A Case and Literature Review of Complicated Gastrointestinal Stromal Tumors

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract and are believed to originate from the interstitial cells of Cajal. GISTs have a slight male predominance and arise most commonly from the stomach or small intestine, with a median age of 60 years at presentation. Although surgery remains the treatment of choice for localized tumors, imatinib mesylate (Gleevec, Novartis) and more recently sunitinib malate (Sutent, Pfizer), both specific inhibitors of the KIT tyrosine kinase function, have revolutionized the management of unresectable, recurrent, and metastatic GISTs. The treatment paradigm for GISTs has undergone a dramatic advancement and is increasingly being studied as a model for a multidisciplinary approach involving surgery and targeted molecular therapy for management of other solid tumors. Here, we present the case of a GIST in a 61-year-old woman and review the associated literature.

Case Report

A 61-year-old African-American woman presented to our institution with complaints mainly of fatigue and breathlessness upon exertion for 1 year, which had worsened over the prior 2 months. She admitted to a 30-pound weight loss with early satiety, nausea, and dark-colored stools and also complained of left shoulder pain without radiation. Her past medical history was significant for a stroke of unknown etiology and a complete hysterectomy, and overall, she had very little medical follow-up and was not taking any medications. On physical examination, the patient's vital signs were normal, and she was cachectic and appeared older than her stated age. The patient had marked conjunctival pallor, a grade 2/6 systolic murmur at the left upper sternal border, and decreased breath sounds over the left lower lung field. Abdominal examination revealed a large firm mass with poorly defined borders in the left upper quadrant that extended down to the umbilicus. The patient's laboratory examinations were significant for hemoglobin of 6 g/dL, hematocrit of 17.8%, mean corpuscular volume of 55 fL, iron of 9 μg/mL, and total iron binding capacity of 232 μg/mL, with an iron saturation level of 3.9%, which is consistent with severe iron deficiency anemia. In addition, peripheral blood smear was noteworthy for marked microcytosis, hypochromia, and thrombocytosis.

Esophagogastroduodenoscopy performed to evaluate the cause of melena was notable for a 5-cm ulcerated submucosal lesion with a central umbilication in the proximal body of the stomach. There was evidence of chronic bleeding and a long tubular stomach that was suggestive of external compression (Figure 1). A submucosal tumor was suspected; however, endoscopic biopsies were inconclusive. A contrast-enhanced computed tomography (CT) scan of the abdomen revealed a 17 cm × 12 cm × 21 cm heterogeneous mass arising from the body of the stomach, with no evidence of liver metastases, though there were multiple hepatic cysts (Figure 2). In light of the uncertain nature of the biopsies, a CT-guided core biopsy of the abdominal mass was undertaken and revealed spindle-shaped cells scattered with minimal stromal components. Immunohistochemical stains were positive for CD117 (c-KIT), which is diagnostic of a GIST (Figure 3).

Figure 1.

Esophagogastroduodenoscopy demonstrating retroflexed views of the mass with an umbilicated necrotic center (A and B). Long tubular stomach caused by external compression (C).

Figure 2.

Sagittal view of computed tomography scan of the abdomen showing a large intra-abdominal mass causing extensive external compression of the adjacent organs (A). Coronal view of the same mass (B).

Figure 3.

Histomorphology of the abdominal mass, including hematoxylin and eosin stain, 10× (A) and 40× (B), demonstrating abundant spindle-shaped cells scattered within a minimal stroma and positive CD 117 stain, 10× (C) and 40× (D), diagnostic of gastrointestinal stromal tumor.

After being diagnosed with a GIST, the patient underwent an exploratory laparotomy with the intention of having the tumor resected; however, the tumor was not amenable to resection secondary to extensive involvement of the adjacent organs. As a result, she was started on imatinib mesylate therapy. Follow-up CT scans at 3 and 6 months after initiation of the medical therapy have shown considerable reduction in tumor size and overall tumor burden. There has been no metastasis to date, and the patient is currently doing well on medical treatment, 1 year postdiagnosis.

Discussion

GISTs represent more than 80% of all mesenchymal tumors found in the gastrointestinal tract, though they account for only approximately 3% of all gastrointestinal malignancies.^1–3 Historically, various terms and acronyms have been used to describe GISTs such as leiomyomas, leiomyoblastomas, leiomyosarcomas, gastrointestinal autonomic nerve tumor (GANT), smooth muscle tumor of uncertain malignant potential (STUMP), and, most recently, gastrointestinal pacemaker cell tumor (GIPACT).^4–6 These variable classifications could be attributed to a wide array of conflicting histopathologic and electron microscopic features recognized over the past 20 years. It was only in the late 1990s that their distinct cell of origin was identified, and it was shown that GISTs share morphologic, immunophenotypical, and genetic characteristics with the interstitial cells of Cajal.⁷ It has now been well established that GISTs arise from the interstitial cells of Cajal, which are specialized pacemaker cells located around the myenteric plexus of the gut wall, particularly in the stomach and small intestine.^6–10

Physiology of the c-KIT Receptor Tyrosine Kinase and Mutations

More than 90% of GISTs result from gain-of-function mutations of the c-KIT/KIT proto-oncogene.^7,11 KIT encodes for the transmembrane KIT receptor tyrosine kinase. Under physiologic conditions, when the KIT tyrosine kinase receptor is stimulated by its ligand or stem cell factor (also known as steel factor or mast cell growth factor), it is associated with cellular proliferation, differentiation, maturation, survival, chemotaxis, and adhesion.¹² GISTs result from constitutive tyrosine kinase activation (ligand-free activation) by a gain-of-function mutation, which leads to unregulated cell growth and proliferation, resistance to apoptosis, and eventual malignant transformation.^12–14

Most KIT mutations occur as deletions and insertions or point mutations in the juxtamembrane domain encoded by exon 11 (70%).^15,16 Less commonly, they occur in the extracellular region encoded by exons 9 (14%), 13 (4%), or 17 (2%), all of which encode the tyrosine kinase domain.^15,17–19 Approximately 10% of GISTs result from mutations in the KIT-related kinase gene, platelet derived growth factor receptor alpha (PDGFRA).^2,16,17,20 They are seen more often in exon 18 (5.6%) and very rarely in exons 12 (1.5%) and 14 (0.5%). A small percentage of GISTs are wild-type, and some may also be part of familial syndromes such as von Recklinghausen neurofibromatosis (NF1) and the Carney triad (GIST, paraganglioma, and pulmonary chordoma).^15,21 A Swedish study reports a 500-fold increased incidence of GISTs in patients with NF1.²²

Incidence

It is difficult to ascertain the true incidence of GISTs due to the fact that many of them have been misclassified in the past. Data published by the Surveillance, Epidemiology, and End Results program from the National Cancer Institute suggest that the incidence of all gastrointestinal mesenchymal tumors was 0.31 per 1,00,000 in 2002.^15,23 Tis rate reflects an overall increase in incidence, which could be attributed to improved screening of suspected gastrointestinal mesenchymal tumors and improved diagnostic criteria using immunophenotypical features and histologic classification. The National Comprehensive Cancer Network (NCCN) Task Force Report 2007 reports GIST incidence as approximately 14.5 per million people per year or at least 4,500–6,000 new cases per year in the United States.²⁴

Epidemiology

GISTs are generally found in adults over 40 years of age (range, 40–80 years), with a median age of 60 years at presentation and a slight male predominance. Approximately 60% of GISTs arise in the stomach, followed by the small intestine (25–35%) and then the colon and rectum (5–10%).^25–27 True smooth muscle tumors tend to be predominantly in the esophagus. In rare cases, they develop outside of the gastrointestinal tract and have been reported in the mesentery, omentum, or retroperitoneum.^1,27,28

Clinical Features

GISTs vary in size from less than 2 cm to as large as 20 cm, and they can be submucosal, intramural, or subserosal. Smaller tumors (<2 cm) are usually asymptomatic, and they are generally detected incidentally on endoscopy, radiologic imaging, or laparotomy performed for other indications. GISTs tend to displace adjacent tissue and organs without truly infiltrating them and hence can grow remarkably large prior to becoming symptomatic.²⁹ Symptoms depend largely upon the anatomic location and size of the tumor. In two studies published recently, symptomatic tumors were approximately 7 cm in size, asymptomatic tumors were 2 cm, and GISTs detected at autopsy were approximately 1.5 cm.^27,29 Approximately 70% of GISTs are symptomatic at presentation, 20% are asymptomatic and found incidentally, and approximately 10% are found at autopsy. Nonspecific symptoms such as nausea, vomiting, bloating, abdominal pain or discomfort, or increased abdominal girth are commonly seen. GISTs located submucosally often cause ulceration of the overlying mucosa, which leads to melena.²⁷ Hematemesis or hematochezia is rarely a presenting symptom. As with our patient, GISTs can cause chronic occult gastrointestinal bleeding, and patients can present with melena and signs and symptoms consistent with iron deficiency anemia. Depending upon the anatomic location, GISTs can cause dysphagia, biliary obstruction, intussusception, and, rarely, intestinal obstruction in the small bowel.^29,30 Most GISTs are known to possess malignant potential and frequently metastasize to the liver (65%), followed by the peritoneum (25%), and less commonly the omentum. Lymphatic metastasis is rare, as is hematogenous metastasis to organs outside of the gastrointestinal tract, which usually occurs late in the course with fairly advanced disease. Although the literature suggests that most GISTs are symptomatic, there is a possibility that tumors are incidentally found on investigations performed for other indications. Case studies in the literature describing symptomatic GISTs generally represent patients with larger tumors that were symptomatic. More population-based studies are required to further elaborate these observational discrepancies.

Histopathology

These tumors are usually well circumscribed and generally unencapsulated, though a pseudocapsule may be present on rare occasions. On cut sections, they vary in color from gray or white to red or brown, depending upon the degree of necrosis and hemorrhaging. Histologically, two distinct patterns have been described: spindle cell (60–70%) and epithelioid (20–30%), with approximately 10% of GISTs demonstrating both cellular types in variable proportions.^6,11,17,25

Diagnosis

Knowledge of the oncogenesis of GISTs, coupled with the availability of monoclonal and polyclonal antibodies, has greatly aided in achieving a definitive GIST diagnosis. More than 90% of GISTs stain positive for c-KIT/CD117, the current immunohistochemical marker of choice. Approximately 60–70% of GISTs are also positive for CD34, 30–40% are positive for smooth-muscle actin, and approximately 5% stain positive for S-100 protein.^6,7,31,32 GISTs rarely express desmin or vimentin, which is commonly expressed by smooth muscle tumors, as opposed to CD117, which is not expressed in smooth muscle or neural tumors.²¹ Thus, these various tumor markers aid in differentiating GISTs from true smooth muscle tumors and other mesenchymal tumors of neural origin. Suspected GIST tumors in which CD117 immunostaining is negative should be considered for molecular analysis for KIT or PDGFRA mutations in specialized laboratories.³³

Clinical Diagnosis

As with our patient, if the tumor is large, a palpable abdominal mass may be present on physical examination; however, this scenario is rare. Normally, GISTs are detected during routine radiologic and endoscopic investigations for abdominal symptoms.

Contrast-enhanced CT is the radiologic modality of choice for evaluating primary tumors and metastasis, as well as assessing the efficacy of treatment and follow-up. Typically, the tumor appears as a well-circumscribed, hyperdense-enhancing mass closely associated with the stomach or small intestine growing in an extraluminal manner. The tumor often demonstrates a heterogeneous pattern secondary to underlying necrosis or intratumoral hemorrhage.^27,29 GISTs demonstrate hypermetabolic uptake on [18^F] fluorodeoxyglucose (FDG) positron emission tomography (PET) scanning. FDG-PET scans provide high-sensitivity results not only for initial diagnoses, but also for serial monitoring of treatment response; however, they remain underutilized due to cost and limited availability.³⁴

Role of Endoscopy and Endoscopic Ultrasound

On endoscopic examination, GISTs appear as submucosal firm masses often with superficial ulcerations or dimpling. However, there are no absolute diagnostic features on endoscopy. In addition, as most GISTs arise submucosally, it is difficult to obtain adequate biopsy specimens, and the overall diagnostic yield is often low. Endoscopic ultrasonography (EUS) is a valuable tool in evaluating submucosal tumors (SMTs), differentiating true SMTs from extraluminal lesions, and assessing tumor extent and staging. On EUS, a GIST appears as a hypoechoic lesion, usually arising from the muscularis propria (the fourth hypoechoic EUS layer) and less frequently in the muscularis mucosa.³⁵ EUS findings such as a tumor size of greater than 4 cm, irregular extraluminal borders, and the presence of cystic spaces and echogenic foci have been noted to be associated with malignancy. EUS-guided fine-needle aspiration (EUS-FNA) has shown great promise in improving the diagnostic yield. Coupled with immunohistochemical analysis of GISTs, Akahoshi and colleagues and Okubo and associates have recently reported the overall diagnostic accuracy of EUS-FNA to be 86% and 97% respectively.^36,37 However, routine use of preoperative biopsy for a large or symptomatic lesion is not advocated due to the potential risk of tumor rupture and hemorrhage. In addition, preoperative biopsy is discouraged when the tumor is easily resectable.²⁴ Biopsy is appropriate only under certain conditions: when lymphoma is suspected, neoadjuvant therapy is desirable, or management would be affected by the results.^3,12,29 An EUS-guided biopsy is preferred due to the decreased risk of peritoneal and biopsy track seeding in comparison to CT-guided biopsy.²⁴

Prognostic Factors

As even several small GISTs have been shown to have metastatic potential, all GISTs are currently regarded as malignant unless proven otherwise. Tumor size and mitotic index are the two most important prognostic factors used for risk stratification of GIST (Table 1).

Table 1.

Risk Stratification of Gastrointestinal Stromal Tumors Based Upon Size and Mitotic Index (Predictors of Malignant Potential)

Risk category	Tumor size (cm)	Number of mitoses per 50 high-power fields
Very low	<2	<5
Low	2–5	<5
Intermediate	<5 5–10	6–10 <5
High	>5 >10 >Any	>5 Any >10

Adapted from Fletcher CD, et al.²¹

Additional factors such as anatomic location, histologic variant, and type of mutations have been associated with varying prognoses and differences in overall survival rates.²⁵ Those arising from the stomach generally show a favorable outcome following surgery, whereas small-bowel tumors are more aggressive.^12,38,39 It has been demonstrated that the type of mutation has a clear impact on prognosis, overall survival, and response to targeted molecular agents. Deletion mutations behave more aggressively in comparison with insertions and point mutations. With c-KIT, exon 9 mutations are associated with small intestinal localization and aggressive behavior and are found in frankly malignant GISTs. Exon 13 mutations are associated with increased resistance to treatment with imatinib, whereas exon 11 mutations are more responsive.^{15–17,39–42} With PDGFRA, tumors with exon 12 mutations show good response to imatinib whereas those with exon 18 mutations are known to be considerably resistant.^18,19,30 Thus, although routine mutational analysis and genotyping are currently not recommended, they could very well become the standard of care in the future, with targeted molecular therapy thus tailored accordingly.

Treatment

Surgery remains the modality of choice for primary, localized, and resectable GIST. Specific tyrosine kinase inhibitors (TKIs), namely imatinib mesylate and more recently sunitinib malate, have proven to be dramatically effective for unresectable, metastatic, and recurrent disease and are approved by the US Food Drug Administration for the abovementioned indications. Traditional cancer treatment modalities such as chemotherapy and radiotherapy have been shown to be ineffective while treating GIST.^1,30,34

Surgery

As several studies have shown that even smaller GISTs could potentially be malignant, complete surgical resection is recommended whenever feasible. An en bloc resection technique is preferred for patients with localized and resectable disease. Complete tumor excision has been reported in as many as 70% of patients with primary non-metastatic disease.^38,43 Surgical resection is classified as R0 (microscopically negative margins), R1 (microscopically positive margins), or R2 (macroscopically incomplete resection). Not surprisingly, incomplete resections (R2) are associated with a very low 5-year overall survival rate (6–8%), whereas an R0 or R1 improves survival to more than 50%, thus emphasizing the importance of complete resection whenever feasible. More than 60% of GISTs recur usually within the first 2 years after surgical resection, with the liver (65%) and the peritoneum (30%) as the most common initial sites of recurrence.^{1,15,34,44–48} Table 2 summarizes recurrence rates and 5-year overall survival rates from various studies evaluating outcomes after GIST surgery.

Table 2.

Outcome Studies After Complete Surgical Resection (R0/R1) of Primary Localized Gastrointestinal Stromal Tumors

Study	Year	Number of patients	Complete resection (%)	Recurrence/ Metastases (%)	Overall survival
DeMatteo RP, et al.1	2000	200	57	40	54 (5-year)
Crosby JA, et al.34	2001	50	70	43	42
Singer S, et al.39	2002	48	88	Not reported	41
Pierie JP, et al.47	2001	69	59	60	42
Langer C, et al.46	2003	39	90	26	87 (2-year)
Wu PC, et al.48	2003	57	28	Not reported	40 (2-year)
Carboni F, et al.45	2003	15	100	13	87 (2-year)
Besana-Ciani I, et al.44	2003	19	79	Not reported	63 (2-year)
Fujimoto Y, et al.25	2003	140	76	20	93 (2-year)

Lymphadenectomy is seldom required, whereas local peritoneal resection is recommended whenever possible.³⁸ In the past, smaller GISTs (<2 cm) that were confined to the mucosa and submucosa were managed with endoscopic submucosal resection; however, due to the inherent risks of positive tumor margins and tumor spillage, endoscopic submucosal resection is no longer advocated. For similar reasons, the NCCN and the European Society of Medical Oncology generally discourage laparoscopic resection for GIST.³³ More data are needed to weigh the benefits of laparoscopic resection of GISTs against the associated risks of tumor rupture and tumor seeding.

Targeted Molecular Therapy Using Tyrosine Kinase Inhibitors

With the advent of imatinib mesylate, a specific TKI, management of GIST has been revolutionized. Imatinib inhibits cellular proliferation and promotes apoptosis in GIST cells by interrupting tyrosine kinase–mediated intracellular signaling. Apart from c-KIT, imatinib also shows activity against several other tyrosine kinases, including PDGFRA and ABL, the Abelson proto-oncogene.^20,49 The standard starting dose of imatinib for GIST treatment is 400 mg daily. There have been no significant differences in tumor response rates or duration of response using 400 mg or 800 mg of daily imatinib, and optimum dosing remains under extensive investigation. In addition, the duration of therapy has not been well defined; however, it is now known that interrupted therapy leads to disease progression in more than 60% of cases.^15,50

As TKIs reduce tumor burden and induce pharmacologic tumor reduction, it could be possible that previously unresectable GISTs become amenable to surgical resection after treatment with TKIs. Recent studies have clearly validated this hypothesis and have shown improved overall survival rates in patients undergoing surgery following treatment with TKIs.^3,15,51–54

Resistance to Imatinib

Approximately 10% of patients exhibit primary resistance to imatinib. A majority of the cases of secondary imatinib resistance is caused by acquisition of novel and additional KIT or PDGFRA mutations in tumor cells.^55,56 In January 2006, the US Food and Drug Administration approved sunitinib malate for the treatment of metastatic and unresectable GIST. Sunitinib inhibits multiple tyrosine kinases, including KIT, PDGFRA, vascular endothelial growth factor receptor, and Flt-3.^57,58 The efficacy of sunitinib for treatment of imatinib-resistant GISTs is dependent upon the type of mutation responsible for resistance. As a result, mutational analyses are required to tailor therapy in individual imatinib-resistant GISTs. The recommended dose of sunitinib is 50 mg daily, and more trials are underway to ascertain the duration, dosage variations, and side-effect profile. Figure 4 demonstrates a summary of the current multimodality approach used for management of gastrointestinal tumors.

Figure 4.

Summary of the current multimodality approach used for management of gastrointestinal stromal tumors (GISTs).

Follow-up

The NCCN Soft Tissue Sarcoma Group 2007 has recommended standard guidelines for the follow-up of patients with GISTs. Those with a complete resection of the tumor should be observed with a history and physical examination every 3–6 months for 5 years and then annually, along with abdominal/pelvic CTs every 3–6 months for 3–5 years and then annually. High-risk patients should be started on imatinib, and more trials are underway to address the issue. Patients with incomplete resection, persistent gross disease (R2 resection), and metastatic disease should undergo history, physical examination, and abdominal/pelvic CT every 3–6 months. Less aggressive surveillance is acceptable for GISTs smaller than 2 cm and is up to the discretion of the managing physician.²⁴

Summary

GISTs are the most common mesenchymal tumors of the gastrointestinal tract, and the introduction of TKIs has revolutionized the management paradigm. Although most GISTs are symptomatic, a significant percentage is found incidentally, and hence a high degree of suspicion should be kept in mind when examining patients. For suspected mesenchymal tumors of the gastrointestinal tract, an immunohistochemical assay for KIT (CD117) should be performed. For primary, localized, and resectable GISTs, surgery continues to be the first-line treatment of choice. Imatinib mesylate has proven to be a dramatic and valuable discovery for the management of unresectable, recurrent, and metastatic GISTs, and more recently, sunitinib malate has shown promising results in the treatment of imatinib-resistant GISTs. Although currently not recommended, mutational analyses for risk-profile stratification will quite likely become standards of care in the near future. Data from ongoing trials evaluating adjuvant and neoadjuvant imatinib are expected to add more value to the current multidisciplinary approach for the optimal management of GISTs.