factors known to predict outcomes such as mutation type and tumor rupture are not included.

Operative resection remains the treatment of choice for a localized GIST (Table 28.2). Complete surgical resection of the gross tumor and pseudocapsule including en bloc resection of any involved adjacent organs is recommended if possible. GISTs are fragile and should be handled with care to avoid tumor rupture. Both nonradical resection with a positive margin (R1) and tumor rupture are associated with adverse outcomes. Because lymph node involvement is exceedingly rare, extensive lymphadenectomy does not provide a survival advantage and is not recommended. Repeat resection is generally not indicated for microscopically positive margins on final pathology, although every effort should be made to obtain negative microscopic margins at the initial operation.

Most gastric GISTs can be resected using a wedge resection with a 1–2 cm margin. For tumors along the greater curvature of the stomach, the omentum is removed from the stomach near the tumor. For lesser curvature lesions, a pyloromyotomy should be performed if the vagal nerves supplying the pylorus are disrupted. Many GISTs may be resected using a laparoscopic approach. Extraluminal tumors (serosal based) are easily localized laparoscopically, while endoluminal tumors may require concurrent upper endoscopy. In laparoscopic resections, the specimen should be removed from the abdomen in an endoscopic retrieval bag to avoid spillage or seeding of port sites. Sphincter-sparing surgery should be considered for rectal GISTs. In selected cases, neoadjuvant imatinib therapy may enable sphincter-sparing surgery and improve outcomes in patients with low rectal GISTs. Even when complete resection is achieved, many tumors can recur, often involving the liver and peritoneum.

Systemic chemotherapy and radiation have minimal activity against GISTs and are not routinely recommended. Since tyrosine kinase activation occurs in the majority of cases, tyrosine kinase inhibition (TKI) has emerged as the primary therapeutic modality for metastatic or recurrent GISTs (Table 28.3).