Section 2 -

Gastrointestinal Stromal Tumors (GISTs) Brian Rubin University of Washington Medical Center Seattle, WA

Clinical Features: While GISTs were originally thought to be very rare, it is now apparent that they are much more common than previously thought, with as many as 4,500-6,000 new cases in the USA each year. [1] They have an equal sex predilection and although they arise over a wide age range, from pediatric to elderly patients, 75% of GISTs occur in individuals over the age of 50. [1] Overall, the median age is 58 years. [1] GISTs can arise anywhere along the gastrointestinal (GI) tract. Approximately 5% arise within the esophagus, 50% in the stomach, 25% in the small bowel, and 10% in the colon and rectum. Most of the colorectal lesions are found within the rectum. In approximately 10% of patients, GISTs arise outside of the tubal gut, within the mesentery, omentum, retroperitoneum, or pelvis and are known collectively as EGISTs. [2] Presenting symptoms include early satiety, bloating, gastrointestinal bleeding, or fatigue related to anemia. [1] Clinically aggressive GISTs metastasize to the liver or disseminate diffusely throughout the abdomen. [5] GISTs rarely (<<1%) metastasize to lymph nodes or spread outside of the abdomen. Pathologic Features: GIST can be identified as incidental lesions identified at routine endoscopy or in resection specimens that are removed for other reasons (ie-gastric carcinoma). GISTs vary in size from less than 1 cm to very large lesions measuring more than 35 cm. The median size is approximately 5 cm. [4] GISTs are usually centered on the bowel wall but may extend inward towards the mucosa, outwards towards the bowel wall, or have a dumbbell configuration with both mucosal and serosal based masses. They are usually uninodular but may present as multiple/numerous nodules. On cut section, GISTs are usually fleshy and solid but may have central cystic degeneration, hemorrhage, or necrosis. GISTs can exhibit either epithelioid or spindle cell cytomorphology and mixed spindle cell and epithelioid GISTs are common. [5] Spindle cell GISTs are usually arranged in fascicles while epithelioid lesions may be arranged in nests or sheets. The stroma can be hyalinized or myxoid and blood vessels can be very prominent, mimicking solitary fibrous tumor/hemangiopericytoma. Cytologically, GISTs are very monomorphic, with rounded to elongated nuclei with fine chromatin and inconspicuous nucleoli, and abundant pale pink fibrillary cytoplasm. They can also exhibit prominent paranuclear vacuoles, extensive nuclear palisading, and hyaline eosinophilic cytoplasmic structures known as "skenoid" fibers. [5] Mitotic activity is usually very minimal (<1 mitotic figure/10 HPF). Necrosis can be seen. Pleomorphism is very rare; present in approximately 2% of all GISTs. [5] Diffuse pleomorphism involving entire resection specimens, is virtually never seen in GISTs. Immunohistochemical Features: Approximately 95% of GISTs are positive for KIT (CD117), 60-70% are positive for CD34, 30-40% for smooth muscle actin (SMA), 5% are positive for S-100 protein, and 1-2% are positive for desmin or keratin. [5] KIT positivity is usually diffuse and strong and can have a cytoplasmic, membranous, or paranuclear "dot-like" distribution. Approximately 5% of GISTs are negative for KIT. [6] Identification of KIT or PDGFRA mutations can be helpful in confirming the diagnosis of GIST in morphologically unusual or KIT negative cases. Cytogenetic Features: GISTs tend to have relatively simple karyotypes. Loss of chromosome 14 followed by losses of 1p, 9p, 11p, or 22q are the most common cytogenetic findings. [11] High-grade lesions typically, have at least three cytogenetic changes. Loss of 9p is associated with aggressive/malignant behavior and appears to represent loss of the p16Ink4a tumor suppressor gene. [8] Molecular Features: KIT is a receptor tyrosine kinase that is involved in the development and maintenance of germ cells, hematopoietic cells, melanocytes, and interstitial cells of Cajal. [7] GISTs are believed to arise from interstitial cell of Cajal precursors through activating KIT or platelet derived growth factor receptor A gene (PDGFRA) mutations. [9, 10, 11] KIT mutations are identified in 85-90% of GISTs regardless of size. Studies have shown that these mutations result in ligand independent activation of KIT. [9] Approximately 3-4% of GISTs have mutations within PDGFRA. [11] These mutations are very similar to KIT mutations and also result in ligand independent kinase activation. A small number of families, with familial GISTs, inherited with an autosomal dominant pattern of inheritance, harbor germline activating KIT or PDGFRA mutations identical to those seen in sporadic (non-familial) GISTs. [7, 12] Interestingly, all patients that harbor germline activating KIT or PDGFRA mutations develop ICC hyperplasias and GISTs. Recently, two mouse GIST models have been developed by transgenic "knock-in" technology that harbor germline activating KIT mutations of the type seen in sporadic and familial GISTs. [13, 14]A s is seen in humans, mice harboring the activated KIT alleles develop ICC hyperplasia and/or GISTs with 100% penetrance. Prognostic Factors and Risk Stratification: The most important prognostic factors are size and mitotic count. [15] However, low mitotic rate and small size does not absolutely guarantee a benign clinical course. Small GISTs with a low mitotic rate have been known to metastasize. [15] This prompted the development of guidelines for defining risk of aggressive behavior based on size and mitotic rate. [5] Central to these guidelines is the idea that all GISTs have potential for aggressive clinical behavior. The guidelines were developed during a consensus conference at the United States National Institutes of Health in April, 2001. The guidelines are summarized in Table 1. Table 1 – Proposed Guidelines for Defining Risk of Aggressive Behavior in GISTs [5] Size Mitotic Count Very Low Risk < 2 cm < 5 per 50 HPF Low Risk 2-5 cm < 5 per 50 HPF Intermediate Risk < 5 cm 5-10 cm 6-10 per 50 HPF < 5 per 50 HPF High Risk > 5 cm > 10 cm Any size > 5 per 50 HPF Any mitotic rate > 10 per 50 HPF Therapeutic Considerations: The revelation that most GISTs harbor activating KIT mutations spawned the hypothesis that targeting KIT might be useful in treating GISTs. [16] This was particularly important since prior to the onset of targeted therapy, GISTs did not respond to any known chemotherapy or radiation therapy. However, with the availability of imatinib mesylate (Gleevec®, Glivec®), a small molecule inhibitor that binds to the kinase domain of KIT and PDFRA, cooperative group studies were initiated to study the efficacy in GIST. These studies have shown that GIST responds well to imatinib, although the response is dependent on the location of the KIT mutation within the KIT gene. [17] While primary resistance to imatinib does occur, the majority of KIT mutations are responsive to imatinib and a proportion of PDGFRA mutations also respond. Imatinib has largely been studied as salvage therapy for recurrent/metastatic GISTs but ongoing studies are looking at using imatinib in the neoadjuvant and adjuvant setting. Finally, acquired, secondary resistance to imatinib is an emerging problem. [18] The mechanism of resistance is due to acquisition of a second site mutation within KIT or PDGFRA that disrupts the interaction with imatinib. Differential Diagnosis: The main differential diagnosis of conventional GIST includes true smooth muscle tumors (leiomyomas and leiomyosarcomas), schwannoma, inflammatory fibroid polyp, and desmoid fibromatosis. Immunohistochemical studies are extremely helpful in sorting out this differential diagnosis. True smooth muscle tumors are positive for smooth muscle actin and desmin and are negative for KIT. Schwannomas are positive for S-100 protein and are negative for KIT. Inflammatory fibroid polyps can be positive for CD34. However, they are negative for KIT and contain inflammatory cells including eosinophils. There is some controversy about whether or not desmoid fibromatosis is positive for KIT. However, reports of KIT immunoreactivity in desmoids seem to be related to overzealous antigen retrieval. For this reason, we do not use antigen retrieval with KIT immunohistochemistry and have found KIT to be negative in fibromatosis. However, care should be taken in the use of KIT immunohistochemistry since melanomas, germ cell tumors, angiosarcomas and some carcinomas are also positive for KIT. Fortunately, these lesions can usually be excluded on the basis of their characteristic morphologic features and immunoreactivity for other antibodies that are not positive in GIST. References Rubin, BP. Gastrointestinal stromal tumors: an update. Histopathology. 2006;48:83-96. Reith JD, Goldblum JR, Lyles RH, et al. Extragastrointestinal (soft tissue) stromal tumors: an analysis of 48 cases with emphasis on histologic predictors of outcome. Mod Pathol. 2000;13:577-585. Miettinen M and Lasota J. Gastrointestinal stromal tumors--definition, clinical, histological, immunohistochemical, and molecular genetic features and differential diagnosis. Virchows Arch. 2001;438:1-12. Hasegawa T, Matsuno Y, Shimoda T, et al. Gastrointestinal stromal tumor: consistent CD117 immunostaining for diagnosis, and prognostic classification based on tumor size and MIB-1 grade. Hum Pathol. 2002;33:669-676. Fletcher CD, Berman JJ, Corless C, et al. Diagnosis of gastrointestinal stromal tumors: A consensus approach. Hum Pathol. 2002;33:459-465. Medeiros F, Corless CL, Duensing A, et al. KIT-negative gastrointestinal stromal tumors: proof of concept and therapeutic implications. Am J Surg Pathol. 2004;28:889-894. Heinrich MC, Rubin BP, Longley J, et al. Biology and genetic aspects of gastrointestinal stromal tumors: KIT activation and cytogenetic alterations. Hum Pathol. 2002;33-484-495. Schneider-Stock R, Boltze C, Lasota J, et al. High prognostic value of p16INK4 alterations in gastrointestinal stromal tumors. J Clin Oncol. 2003;21:1688-1697. Hirota S, Isozaki K, Moriyama Y, et al. Gain-of-function mutations in c-kit in human gastrointestinal stromal tumors. Science. 1998;279:577-80. Rubin BP, Singer S, Tsao C, et al. KIT activation is a ubiquitous feature of gastrointestinal stromal tumors. Cancer Res. 2001;61:8118-8121. Heinrich MC, Corless CL, Duensing A, et al. PDGFRA activating mutations in gastrointestinal stromal tumors. Science. 2003;299:708-710. Nishida T, Hirota S, Taniguchi, et al. Familial gastrointestinal stromal tumours with germline mutation of the KIT gene. Nat Genet. 1998;19:323-324. Rubin BP, Antonescu CR, Scott-Browne JP, et al. A knock-in mouse model of gastrointestinal stromal tumor harboring Kit K641E. Cancer Res. 2005;65:6631-6639. Sommer G, Agosti V, Ehlers I, et al. Gastrointestinal stromal tumors in a mouse model by targeted mutation of the Kit receptor tyrosine kinase. Proc Natl Acad Sci USA.2003;100:6706-6711. Miettinen M, El-Rifai W, Sobin LH, et al. Evaluation of malignancy and prognosis of gastrointestinal stromal tumors: a review. Hum Pathol. 2002;33:478-483. Dematteo R, Heinrich MC, El-Rifai W, et al. Clinical management of gastrointestinal stromal tumors: before and after STI-571. Hum Pathol. 2001;33:466-477. Heinrich MC, Corless CL, Demetri GD, et al. Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol. 2003;21:4342-4349. Chen LL, Sabripour M, Andtbacka RH, et al. Imatinib reistance in gastrointestinal stromal tumors. Curr Oncol Rep. 2005;7:293-299.