2010年NCCN胃肠间质瘤诊疗指南

and Jeffrey D. Wayne Raut, Richard F. Riedel, Scott Schuetze, Hema M. Sundar, Jonathan C. Trent P.DeMatteo, Kristen N. Ganjoo, Robert G. Maki, Peter W.T. Pisters, Chandrajit George D. Demetri, Margaret von Mehren, Cristina R. Antonescu, Ronald P. with Gastrointestinal Stromal Tumors NCCN Task Force Report: Update on the Management of Patients Harborside Press, 37 Main Street, Cold Spring Harbor, NY 11724 is published by JNCCN – The Journal of the National Comprehensive Cancer Network Print ISSN: 1540-1405. Online ISSN: 1540-1413. . All rights reserved. Copyright © 2010 by the National Comprehensive Cancer Network 2010;8:S-1-S-41J Natl Compr Canc Netw Online article http://www.jnccn.org/content/8/Suppl_2/S-1.full Supplemental Material Suppl_2.S-1.DC1.html http://www.jnccn.org/http://www.jnccn.org/content/suppl/2011/07/19/8. Subscriptions http://www.jnccn.org/site/subscriptions/ is online at Comprehensive Cancer Network JNCCN – The Journal of the NationalInformation about subscribing to Permissions http://www.NCCN.org/permissionsmaterial, please go online to For information about photocopying, republishing, reprinting, or adapting NCCN.org . Al l r ig ht s re se rv ed . Co py rig ht © 2 01 0 by th e Na tio na l C om pr eh en siv e Ca nc er N et wo rk fro m 0 0. 00 0. 00 0. 0 o n M ar ch 7 , 2 01 3 by g ue st jnc cn .or g D ow nl oa de d fro m Supplement © Journal of the National Comprehensive Cancer Network | Volume 8 Supplement 2 | April 2010 S-1 Key Words NCCN, gastrointestinal stromal tumor, GIST, gastric mass, stomach cancer, abdominal tumor, small bowel tumor, gastrointestinal tract, liver metastasis, tyrosine kinase inhibitors, TKIs, KIT, CD117, PDGFRA, wild-type GISTs, gene expression profiling, GEP, imatinib, sunitinib Abstract The standard of care for managing patients with gastrointestinal stromal tumors (GISTs) rapidly changed after the introduction of effective molecularly targeted therapies involving tyrosine kinase inhibitors (TKIs), such as imatinib mesylate and sunitinib malate. A better understanding of the molecular characteristics of GISTs have improved the diagnostic accuracy and led to the discovery of novel immunomarkers and new mechanisms of resistance to TKI therapy, which in turn have resulted in the development of novel treatment strategies. To address these issues, the NCCN organized a task force consisting of a multidisciplinary panel of experts in the fields of medical oncology, surgical oncology, molecular diagnos- tics, and pathology to discuss the recent advances, identify areas of future research, and recommend an optimal approach to care for patients with GIST at all stages of disease. The task force met for the first time in October 2003 and again in December 2006 and Oc- tober 2009. This supplement describes the recent developments in the field of GIST as discussed at the October 2009 meeting. (JNCCN 2010;8[Suppl 2]:S1–S40) in one of the receptor protein tyrosine kinases: KIT (CD117) or platelet-derived growth factor receptor alpha (PDGFRA). The standard of care in the management of patients with GIST rapidly changed after the introduction of ty- rosine kinase inhibitors (TKIs), such as imatinib mesyl- ate and sunitinib malate. This supplement describes the recent developments in the field of GIST. Given the limitations of these data, the authors encourage enroll- ment of patients in clinical trials when possible. Epidemiology SEER (Surveillance, Epidemiology, and End Re- sults) data from the National Cancer Institute in the mid-1990s indicated that sarcomas account for 2.2% of gastric cancers, 13.9% of small bowel cancers, and 0.1% of colorectal cancers. Most of these gastrointes- tinal sarcomas are presumably GISTs.2 These percent- ages suggested that only 500 to 600 new cases of GIST would occur each year in the United States, but this significantly underestimated the true incidence, because many cases were not captured in the SEER registries for various reasons. The age-adjusted yearly incidence rate of GIST was 6.8 per million in the SEER data from 1992 to 2000, with 54% men and 46% women.3 Population-based studies from Iceland, the Netherlands, Spain, and Swe- den reported annual incidence rates ranging from 6.5 to 14.5 cases per million, but these figures may also contain GISTs detected incidentally and at autopsy.4–7 Assum- ing an annual incidence rate of 10 per million, approxi- mately 3000 GISTs might be diagnosed in the United Background Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. Neoplastic GIST cells seem to arise from a com- mon precursor cell, which gives rise to the interstitial cells of Cajal in the normal myenteric plexus.1 GISTs can arise anywhere along the gastrointestinal tract but are most common in the stomach and small intestine, most commonly resulting from activating mutations NCCN Task Force Report: Update on the Management of Patients with Gastrointestinal Stromal Tumors George D. Demetri, MD; Margaret von Mehren, MD; Cristina R. Antonescu, MD; Ronald P. DeMatteo, MD; Kristen N. Ganjoo, MD; Robert G. Maki, MD, PhD; Peter W.T. Pisters, MD; Chandrajit P. Raut, MD, MSc; Richard F. Riedel, MD; Scott Schuetze, MD, PhD; Hema M. Sundar, PhD; Jonathan C. Trent, MD, PhD; and Jeffrey D. Wayne, MD . Al l r ig ht s re se rv ed . Co py rig ht © 2 01 0 by th e Na tio na l C om pr eh en siv e Ca nc er N et wo rk fro m 0 0. 00 0. 00 0. 0 o n M ar ch 7 , 2 01 3 by g ue st jnc cn .or g D ow nl oa de d fro m Supplement NCCN Task Force Report © Journal of the National Comprehensive Cancer Network | Volume 8 Supplement 2 | April 2010 S-2 Extragastrointestinal (soft tissue) stromal tumors are histologically and immunophenotypically similar to their gastrointestinal counterpart but have an ag- gressive course similar to small intestinal than gas- tric stromal tumors.15 Recurrence after resection is predominantly intra-abdominal, and the liver is the most common site of recurrence in patients with primary presentation and those with metastatic dis- ease at presentation.16 Lymph node metastases are extremely uncommon; spread to the lungs or other extra-abdominal locations are also extremely rare. GISTs are associated with a broad range of pre- sentations. Many are identified clinically because they cause symptoms and some are identified at au- topsy. Small GISTs that are smaller than 2 cm usu- ally do not produce any symptoms and are detected incidentally during abdominal exploration, endos- copy, or radiologic imaging.17 In a recent population- based study, the median tumor size of GISTs that were detected based on symptoms, incidental find- ings, or during an autopsy were 8.9, 2.7, and 3.4 cm, respectively.7 In general, patients with a suspected GIST may present with various symptoms, including but not limited to early satiety, fatigue secondary to anemia, intraperitoneal hemorrhage, intraluminal gastroin- testinal bleeding, or abdominal discomfort from pain or swelling. Some patients may present with an acute abdomen (as result of tumor rupture, gastrointesti- nal obstruction, or appendicitis-like pain), which requires immediate medical attention. Pathology and Differential Diagnosis GISTs range in size from incidental lesions a few mil- limeters in diameter to large masses of 35 cm or more; the median size at presentation is approximately 5 cm. The tumors are generally centered on the bowel wall, but may form polypoid serosal- or mucosal- based masses. Ulceration of the mucosa is often as- sociated with gastrointestinal bleeding. Most GISTs present as a single, well-circumscribed nodule. The cut surface is fleshy and may show areas of cystic de- generation, necrosis, or hemorrhage. Occasionally, satellite nodules are within the adjacent peritoneal surface. Rarely, a patient will have 2 separate GISTs at different locations in the gastrointestinal tract. In these cases, familial GIST should be considered, which is typically associated with interstitial cell of States per year. The incidence of GIST is not known for all populations; most data refer to Caucasian in- dustrialized populations. The diagnosis of GIST has dramatically increased since 1992, and survival has greatly improved since 2002, when the FDA ap- proved imatinib mesylate.8 The increase in the num- ber of GISTs diagnosed per year is likely from greater awareness and improved histopathologic detection, although the true incidence also may be increasing.9 Small GISTs (only a few millimeters in diam- eter) are common in the general adult population. These “mini-GISTs” are immunopositive for KIT and often contain an oncogenic mutation in the KIT or PDGFRA gene.10 In a series of consecutive autop- sies performed in Germany, small GISTs (1–10 mm) were grossly detectable in 22.5% of the autopsies in individuals older than 50 years.10 These findings sug- gest that most small GISTs do not progress rapidly into large macroscopic tumors despite the presence of a KIT or PDGFRA mutation. GIST has been reported in all age groups, in- cluding newborn infants. However, it is extremely rare in patients younger than 30 years. The median age at diagnosis ranges from 66 to 69 years in popula- tion-based series that include cases found at autopsy, which are diagnosed about a decade later than symp- tomatic GISTs.4,7 In a study of 1765 gastric GISTs, the median age at diagnosis was 63 years.11 In a series consisting of 906 jejunal and ileal GISTs, the mean age was 59 years.12 In the latter 2 series, only 2.7% of gastric GISTs and 0.6% of small bowel GISTs were detected in patients younger than 21 years. Thus, this supplement refers to the manage- ment of GIST in adult patients. Pediatric GIST and other GIST variants (familial GIST and neurofibromatosis-1 [NF-1]-associated GIST) that require specialized management are briefly discussed. Clinical Presentation In adult GISTs, the stomach (60%) and small in- testine (30%) are the most common primary sites; duodenum (5%) and colorectum (< 5%) are the less common primary sites. Rectal GISTs are uncommon, and GISTs originating in the colon are rare. Only a small number of cases (< 1%) have been reported in the esophagus and appendix. On rare occasions GISTs develop outside the gastrointestinal tract in the mesentery, omentum, or retroperitoneum.13,14 . Al l r ig ht s re se rv ed . Co py rig ht © 2 01 0 by th e Na tio na l C om pr eh en siv e Ca nc er N et wo rk fro m 0 0. 00 0. 00 0. 0 o n M ar ch 7 , 2 01 3 by g ue st jnc cn .or g D ow nl oa de d fro m Supplement Management of GIST © Journal of the National Comprehensive Cancer Network | Volume 8 Supplement 2 | April 2010 S-3 Cajal hyperplasia within myenteric plexus. Most GISTs show 1 of 3 histologic patterns: spindle cell type (70%; Figure 1), predominantly epithelioid cell type (20%; Figure 2), or a mixture of both spindle and epithelioid cells.14 Epithelioid GISTs may have either a diffuse or nested architec- ture, whereas spindle cells GISTs are arranged in short fascicles or whorls. The stroma is usually scanty but may vary from hyalinized to myxoid; extensive- ly myxoid GISTs are rare. Most spindle cell GISTs have a uniform cytology, with fibrillary eosinophilic cytoplasm and nuclei containing fine chromatin and inconspicuous nucleoli. Marked cytologic pleomor- phism is rare and should raise the possibility of an alternative diagnosis. However, epithelioid GIST may often show evidence of bi- or multinucleation, and a more significant nuclear atypia, compared with the spindle cell counterpart. Unusual but strik- ing features seen in a subset of cases are prominent paranuclear vacuoles (usually in gastric lesions), hyaline eosinophilic material known as skeinoid fi- bers (mainly in small bowel lesions), and extensive nuclear palisading. The morphologic differential diagnosis of spin- dle cell GIST is broad and includes both benign and malignant lesions, such as smooth muscle tu- mors (leiomyoma, leiomyosarcoma), schwanno- ma, intra-abdominal desmoid-type fibromatosis, inflammatory myofibroblastic tumor, solitary fi- brous tumor, and sarcomatoid carcinoma. The dif- ferential diagnosis for epithelioid GIST includes carcinoma, metastatic melanoma, clear cell sar- coma, epithelioid variants of leiomyosarcoma, and epithelioid hemangioendothelioma. Obtaining adequate tumor tissue material for de- finitive diagnosis before surgical resection has been challenging. Because these tumors tend to be soft and friable, biopsy may cause tumor rupture and be associ- ated with an increased risk for tumor dissemination. Furthermore, the diagnosis of GIST can be highly suspected based on endoscopic ultrasound (EUS) or esophagogastroduodenoscopy. Recent reports have suggested that definitive diagnosis of GIST requires tissue acquisition through EUS-guided fine-needle aspiration.18 However, biopsy may not be necessary if the tumor is easily resectable and preoperative therapy is not required. Conversely, biopsy might be needed if preoperative therapy is being considered for unresectable or marginally resectable tumors. The diagnosis of GIST has evolved over a short period. In patients with a remote history of an ab- dominal or pelvic tumor diagnosed as something different, such as a leiomyosarcoma or leiomyoblas- toma, re-examination of the tumor using current morphologic, immunophenotypic, and genotypic Figure 1 Spindle cell gastrointestinal stromal tumor (GIST). Typical morphology of a low-risk GIST comprised predomi- nantly of spindle cells. This tumor was strongly KIT-positive and harbored a mutation in KIT exon 11 (H&E stain; original magnification, 400x). Courtesy of Christopher L. Corless, MD, PhD, Oregon Health & Science University. Figure 2 Intermediate-risk gastrointestinal stromal tumor (GIST) comprised predominantly of epithelioid cells. The tumor was KIT-positive and contained a mutation in KIT exon 9 (H&E stain; original magnification, 400x). Courtesy of Christopher L. Corless, MD, PhD, Oregon Health & Science University. . Al l r ig ht s re se rv ed . Co py rig ht © 2 01 0 by th e Na tio na l C om pr eh en siv e Ca nc er N et wo rk fro m 0 0. 00 0. 00 0. 0 o n M ar ch 7 , 2 01 3 by g ue st jnc cn .or g D ow nl oa de d fro m Supplement NCCN Task Force Report © Journal of the National Comprehensive Cancer Network | Volume 8 Supplement 2 | April 2010 S-4 able (47% in small bowel and 96%–100% in the rec- tum and esophagus), whereas SMA expression was most frequent in small bowel GISTs (47%) and rare in GISTs of the rectum and esophagus (10%–13%). Desmin was seen only occasionally. S100 positivity was rare but was seen most frequently in small intes- tinal GISTs (15%).22 In contrast to GIST, leiomyoma and leiomyosar- coma are positive for SMA and desmin and negative for KIT and CD34. Malignant melanoma exhibits diffuse immunoreactivity for S100 protein, but can be focally positive for KIT. Schwannomas are strong- ly and diffusely immunoreactive for S100 protein and negative for KIT. Intra-abdominal desmoid-type fibromatosis may show weak, nonspecific staining for KIT, but express nuclear reactivity for beta-catenin. Sarcomatoid carcinoma tends to be pleomorphic, highly mitotically active, positive for cytokeratins, and negative for KIT and CD34. KIT-Negative GISTs: Approximately 5% of GISTs are truly negative for detectable KIT expression, the so-called “KIT-negative GISTs.”23,24 Establishing the diagnosis of KIT-negative GIST remains a challenge and is best handled by a reference pathologist with expertise in this area. Precise diagnosis is of utmost importance because some KIT-negative tumors are known to be sensitive to imatinib. The location and morphology of the tumor and the results of immu- nohistochemical staining for KIT are essential to confirm diagnosis. In a proportion of KIT-negative GISTs, the genotypic analysis shows mutations in the PDGFRA gene rather than KIT. 25–27 Many of these PDGFRA-mutant GISTs have an epithelioid mor- phology (Figure 3). Immunostaining with PDGFRA has been shown in this particular setting to be help- ful in discriminating between KIT-negative GISTs and other gastrointestinal mesenchymal lesions.28–30 BRAF mutations have also been reported in a small subset of intestinal high-risk GISTs (imatinib- naive or -resistant) lacking KIT/PDGFRA muta- tions.31 This observation delineates a subgroup of patients who may benefit from selective BRAF in- hibitors as an alternative to imatinib. These prelimi- nary findings must be confirmed in a larger cohort. Protein kinase C theta (PKCtheta) is a down- stream effector in the KIT signaling pathway. It may play an important role in the diagnosis of KIT-nega- tive GISTs, because it is expressed strongly in GISTs but not in leiomyosarcoma or other tumors that are criteria might result in its reclassification as GIST. Immunohistochemistry GISTs have a characteristic immunohistochemi- cal profile that is useful for confirming a suspected diagnosis.19 Approximately 95% are positive for KIT (CD117). In general, KIT staining in GISTs is strongly and diffusely positive, but is not necessarily uniform across different regions of the tumor. Stain- ing may appear in a cytoplasmic (most common), membranous, or a concentrated dot-like perinuclear pattern. Some cases show combinations of these pat- terns. Epithelioid GISTs tend to have a weaker and patchier staining pattern than spindle cell GISTs. Because KIT is expressed in nearly all GISTs and KIT positivity was a requirement in early trials of imatinib, this marker has been emphasized in the biomedical literature and is often used for diagnosis. However, caveats exist to the use of this marker. First, the CD117/KIT antibody must be properly tittered. Overstaining for KIT has been a problem in some laboratories and has caused other mesenchymal tu- mors to be misdiagnosed as GIST. Second, the inten- sity of KIT staining in GISTs is somewhat variable. Third, staining intensity does not predict the likeli- hood of a response to treatment with imatinib,20 and although KIT-positivity is a major defining feature for GIST, KIT-positivity alone may not be sufficient for diagnosis. Non-GISTs that are positive for KIT include metastatic melanoma, angiosarcoma (50%), Ewing’s sarcoma family of tumors (50%), childhood neuroblastoma (30%), extramedullary myeloid tu- mor, seminoma, and small cell lung carcinoma.21 GIST can be confidently diagnosed if the morpholo- gy and immunophenotype are concordant; however, tumors with any unusual features should be sent to a referral institution with special expertise. Other commonly expressed markers include CD34 antigen (70%), smooth muscle actin (SMA; 30%–40%), desmin (< 5%), and S100 protein (~5%).19 The immunophenotype of GISTs varies de- pending on anatomic sites: CD34 is often positive in esophageal, gastric, and rectal lesions, whereas SMA is most often positive in small bowel tumors. S100 is more common in small intestinal GISTs than in gas- tric GISTs. CD34 and SMA staining can be either diffuse or focal. Staining for the other markers, when present, is usually patchy and weak. In an immuno- histochemical analysis of 292 GISTs originating in the gastrointestinal tract, CD34 expression was vari- . Al l r ig ht s re se rv ed . Co py rig ht © 2 01 0 by th e Na tio na l C om pr eh en siv e Ca nc er N et wo rk fro m 0 0. 00 0. 00