REVIEW URRENT C OPINION
Gastrointestinal stromal tumors in the setting of multiple tumor syndromes Adam M. Burgoyne a, Neeta Somaiah b, and Jason K. Sicklick c
Purpose of review Knowledge related to gastrointestinal stromal tumor (GIST) in the setting of nonhereditary and hereditary multiple tumor syndromes continues to expand. This review describes associations between sporadic GIST and second malignancies, as well as new contributions to our knowledge about hereditary GIST multiple tumor syndromes. Recent findings Sporadic GIST patients have increased risk of developing synchronous/metachronous cancers, including nonhematologic and hematologic malignancies. Data suggest these associations are nonrandom, more prevalent in men and increase with age. New adrenal tumors have also been associated with nonhereditary Carney’s triad. Meanwhile, understanding of the molecular basis of heritable GIST syndromes has improved. Several new familial GIST kindreds have been reported, including those with germline KIT and PDGFRa mutations. Knowledge about succinate dehydrogenase (SDH) deficiency and mutations in hereditary GIST syndromes has expanded. It is now known that neurofibromatosis-1-associated GISTs are SDHB-positive, whereas Carney–Stratakis syndrome-associated GISTs are SDHB-deficient with underlying germline mutations in SDH subunits A–D. Summary Recognition and early diagnosis of GIST syndromes allows for improved comprehensive medical care. With additional understanding of the molecular pathogenesis of GIST multiple tumor syndromes, we can refine our screening programs and management of these patients and their families. Keywords Carney’s triad, Carney–Stratakis syndrome, gastrointestinal stromal tumor, hereditary, neurofibromatosis
INTRODUCTION It is now known that approximately 5–10% of all cancers are hereditary. Well known examples of cancer syndromes include hereditary breast and ovarian cancer syndrome caused by mutations in the BRCA1 and BRCA2 genes, Li-Fraumeni syndrome caused by mutations in the TP53 gene and familial adenomatous polyposis caused by mutations in the APC gene. In line with these syndromes, hereditary gastrointestinal stromal tumor (GIST) syndromes are caused by germline genomic alterations in KIT (c-KIT or CD117), PDGFRa, neurofibromin-1 (NF-1) and succinate dehydrogenase (SDH) [1]. Patients with these GIST syndromes frequently develop multiple additional benign and malignant tumors. However, the aforementioned syndromes account for less than 5% of GIST cases [1,2 ,3–5]. Even patients with nonhereditary (e.g. sporadic) GIST have up to a one-in-five chance of developing synchronous or metachronous malignancies [4,6–8]. &
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NONHEMATOLOGIC MALIGNANCIES IN SPORADIC GASTROINTESTINAL STROMAL TUMOR PATIENTS If all cancer patients survived and cancer occurred randomly, the normal lifetime odds of developing a second primary cancer would be one-in-nine [9,10]. However, evidence has emerged that cancer a
Division of Hematology–Oncology and Department of Medicine, Moores UCSD Cancer Center, University of California, San Diego, La Jolla, California, bDivision of Medical Oncology and Department of Internal Medicine, MD Andersen Cancer Center, University of Texas, Houston, Texas and cDivision of Surgical Oncology and Department of Surgery, Moores UCSD Cancer Center, University of California, San Diego, La Jolla, California, USA Correspondence to Jason K. Sicklick, MD, Assistant Professor of Surgery, Division of Surgical Oncology, Moores UCSD Cancer Center, University of California, San Diego, 3855 Health Sciences Drive, Mail Code 0987, La Jolla, CA 92093-0987, USA. Tel: +1 858 822 3967; 858 822 6173; fax: +1 858 228 5153; e-mail: [email protected] Curr Opin Oncol 2014, 26:408–414 DOI:10.1097/CCO.0000000000000089 Volume 26 Number 4 July 2014
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Gastrointestinal stromal tumor syndromes Burgoyne et al.
KEY POINTS Less than 5% of GIST cases are thought to occur due to hereditary GIST multiple tumor syndromes. Approximately one-in-five nonhereditary (e.g. sporadic) GIST patients will develop an additional malignancy, including both nonhematologic and hematologic malignancies. Carney’s triad, a nonhereditary syndrome that includes gastric GIST, pulmonary chondroma and extraadrenal paraganglioma, is also associated with benign unilateral and bilateral adrenal adenomas, suggesting that this may be a quadrad. Familial GIST syndrome has been reported in 27 kindreds and is caused by activating germline mutations in KIT (c-KIT or CD117) or PDGFRa that lead to multifocal GIST, as well as several additional phenotypes. Hereditary GIST multiple tumor syndromes are caused by germline mutations in the NF-1 gene, which lead to neurofibromatosis type 1, as well as the SDH subunits, which lead to Carney–Stratakis syndrome (GIST and paraganglioma).
survivors have a two-fold higher risk of developing a second primary malignancy. This increased risk is thought to be due to several factors, including the same risk factor(s) that produced the first cancer (i.e. smoking and alcohol), the person’s genomic profile, environmental exposures, and, in some cases, the treatment for the first cancer (i.e. chemotherapy or radiotherapy). There are two critical factors determining the increased risk of developing a second malignancy. First is the probability of surviving the first neoplasm. Second is the detection bias of discovering otherwise clinically unrecognized incidental malignancies during the workup or treatment of the first malignancy [9,10]. These findings are true in the GIST population as well. Three studies demonstrated that GIST patients are at a high risk of developing additional malignancies [6–8]. Agaimy et al. [7] initially found that the most common associations with GIST are gastric carcinoma (47%), prostate cancer (9%), lymphoma/leukemia (7%) and breast cancer (7%). The group from MD Andersen Cancer Center led by Trent subsequently evaluated 783 GIST patients between 1995 and 2007 and confirmed these earlier findings [6]. In their study, 153 patients (20%) had at least one additional primary malignancy. Interestingly, primary malignancies observed before GIST were cancers of the prostate, breast, esophagus and kidney as well as melanoma, whereas only kidney and lung cancers were most frequently observed after GIST. The latter
tumors may have been discovered in part due to detection bias seen with the enhanced long-term surveillance of GIST in these cancer survivors. As previously noted, GISTs may be incidentally discovered at the time of other tumor resections. Liu et al. [11] reported that 17.4% of patients with resected abdominal malignancies (i.e. esophageal, gastric, pancreatic and colorectal cancers) had incidental, synchronous GISTs that were more common in men. Another study of 207 patients undergoing gastrectomy or esophagectomy for non-GIST neoplasms identified 15 (7.2%) incidental, synchronous GISTs in the upper gastrointestinal tract [12]. In their study, these GISTs did not impact long-term survival. Similar to the previous study, GISTs were more prevalent in men. Another report from the United Arab Emirates found that five out of 21 cases (24%) of GISTs were discovered to be either synchronously or metachronously associated with extragastrointestinal neoplasms [13]. In contrast to previous studies, these GISTs were only seen in women. Most recently, Kakkar et al. [14] reported an incidental GIST discovered synchronously with a gastric lymphoepithelioma-like carcinoma, suggesting the cooccurrence of two rare gastric malignancies. Taken together, the frequent incidental discovery of GIST needs to be kept in mind when reviewing preoperative imaging, when intraoperatively evaluating the bowel, as well as when pathologists are reviewing pathologic specimens in order to avoid missing these tumors. Outside of the gut proper, a recent multiinstitutional case series reported the coexistence of desmoid tumors in patients with GIST [15]. This case series analyzed a cohort of 830 GIST and 315 desmoid tumor (deep fibromatosis) patients from 10 institutions. They identified 28 patients with concurrent GISTs and desmoid tumors. When compared with incidence data from patients with either GIST or desmoid tumors alone, there was a statistically significant increase in the standardized incidence ratio [82; 95% confidence interval (CI) 44–133] of concurrent desmoid tumors in patients with GIST. These data suggest that this association is nonrandom and raise suspicion for a cancer predisposition syndrome.
HEMATOLOGIC MALIGNANCIES IN SPORADIC GASTROINTESTINAL STROMAL TUMOR PATIENTS Beyond solid tumors, there are also series of GIST patients developing hematologic malignancies [8]. Pitini et al. [16] reported a case of a GIST patient with concurrent acute myeloid leukemia (AML) that progressed from refractory anemia with excess blasts-1
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(RAEB-1), a type of myelodysplastic syndrome. Another retrospective analysis of tumor registry data from the Armed Forces Institute of Pathology investigated the incidence of AML in 1892 patients with GIST. In comparison to the expected number of events in the age-matched general population reported in the Surveillance, Epidemiology, and End Results Program (published by the National Cancer Institute), there was a statistically significant increase in the standardized incidence ratio of AML in GIST patients (2.96; 95% CI, 1.07–5.8) [8]. These authors also reported an association between chronic myeloid leukemia (CML) and GIST, although the increase in incidence was not statistically significant. It is coincidental that imatinib (Gleevec, Novartis Pharmaceutical, Basel, Switzerland), which was originally developed to target the BCR-ABL1 fusion product present in Philadelphia chromosome-positive CML, is also an active anti-KIT therapy used to treat GIST. As such, treatment of GIST patients with imatinib would likely induce a hematologic remission in patients with undiagnosed CML. Thus, the true incidence of GIST with concurrent CML may be underreported. It should also be noted that KIT activating mutations are described in patients with AML with structural and functional similarity to those found in GIST patients. Although unstudied, this fact may provide some genetic information on the link between concurrent AML and GIST. In addition to its association with myeloid leukemias, there is a growing body of evidence to suggest an association between GISTs and myeloproliferative neoplasms (MPNs), a family of hematologic disorders with shared clinical and genetic features composed of myelofibrosis, polycythemia vera and essential thrombocythemia. Recently, Del Biondo et al. [17] reported a case of a GIST patient with both essential thrombocythemia and CML. There is also a German case series of 346 patients with GIST in which three patients had concomitant polycythemia vera [18]. One of these patients also had a concurrent diagnosis of essential thrombocythemia. Because patients with GIST often develop tumor bleeding, this can lead to anemia in nonpolycythemia vera patients or an inappropriately normal hematocrit in polycythemia vera patients. Thus, the true incidence of GIST with concurrent polycythemia vera may be underreported. Patients with MPNs have somatic driver mutations that are well described. JAK2V617F is the hallmark mutation found in 95% of cases of polycythemia vera. It is also present in up to 50% of patients with essential thrombocythemia and myelofibrosis [19]. Mutations of myeloproliferative leukemia virus oncogene, which activates JAK2, 410
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have also been described in MPNs [20]. GIST patients also have well characterized somatic mutations. Approximately 70–80% of sporadic GISTs are caused by gain-of-function mutations in KIT, whereas 5–10% are caused by gene mutations, deletions or insertions that activate PDGFRa [21,22]. Another 10–15% are wild-type for KIT and PDGFRa but may contain BRAFV600E mutations (up to 15%) or SDH mutations (2%) [21–24]. There is certainly cross-talk between the molecular pathways mutated in MPNs and GIST, as both KIT and PDGFRa activate JAK2 signaling. However, it is only a subset of patients that have these coexisting conditions. Both MPNs and GIST are rare malignancies. GIST occurs in up to two cases per 100 000 per year, and MPNs have an age-adjusted incidence of up to 60.4 cases per 100, 000 per year [25]. The emerging evidence that these rare malignancies are occurring concurrently raises suspicion that the frequency is higher than that of chance alone. However, despite the fact that familial clustering of polycythemia vera, essential thrombocythemia and myelofibrosis has been well described [26–28], the presence of the JAK2 mutation does not appear to represent the genetic predisposing factor [26,29,30–32]. Further work will be required to elucidate factors that predispose patients to concurrent GIST and other malignancies, including MPNs.
NONHEREDITARY CARNEY’S TRIAD (QUADRAD) Carney’s triad is a rare nonheritable syndrome in young women associated with gastric GIST, as well as benign paragangliomas and pulmonary chondromas [33]. Approximately 150 cases of Carney’s triad have been reported thus far [34]. Recently, 14 patients with a fourth component of the triad, namely asymptomatic benign adrenal adenomas, were described [35 ]. In this series, bilateral adenomas were observed in four patients (29%). Taken together, this syndrome may represent a quadrad rather than the classically described triad. New insight has also been gained into the molecular biology of this syndrome. There was a recent report of overexpression of insulin-like growth factor 1 receptor (IGF1R) in three patients with Carney’s triad [36 ]. This is interesting because wild-type GISTs (e.g. those lacking KIT or PDGFRa mutations) have also been shown to overexpress IGF1R, which may be a targetable receptor [37]. Additional insights into the molecular pathogenesis of Carney’s triad have been reported. Given that Carney’s triad has some shared molecular and clinical features with the hereditary Carney–Stratakis syndrome, additional recent findings will be discussed below. &
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FAMILIAL GIST SYNDROME As early as 1990, there were reports of multiple primary GISTs in kindreds [38]. Subsequently, Nishida et al. [39] identified a germline KIT mutation as the cause of an inherited predisposition to GIST. Given the prevalence of somatic KIT mutations in sporadic GIST, it is not surprising that the most widely reported mutations in familial GIST syndromes are germline KIT mutations. There are now 24 reported kindreds with germline KIT mutations and associated familial GIST [2 ]. These mutations map to KIT exon 11 in the majority of kindreds (66.7%, 16 of 24). Mutations in KIT exons 8, 13 and 17 have also been described [2 ]. The inheritance pattern is autosomal dominant, and the median age at diagnosis tends to be at least a decade younger than typical age for sporadic GIST presentation. In addition to a predisposition to developing GIST, the clinical syndrome has a variable expression pattern without clear genotypephenotype association. Patients may also develop pigment changes of the skin, urticarial pigmentosa/ mastocytosis, diffuse hyperplasia of the myenteric (Auerbach’s) plexus and dysphagia. Histologically, familial GISTs are similar to sporadic tumors, but the mitotic indices tend to be lower, even in the setting of metastatic disease [2 ]. Similar to patients with somatic KIT mutations, patients with germline KITmutated GISTs often respond to treatment with imatinib. Because KIT is known to regulate proliferation and differentiation of melanocytes, this may also explain the associated skin findings in familial GIST patients. Interestingly, these cutaneous pigmentary changes also have been demonstrated to respond to tyrosine kinase inhibition [40]. Analogous to the characterized somatic mutations in sporadic GIST, there are also reports of three germline PDGFRa mutations in familial GIST kindreds [41 ]. Similar to familial KIT mutations, these familial PDGFRa mutations occur in exons frequently mutated in sporadic GISTs. These include two exon 12 mutations (e.g. Y555C and V561D) [42,43] and one exon 18 mutation (D846Y) [44]. Patients in the PDGFRaY555C kindred also had intestinal neurofibromatosis without other classic features of neurofibromatosis type 1 (NF-1) [42]. These findings are interesting because GIST is associated with NF-1 as described below. Another patient with a germline PDGFRaV561D mutation had associated lipomas and fibrous tumors of the small intestine [43]. Finally, patients in the PDGFRaD846Y kindred were also noted to have large hands [44]. In line with this finding, Boguszewski et al. [45] reported a single case of a GIST patient with associated acromegaly, pheochromocytoma and thyroid follicular adenoma without clear association with multiple endocrine &
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neoplasia syndromes or familial GIST syndromes. Although KIT and PDGFRa mutations were not described in that report, the cooccurrence of acromegaly and GIST raises the possibility of PDGFRa pathway involvement given the large hands seen in patients with germline mutations of PDGFRa.
NEUROFIBROMATOSIS TYPE 1 NF-1, von Reckinghausen’s disease, is a disorder classically characterized by cutaneous (i.e. cafe´ au lait spots, axillary/inguinal freckling, and dermal neurofibromas) and ocular (i.e. iris hamartomas and Lisch nodules) manifestations, as well as nervous system tumors (i.e. gliomas, plexiform neurofibromas, ganglioneuromas and malignant peripheral nerve sheath tumors) and GISTs. In recent years, there is a growing body of literature demonstrating that additional gastrointestinal tumors (i.e. periampullary neuroendocrine tumors, pancreatic neuroendocrine tumors including somatostatinomas, and juvenilelike inflammatory/hyperplastic mucosal polyps), sarcomas (i.e. leiomyosarcoma and osteosarcoma) and pheochromocytomas are associated with NF-1 [46 ,47–51]. Regarding GISTs, they are not uncommon in NF-1 patients. A Swedish Cancer Registry study revealed that 7% of NF-1 patients had GISTs [52]. These NF-1-associated GISTs are more frequent in the small bowel than the stomach and account for 1.5% of all GISTs [53]. Underlying this phenotype, NF-1 is an autosomal dominant disease that results from germline mutations in the NF-1 gene, which encodes neurofibromin. Because the NF-1 gene has a high rate of de-novo mutations, approximately half of NF-1 cases occur in the absence of a family history [54]. Given that the interstitial cell of Cajal (ICC) is the cellular origin of GIST, it is not surprising that ICC hyperplasia is common in NF-1 patients [53]. In contrast to familial GISTs, wherein ICC hyperplasia is believed to be a direct consequence of constitutive KIT or PDGFRa activation, ICC hyperplasia in NF-1 patients it is thought to be secondary to NF-1 haploinsufficiency [55]. The emergence of GIST is likely due to subsequent loss of heterozygosity at NF-1 and accumulation of additional chromosomal alterations. In turn, GIST represents the most common gastrointestinal manifestation of NF-1 [46 ]. In this patient population, GISTs tend to be diagnosed in the fifth or sixth decade of life with a slight female predominance [53,56]. NF-1-associated GISTs mostly present asymptomatically as multiple small tumors with low mitotic activity. As a result, they typically have a relatively indolent biology. However, recent reports have suggested that some patients can present symptomatically with bleeding and anemia, perforation, obstruction or pain with invasion into
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adjacent structures, suggesting that the risk of complications and aggressive disease biology should not be underestimated in NF-1 patients [57–60]. Neurofibromin is a tumor suppressor protein that negatively regulates Ras signal transduction and downstream mitogen-activated protein kinase (MAPK) pathway activation. As a result, NF-1 inactivation results in constitutive mitogenic MAPK signal transduction, which leads to tumorigenesis [61]. Similarly, MAPK pathway activation occurs in sporadic GISTs due to gain-of-function mutations in KIT or PDGFRa. Moreover, the NF-1-associated GISTs have several other similarities to the various subsets of sporadic GISTs. Like many KIT and PDGFRamutated GISTs, they are uniformly KIT positive by immunohistochemistry [46 ], as well as retain mitochondrial expression of SDH subunit B (SDHB) [62,63]. However, similar to sporadic wild-type GISTs lacking KIT and PDGFRa mutations, NF-1associated GISTs rarely harbor somatic KIT/PDGFRa mutations [64] and have variable imatinib sensitivity [65,66]. &&
CARNEY–STRATAKIS SYNDROME Classically, Carney–Stratakis syndrome results from a germline mutation in the B, C and D subunits of SDH. This appears to be an autosomal dominant syndrome with incomplete penetrance and variable manifestations. Affected patients develop paragangliomas, GISTs or the dyad of both [67–69]. These SDH-deficient GISTs are characterized by gastric location, frequent lymph node metastases and an indolent metastatic disease [70]. The GISTs in these individuals do not have KIT or PDGFRa mutations, but rather show loss of SDHB expression by immunohistochemistry with an underlying SDH gene mutation [71]. This SDHB deficiency signals the loss of function of the SDH complex consisting of mitochondrial inner membrane proteins. More recently, germline mutations in SDH subunit A (SDHA) have been identified in 30% of SDHdeficient GISTs [72 ,73 ]. These SDHA mutations also correlated with loss of SDHA expression. Thus, germline mutations in SDH subunits A, B, C and D must be considered when an SDH-deficient GIST is encountered. Analogous to Carney–Stratakis syndrome, GISTs associated with Carney’s triad lack KIT/ PDGFRa mutations and are SDH-deficient by immunohistochemistry. However, unlike Carney–Stratakis syndrome, associated SDH gene mutations have not been identified in Carney’s triad patients [5,74]. Apart from the clinical and genomic distinctions between the dyad (Carney–Stratakis syndrome) and Carney’s triad (quadrad),a recent study has also &
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described their distinction based upon the differential expression of 34 miRNAs [75]. However, a larger cohort of patients is needed to confirm this finding and determine its significance. Taken together, Carney–Stratakis syndrome and Carney’s triad represent distinct disease entities with inherent differences in their heritability, molecular pathogenesis and clinical presentations.
CONCLUSION We continue to gain further insight into the nonrandom association between GIST and other malignancies, as well as the underlying biology of hereditary GIST syndromes. In turn, this knowledge can be utilized to shape the clinical management of these patients, including: cancer screening recommendations; prevention strategies; familial genetic counseling and screening; and development of anticancer therapies against unappreciated targets in patients with GIST multiple tumor syndromes. Acknowledgements Authors’ Contributions Acquisition of data, A.M.B., N.S., J.K.S., Conception and design, A.M.B., N.S., J.K.S., Analysis of data, A.M.B., N.S., J.K.S., Interpretation of data, A.M.B., N.S., J.K.S., Drafting of article, A.M.B., N.S., J.K.S., Critical revision of article: A.M.B., N.S., J.K.S. Final approval of the version to be published: A.M.B., N.S., J.K.S. Grant Support: This work was supported by the Jack Kiel Wolf Memorial Research Fund (J.K.S.), the Stuart Manroel Memorial Research Fund (J.K.S.), the UCSD GIST Research Fund (J.K.S.), as well as funding provided by UCSD Moores Cancer Center. Conflicts of interest J.K.S. received honoraria from Novartis Pharmaceuticals Corporation for advisory board consultancy and speaking, as well as reimbursement for travel, lodging, and meals. J.K.S. received honoraria from Genentech Inc. for speaking. No additional authors have conflicts of interest to declare.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Agaimy A, Hartmann A. Hereditary and nonhereditary syndromic gastointestinal stromal tumours. Pathologe 2010; 31:430–437. 2. Neuhann TM, Mansmann V, Merkelbach-Bruse S, et al. A novel germline KIT & mutation (p.L576P) in a family presenting with juvenile onset of multiple gastrointestinal stromal tumors, skin hyperpigmentations, and esophageal stenosis. Am J Surg Pathol 2013; 37:898–905. This is an excellent review of 24 reported kindreds with germline KIT mutations and associated familial GIST.
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Gastrointestinal stromal tumor syndromes Burgoyne et al. 3. Kuroda N, Tanida N, Hirota S, et al. Familial gastrointestinal stromal tumor with germ line mutation of the juxtamembrane domain of the KIT gene observed in relatively young women. Ann Diagn Pathol 2011; 15:358–361. 4. Ponti G, Luppi G, Martorana D, et al. Gastrointestinal stromal tumor and other primary metachronous or synchronous neoplasms as a suspicion criterion for syndromic setting. Oncol Rep 2010; 23:437–444. 5. Stratakis CA, Carney JA. The triad of paragangliomas, gastric stromal tumours and pulmonary chondromas (Carney triad), and the dyad of paragangliomas and gastric stromal sarcomas (Carney-Stratakis syndrome): molecular genetics and clinical implications. J Intern Med 2009; 266:43–52. 6. Pandurengan RK, Dumont AG, Araujo DM, et al. Survival of patients with multiple primary malignancies: a study of 783 patients with gastrointestinal stromal tumor. Ann Oncol 2010; 21:2107–2111. 7. Agaimy A, Wunsch PH, Sobin LH, et al. Occurrence of other malignancies in patients with gastrointestinal stromal tumors. Semin Diagn Pathol 2006; 23:120–129. 8. Miettinen M, Kraszewska E, Sobin LH, Lasota J. A nonrandom association between gastrointestinal stromal tumors and myeloid leukemia. Cancer 2008; 112:645–649. 9. Rheingold S, Neugut A, Meadows A. Secondary cancers: incidence, risk factors, and management. In: Bast RC Jr, Kufe D, Pollock R, editors. HollandFrei cancer medicine. 5th ed. Hamilton, Ontario, British Columbia: Decker; 2000. Chapter 156. 10. Kosary C, Lag R, Miller B. SEER Cancer statistics review 1973-1992: tables and graphs, N. National Cancer Institute, Editor 1995: Bethesda, MD. 11. Liu YJ, Yang Z, Hao LS, et al. Synchronous incidental gastrointestinal stromal and epithelial malignant tumors. World J Gastroenterol 2009; 15:2027– 2031. 12. Chan CH, Cools-Lartigue J, Marcus VA, et al. The impact of incidental gastrointestinal stromal tumours on patients undergoing resection of upper gastrointestinal neoplasms. Can J Surg 2012; 55:366–370. 13. AbdullGaffar B. Gastrointestinal stromal tumors and extra-gastrointestinal tract neoplasms. South Med J 2010; 103:1004–1008. 14. Kakkar A, Gupta RK, Dash NR, et al. Lymphoepithelioma-like carcinoma of the stomach with incidental gastrointestinal stromal tumor (GIST)-a rare synchrony of two tumors. J Gastrointest Cancer 2014. [Epub ahead of print] 15. Dumont AG, Rink L, Godwin AK, et al. A nonrandom association of gastrointestinal stromal tumor (GIST) and desmoid tumor (deep fibromatosis): case series of 28 patients. Ann Oncol 2012; 23:1335–1340. 16. Pitini V, Arrigo C, Sauta MG, Altavilla G. Myelodysplastic syndrome appearing during imatinib mesylate therapy in a patient with GIST. Leuk Res 2009; 33:e143–e144. 17. Del Biondo E, De Raeva H, Huysmans G, et al. Concomitant JAK2 V617F positive essential thrombocytemia and BCR-ABL1 positive chronic myeloid leukaemia masked by imatinib therapy for a gastrointestinal stromal tumour. Belgian J Hematol 2012; 3:105–107. 18. Schoeler D, Klu¨hs C, Pink D, et al. Polycythemia vera in GIST patients. J Clin Oncol 2010; 28:. 2010 (suppl; abstr e20520). 19. Campbell PJ, Green AR. The myeloproliferative disorders. N Engl J Med 2006; 355:2452–2466. 20. Pikman Y, Lee BH, Mercher T, et al. MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia. PLoS Med 2006; 3:e270. 21. Rubin BP, Heinrich MC, Corless CL. Gastrointestinal stromal tumour. Lancet 2007; 369:1731–1741. 22. Corless CL, Barnett CM, Heinrich MC. Gastrointestinal stromal tumours: origin and molecular oncology. Nat Rev Cancer 2011; 11:865–878. 23. Liegl-Atzwanger B, Fletcher JA, Fletcher CD. Gastrointestinal stromal tumors. Virchows Arch 2010; 456:111–127. 24. Agaram NP, Wong GC, Guo T, et al. Novel V600E BRAF mutations in imatinib-naive and imatinib-resistant gastrointestinal stromal tumors. Genes Chromosomes Cancer 2008; 47:853–859. 25. Mehta J, Wang H, Iqbal SU, Mesa R. Epidemiology of myeloproliferative neoplasms in the United States. Leuk Lymphoma 2014; 55:595–600. 26. Landgren O, Goldin LR, Kristinsson SY, et al. Increased risks of polycythemia vera, essential thrombocythemia, and myelofibrosis among 24,577 firstdegree relatives of 11,039 patients with myeloproliferative neoplasms in Sweden. Blood 2008; 112:2199–2204. 27. Hemminki K, Sundquist J, Bermejo JL. Associated cancers in parents and offspring of polycythaemia vera and myelofibrosis patients. Br J Haematol 2009; 147:526–530. 28. Cario H, Goerttler PS, Steimle C, et al. The JAK2V617F mutation is acquired secondary to the predisposing alteration in familial polycythaemia vera. Br J Haematol 2005; 130:800–801. 29. Bellanne-Chantelot C, Chaumarel I, Labopin M, et al. Genetic and clinical implications of the Val617Phe JAK2 mutation in 72 families with myeloproliferative disorders. Blood 2006; 108:346–352. 30. Rumi E, Passamonti F, Pietra D, et al. JAK2 (V617F) as an acquired somatic mutation and a secondary genetic event associated with disease progression in familial myeloproliferative disorders. Cancer 2006; 107:2206– 2211. 31. Pardanani A, Lasho T, McClure R, et al. Discordant distribution of JAK2V617F mutation in siblings with familial myeloproliferative disorders. Blood 2006; 107:4572–4573.
32. Kralovics R, Stockton DW, Prchal JT. Clonal hematopoiesis in familial polycythemia vera suggests the involvement of multiple mutational events in the early pathogenesis of the disease. Blood 2003; 102:3793–3796. 33. Carney JA, Sheps SG, Go VL, Gordon H. The triad of gastric leiomyosarcoma, functioning extra-adrenal paraganglioma and pulmonary chondroma. N Engl J Med 1977; 296:1517–1518. 34. Carney JA. Carney triad. Front Horm Res 2013; 41:92–110. 35. Carney JA, Stratakis CA, Young WF Jr. Adrenal cortical adenoma: the fourth & component of the Carney triad and an association with subclinical Cushing syndrome. Am J Surg Pathol 2013; 37:1140–1149. This report describes 14 patients with a fourth component of Carney’s triad, namely benign unilateral or bilateral adrenal adenomas. 36. Belinsky MG, Rink L, Flieder DB, et al. Overexpression of insulin-like growth & factor 1 receptor and frequent mutational inactivation of SDHA in wild-type SDHB-negative gastrointestinal stromal tumors. Genes Chromosomes Cancer 2013; 52:214–224. Similar to wild-type GISTs, this recent report describes overexpression of IGF1R in three patients with Carney’s triad. 37. Tarn C, Rink L, Merkel E, et al. Insulin-like growth factor 1 receptor is a potential therapeutic target for gastrointestinal stromal tumors. Proc Natl Acad Sci U S A 2008; 105:8387–8392. 38. Marshall JB, Diaz-Arias AA, Bochna GS, Vogele KA. Achalasia due to diffuse esophageal leiomyomatosis and inherited as an autosomal dominant disorder. Report of a family study. Gastroenterology 1990; 98 (5 Pt 1):1358– 1365. 39. Nishida T, Hirota S, Taniguchi M, et al. Familial gastrointestinal stromal tumours with germline mutation of the KIT gene. Nat Genet 1998; 19:323–324. 40. Campbell T, Felsten L, Moore J. Disappearance of lentigines in a patient receiving imatinib treatment for familial gastrointestinal stromal tumor syndrome. Arch Dermatol 2009; 145:1313–1316. 41. Postow MA, Robson ME. Inherited gastrointestinal stromal tumor syndromes: && mutations, clinical features, and therapeutic implications. Clin Sarcoma Res 2012; 2:16. This report reviews three reports of germline PDGFRa mutations in familial GIST kindreds. 42. de Raedt T, Cools J, Debiec-Rychter M, et al. Intestinal neurofibromatosis is a subtype of familial GIST and results from a dominant activating mutation in PDGFRA. Gastroenterology 2006; 131:1907–1912. 43. Pasini B, Matyakhina L, Bei T, et al. Multiple gastrointestinal stromal and other tumors caused by platelet-derived growth factor receptor alpha gene mutations: a case associated with a germline V561D defect. J Clin Endocrinol Metab 2007; 92:3728–3732. 44. Chompret A, Kannengiesser C, Barrois M, et al. PDGFRA germline mutation in a family with multiple cases of gastrointestinal stromal tumor. Gastroenterology 2004; 126:318–321. 45. Boguszewski CL, Fighera TM, Bornschein A, et al. Genetic studies in a coexistence of acromegaly, pheochromocytoma, gastrointestinal stromal tumor (GIST) and thyroid follicular adenoma. Arq Bras Endocrinol Metabol 2012; 56:507–512. 46. Agaimy A, Vassos N, Croner RS. Gastrointestinal manifestations of && neurofibromatosis type 1 (Recklinghausen’s disease): clinicopathological spectrum with pathogenetic considerations. Int J Clin Exp Pathol 2012; 5:852–862. This excellent review summarizes the growing body of literature demonstrating gastrointestinal tumors (i.e. GISTs, periampullary neuroendocrine tumors, pancreatic neuroendocrine tumors including somatostatinomas, and juvenile-like inflammatory/hyperplastic mucosal polyps) in NF-1 patients. 47. Agaimy A, Schaefer IM, Kotzina L, et al. Juvenile-like (inflammatory/hyperplastic) mucosal polyps of the gastrointestinal tract in neurofibromatosis type 1. Histopathology 2014; 64:777–786. 48. Afsar CU, Kara IO, Kozat BK, et al. Neurofibromatosis type 1, gastrointestinal stromal tumor, leiomyosarcoma and osteosarcoma: four cases of rare tumors and a review of the literature. Crit Rev Oncol Hematol 2013; 86:191–199. 49. Tavares AB, Viveiros FA, Cidade CN, Maciel J. Gastric GIST with synchronous neuroendocrine tumour of the pancreas in a patient without neurofibromatosis type 1. BMJ Case Rep 2012; 2012. 50. Cavallaro G, Basile U, Polistena A, et al. Surgical management of abdominal manifestations of type 1 neurofibromatosis: experience of a single center. Am Surg 2010; 76:389–396. 51. Haugvik SP, Røsok BI, Edwin B, et al. Concomitant nonfunctional pancreatic neuroendocrine tumor and gastric GIST in a patient without neurofibromatosis type 1. J Gastrointest Cancer 2011. [Epub ahead of print] 52. Zoller ME, Rembeck B, Ode´n A, et al. Malignant and benign tumors in patients with neurofibromatosis type 1 in a defined Swedish population. Cancer 1997; 79:2125–2131. 53. Miettinen M, Fetsch JF, Sobin LH, Lasota J. Gastrointestinal stromal tumors in patients with neurofibromatosis 1: a clinicopathologic and molecular genetic study of 45 cases. Am J Surg Pathol 2006; 30:90–96. 54. Ferner RE. Neurofibromatosis 1 and neurofibromatosis 2: a twenty first century perspective. Lancet Neurol 2007; 6:340–351. 55. Maertens O, Prenen H, Debiec-Rychter M, et al. Molecular pathogenesis of multiple gastrointestinal stromal tumors in NF1 patients. Hum Mol Genet 2006; 15:1015–1023.
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Sarcomas 56. Takazawa Y, Sakurai S, Sakuma Y, et al. Gastrointestinal stromal tumors of neurofibromatosis type I (von Recklinghausen’s disease). Am J Surg Pathol 2005; 29:755–763. 57. Saha SB, Parmar RA. Mandal, small bowel obstruction in a neurofibromatosis patient-a rare presentation of gastro-intestinal stromal tumors (GISTs): case report and literature review. Indian J Surg 2013; 75 (Suppl 1):415–417. 58. Swain SK, Smile R, Arul T, David D. Unusual presentation of gastrointestinal stromal tumor of stomach in neurofibromatosis type 1: a case report. Indian J Surg 2013; 75 (Suppl 1):398–400. 59. Sawalhi S, Al-Harbi K, Raghib Z, et al. Behavior of advanced gastrointestinal stromal tumor in a patient with von-Recklinghausen disease: Case report. World J Clin Oncol 2013; 4:70–74. 60. Kitagawa M, Koh T, Nakagawa N, et al. Gastrointestinal stromal tumor in a patient with neurofibromatosis: abscess formation in the tumor leading to bacteremia and seizure. Case Rep Gastroenterol 2010; 4:435–442. 61. Gottfried ON, Viskochil DH, Couldwell WT. Neurofibromatosis type 1 and tumorigenesis: molecular mechanisms and therapeutic implications. Neurosurg Focus 2010; 28:E8. 62. Gill AJ, Chou A, Vilain R, et al. Immunohistochemistry for SDHB divides gastrointestinal stromal tumors (GISTs) into 2 distinct types. Am J Surg Pathol 2010; 34:636–644. 63. Wang JH, Lasota J, Miettinen M. Succinate dehydrogenase subunit B (SDHB) is expressed in neurofibromatosis 1-associated gastrointestinal stromal tumors (GISTs): implications for the SDHB expression based classification of GISTs. J Cancer 2011; 2:90–93. 64. Kinoshita K, Hirota S, Isozaki K, et al. Absence of c-kit gene mutations in gastrointestinal stromal tumours from neurofibromatosis type 1 patients. J Pathol 2004; 202:80–85. 65. Lee JL, Kim JY, Ryu MH, et al. Response to imatinib in KIT- and PDGFRA-wild type gastrointestinal stromal associated with neurofibromatosis type 1. Dig Dis Sci 2006; 51:1043–1046. 66. Mussi C, Schildhaus HU, Gronchi A, et al. Therapeutic consequences from molecular biology for gastrointestinal stromal tumor patients affected by neurofibromatosis type 1. Clin Cancer Res 2008; 14:4550–4555.
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67. Carney JA, Stratakis CA. Familial paraganglioma and gastric stromal sarcoma: a new syndrome distinct from the Carney triad. Am J Med Genet 2002; 108:132–139. 68. McWhinney SR, Pasini B, Stratakis CA, et al. Familial gastrointestinal stromal tumors and germ-line mutations. N Engl J Med 2007; 357:1054– 1056. 69. Pasini B, McWhinney SR, Bei T, et al. Clinical and molecular genetics of patients with the Carney-Stratakis syndrome and germline mutations of the genes coding for the succinate dehydrogenase subunits SDHB, SDHC, and SDHD. Eur J Hum Genet 2008; 16:79–88. 70. Miettinen M, Wang ZF, Sarlomo-Rikala M, et al. Succinate dehydrogenasedeficient GISTs: a clinicopathologic, immunohistochemical, and molecular genetic study of 66 gastric GISTs with predilection to young age. Am J Surg Pathol 2011; 35:1712–1721. 71. Gaal J, Stratakis CA, Carney JA, et al. SDHB immunohistochemistry: a useful tool in the diagnosis of Carney-Stratakis and Carney triad gastrointestinal stromal tumors. Mod Pathol 2011; 24:147–151. 72. Dwight T, Benn DE, Clarkson A, et al. Loss of SDHA expression identifies & SDHA mutations in succinate dehydrogenase-deficient gastrointestinal stromal tumors. Am J Surg Pathol 2013; 37:226–233. Back-to-back report first demonstrating the presence of germline SDHA mutations in Carney–Stratakis patients. 73. Miettinen M, Killian JK, Wang ZF, et al. Immunohistochemical loss of succinate & dehydrogenase subunit A (SDHA) in gastrointestinal stromal tumors (GISTs) signals SDHA germline mutation. Am J Surg Pathol 2013; 37:234–240. Back-to-back report first demonstrating the presence of germline SDHA mutations in Carney–Stratakis patients. 74. Matyakhina L, Bei TA, McWhinney SR, et al. Genetics of carney triad: recurrent losses at chromosome 1 but lack of germline mutations in genes associated with paragangliomas and gastrointestinal stromal tumors. J Clin Endocrinol Metab 2007; 92:2938–2943. 75. Kelly L, Bryan K, Ki SY, et al. Posttranscriptional dysregulation by miRNAs is implicated in the pathogenesis of gastrointestinal stromal tumor [GIST]. PLoS One 2013; 8:e64102.
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Gastrointestinal stromal tumors in the setting of multiple tumor syndromes Adam M. Burgoyne a, Neeta Somaiah b, and Jason K. Sicklick c
Purpose of review Knowledge related to gastrointestinal stromal tumor (GIST) in the setting of nonhereditary and hereditary multiple tumor syndromes continues to expand. This review describes associations between sporadic GIST and second malignancies, as well as new contributions to our knowledge about hereditary GIST multiple tumor syndromes. Recent findings Sporadic GIST patients have increased risk of developing synchronous/metachronous cancers, including nonhematologic and hematologic malignancies. Data suggest these associations are nonrandom, more prevalent in men and increase with age. New adrenal tumors have also been associated with nonhereditary Carney’s triad. Meanwhile, understanding of the molecular basis of heritable GIST syndromes has improved. Several new familial GIST kindreds have been reported, including those with germline KIT and PDGFRa mutations. Knowledge about succinate dehydrogenase (SDH) deficiency and mutations in hereditary GIST syndromes has expanded. It is now known that neurofibromatosis-1-associated GISTs are SDHB-positive, whereas Carney–Stratakis syndrome-associated GISTs are SDHB-deficient with underlying germline mutations in SDH subunits A–D. Summary Recognition and early diagnosis of GIST syndromes allows for improved comprehensive medical care. With additional understanding of the molecular pathogenesis of GIST multiple tumor syndromes, we can refine our screening programs and management of these patients and their families. Keywords Carney’s triad, Carney–Stratakis syndrome, gastrointestinal stromal tumor, hereditary, neurofibromatosis
INTRODUCTION It is now known that approximately 5–10% of all cancers are hereditary. Well known examples of cancer syndromes include hereditary breast and ovarian cancer syndrome caused by mutations in the BRCA1 and BRCA2 genes, Li-Fraumeni syndrome caused by mutations in the TP53 gene and familial adenomatous polyposis caused by mutations in the APC gene. In line with these syndromes, hereditary gastrointestinal stromal tumor (GIST) syndromes are caused by germline genomic alterations in KIT (c-KIT or CD117), PDGFRa, neurofibromin-1 (NF-1) and succinate dehydrogenase (SDH) [1]. Patients with these GIST syndromes frequently develop multiple additional benign and malignant tumors. However, the aforementioned syndromes account for less than 5% of GIST cases [1,2 ,3–5]. Even patients with nonhereditary (e.g. sporadic) GIST have up to a one-in-five chance of developing synchronous or metachronous malignancies [4,6–8]. &
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NONHEMATOLOGIC MALIGNANCIES IN SPORADIC GASTROINTESTINAL STROMAL TUMOR PATIENTS If all cancer patients survived and cancer occurred randomly, the normal lifetime odds of developing a second primary cancer would be one-in-nine [9,10]. However, evidence has emerged that cancer a
Division of Hematology–Oncology and Department of Medicine, Moores UCSD Cancer Center, University of California, San Diego, La Jolla, California, bDivision of Medical Oncology and Department of Internal Medicine, MD Andersen Cancer Center, University of Texas, Houston, Texas and cDivision of Surgical Oncology and Department of Surgery, Moores UCSD Cancer Center, University of California, San Diego, La Jolla, California, USA Correspondence to Jason K. Sicklick, MD, Assistant Professor of Surgery, Division of Surgical Oncology, Moores UCSD Cancer Center, University of California, San Diego, 3855 Health Sciences Drive, Mail Code 0987, La Jolla, CA 92093-0987, USA. Tel: +1 858 822 3967; 858 822 6173; fax: +1 858 228 5153; e-mail: [email protected] Curr Opin Oncol 2014, 26:408–414 DOI:10.1097/CCO.0000000000000089 Volume 26 Number 4 July 2014
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Gastrointestinal stromal tumor syndromes Burgoyne et al.
KEY POINTS Less than 5% of GIST cases are thought to occur due to hereditary GIST multiple tumor syndromes. Approximately one-in-five nonhereditary (e.g. sporadic) GIST patients will develop an additional malignancy, including both nonhematologic and hematologic malignancies. Carney’s triad, a nonhereditary syndrome that includes gastric GIST, pulmonary chondroma and extraadrenal paraganglioma, is also associated with benign unilateral and bilateral adrenal adenomas, suggesting that this may be a quadrad. Familial GIST syndrome has been reported in 27 kindreds and is caused by activating germline mutations in KIT (c-KIT or CD117) or PDGFRa that lead to multifocal GIST, as well as several additional phenotypes. Hereditary GIST multiple tumor syndromes are caused by germline mutations in the NF-1 gene, which lead to neurofibromatosis type 1, as well as the SDH subunits, which lead to Carney–Stratakis syndrome (GIST and paraganglioma).
survivors have a two-fold higher risk of developing a second primary malignancy. This increased risk is thought to be due to several factors, including the same risk factor(s) that produced the first cancer (i.e. smoking and alcohol), the person’s genomic profile, environmental exposures, and, in some cases, the treatment for the first cancer (i.e. chemotherapy or radiotherapy). There are two critical factors determining the increased risk of developing a second malignancy. First is the probability of surviving the first neoplasm. Second is the detection bias of discovering otherwise clinically unrecognized incidental malignancies during the workup or treatment of the first malignancy [9,10]. These findings are true in the GIST population as well. Three studies demonstrated that GIST patients are at a high risk of developing additional malignancies [6–8]. Agaimy et al. [7] initially found that the most common associations with GIST are gastric carcinoma (47%), prostate cancer (9%), lymphoma/leukemia (7%) and breast cancer (7%). The group from MD Andersen Cancer Center led by Trent subsequently evaluated 783 GIST patients between 1995 and 2007 and confirmed these earlier findings [6]. In their study, 153 patients (20%) had at least one additional primary malignancy. Interestingly, primary malignancies observed before GIST were cancers of the prostate, breast, esophagus and kidney as well as melanoma, whereas only kidney and lung cancers were most frequently observed after GIST. The latter
tumors may have been discovered in part due to detection bias seen with the enhanced long-term surveillance of GIST in these cancer survivors. As previously noted, GISTs may be incidentally discovered at the time of other tumor resections. Liu et al. [11] reported that 17.4% of patients with resected abdominal malignancies (i.e. esophageal, gastric, pancreatic and colorectal cancers) had incidental, synchronous GISTs that were more common in men. Another study of 207 patients undergoing gastrectomy or esophagectomy for non-GIST neoplasms identified 15 (7.2%) incidental, synchronous GISTs in the upper gastrointestinal tract [12]. In their study, these GISTs did not impact long-term survival. Similar to the previous study, GISTs were more prevalent in men. Another report from the United Arab Emirates found that five out of 21 cases (24%) of GISTs were discovered to be either synchronously or metachronously associated with extragastrointestinal neoplasms [13]. In contrast to previous studies, these GISTs were only seen in women. Most recently, Kakkar et al. [14] reported an incidental GIST discovered synchronously with a gastric lymphoepithelioma-like carcinoma, suggesting the cooccurrence of two rare gastric malignancies. Taken together, the frequent incidental discovery of GIST needs to be kept in mind when reviewing preoperative imaging, when intraoperatively evaluating the bowel, as well as when pathologists are reviewing pathologic specimens in order to avoid missing these tumors. Outside of the gut proper, a recent multiinstitutional case series reported the coexistence of desmoid tumors in patients with GIST [15]. This case series analyzed a cohort of 830 GIST and 315 desmoid tumor (deep fibromatosis) patients from 10 institutions. They identified 28 patients with concurrent GISTs and desmoid tumors. When compared with incidence data from patients with either GIST or desmoid tumors alone, there was a statistically significant increase in the standardized incidence ratio [82; 95% confidence interval (CI) 44–133] of concurrent desmoid tumors in patients with GIST. These data suggest that this association is nonrandom and raise suspicion for a cancer predisposition syndrome.
HEMATOLOGIC MALIGNANCIES IN SPORADIC GASTROINTESTINAL STROMAL TUMOR PATIENTS Beyond solid tumors, there are also series of GIST patients developing hematologic malignancies [8]. Pitini et al. [16] reported a case of a GIST patient with concurrent acute myeloid leukemia (AML) that progressed from refractory anemia with excess blasts-1
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(RAEB-1), a type of myelodysplastic syndrome. Another retrospective analysis of tumor registry data from the Armed Forces Institute of Pathology investigated the incidence of AML in 1892 patients with GIST. In comparison to the expected number of events in the age-matched general population reported in the Surveillance, Epidemiology, and End Results Program (published by the National Cancer Institute), there was a statistically significant increase in the standardized incidence ratio of AML in GIST patients (2.96; 95% CI, 1.07–5.8) [8]. These authors also reported an association between chronic myeloid leukemia (CML) and GIST, although the increase in incidence was not statistically significant. It is coincidental that imatinib (Gleevec, Novartis Pharmaceutical, Basel, Switzerland), which was originally developed to target the BCR-ABL1 fusion product present in Philadelphia chromosome-positive CML, is also an active anti-KIT therapy used to treat GIST. As such, treatment of GIST patients with imatinib would likely induce a hematologic remission in patients with undiagnosed CML. Thus, the true incidence of GIST with concurrent CML may be underreported. It should also be noted that KIT activating mutations are described in patients with AML with structural and functional similarity to those found in GIST patients. Although unstudied, this fact may provide some genetic information on the link between concurrent AML and GIST. In addition to its association with myeloid leukemias, there is a growing body of evidence to suggest an association between GISTs and myeloproliferative neoplasms (MPNs), a family of hematologic disorders with shared clinical and genetic features composed of myelofibrosis, polycythemia vera and essential thrombocythemia. Recently, Del Biondo et al. [17] reported a case of a GIST patient with both essential thrombocythemia and CML. There is also a German case series of 346 patients with GIST in which three patients had concomitant polycythemia vera [18]. One of these patients also had a concurrent diagnosis of essential thrombocythemia. Because patients with GIST often develop tumor bleeding, this can lead to anemia in nonpolycythemia vera patients or an inappropriately normal hematocrit in polycythemia vera patients. Thus, the true incidence of GIST with concurrent polycythemia vera may be underreported. Patients with MPNs have somatic driver mutations that are well described. JAK2V617F is the hallmark mutation found in 95% of cases of polycythemia vera. It is also present in up to 50% of patients with essential thrombocythemia and myelofibrosis [19]. Mutations of myeloproliferative leukemia virus oncogene, which activates JAK2, 410
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have also been described in MPNs [20]. GIST patients also have well characterized somatic mutations. Approximately 70–80% of sporadic GISTs are caused by gain-of-function mutations in KIT, whereas 5–10% are caused by gene mutations, deletions or insertions that activate PDGFRa [21,22]. Another 10–15% are wild-type for KIT and PDGFRa but may contain BRAFV600E mutations (up to 15%) or SDH mutations (2%) [21–24]. There is certainly cross-talk between the molecular pathways mutated in MPNs and GIST, as both KIT and PDGFRa activate JAK2 signaling. However, it is only a subset of patients that have these coexisting conditions. Both MPNs and GIST are rare malignancies. GIST occurs in up to two cases per 100 000 per year, and MPNs have an age-adjusted incidence of up to 60.4 cases per 100, 000 per year [25]. The emerging evidence that these rare malignancies are occurring concurrently raises suspicion that the frequency is higher than that of chance alone. However, despite the fact that familial clustering of polycythemia vera, essential thrombocythemia and myelofibrosis has been well described [26–28], the presence of the JAK2 mutation does not appear to represent the genetic predisposing factor [26,29,30–32]. Further work will be required to elucidate factors that predispose patients to concurrent GIST and other malignancies, including MPNs.
NONHEREDITARY CARNEY’S TRIAD (QUADRAD) Carney’s triad is a rare nonheritable syndrome in young women associated with gastric GIST, as well as benign paragangliomas and pulmonary chondromas [33]. Approximately 150 cases of Carney’s triad have been reported thus far [34]. Recently, 14 patients with a fourth component of the triad, namely asymptomatic benign adrenal adenomas, were described [35 ]. In this series, bilateral adenomas were observed in four patients (29%). Taken together, this syndrome may represent a quadrad rather than the classically described triad. New insight has also been gained into the molecular biology of this syndrome. There was a recent report of overexpression of insulin-like growth factor 1 receptor (IGF1R) in three patients with Carney’s triad [36 ]. This is interesting because wild-type GISTs (e.g. those lacking KIT or PDGFRa mutations) have also been shown to overexpress IGF1R, which may be a targetable receptor [37]. Additional insights into the molecular pathogenesis of Carney’s triad have been reported. Given that Carney’s triad has some shared molecular and clinical features with the hereditary Carney–Stratakis syndrome, additional recent findings will be discussed below. &
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FAMILIAL GIST SYNDROME As early as 1990, there were reports of multiple primary GISTs in kindreds [38]. Subsequently, Nishida et al. [39] identified a germline KIT mutation as the cause of an inherited predisposition to GIST. Given the prevalence of somatic KIT mutations in sporadic GIST, it is not surprising that the most widely reported mutations in familial GIST syndromes are germline KIT mutations. There are now 24 reported kindreds with germline KIT mutations and associated familial GIST [2 ]. These mutations map to KIT exon 11 in the majority of kindreds (66.7%, 16 of 24). Mutations in KIT exons 8, 13 and 17 have also been described [2 ]. The inheritance pattern is autosomal dominant, and the median age at diagnosis tends to be at least a decade younger than typical age for sporadic GIST presentation. In addition to a predisposition to developing GIST, the clinical syndrome has a variable expression pattern without clear genotypephenotype association. Patients may also develop pigment changes of the skin, urticarial pigmentosa/ mastocytosis, diffuse hyperplasia of the myenteric (Auerbach’s) plexus and dysphagia. Histologically, familial GISTs are similar to sporadic tumors, but the mitotic indices tend to be lower, even in the setting of metastatic disease [2 ]. Similar to patients with somatic KIT mutations, patients with germline KITmutated GISTs often respond to treatment with imatinib. Because KIT is known to regulate proliferation and differentiation of melanocytes, this may also explain the associated skin findings in familial GIST patients. Interestingly, these cutaneous pigmentary changes also have been demonstrated to respond to tyrosine kinase inhibition [40]. Analogous to the characterized somatic mutations in sporadic GIST, there are also reports of three germline PDGFRa mutations in familial GIST kindreds [41 ]. Similar to familial KIT mutations, these familial PDGFRa mutations occur in exons frequently mutated in sporadic GISTs. These include two exon 12 mutations (e.g. Y555C and V561D) [42,43] and one exon 18 mutation (D846Y) [44]. Patients in the PDGFRaY555C kindred also had intestinal neurofibromatosis without other classic features of neurofibromatosis type 1 (NF-1) [42]. These findings are interesting because GIST is associated with NF-1 as described below. Another patient with a germline PDGFRaV561D mutation had associated lipomas and fibrous tumors of the small intestine [43]. Finally, patients in the PDGFRaD846Y kindred were also noted to have large hands [44]. In line with this finding, Boguszewski et al. [45] reported a single case of a GIST patient with associated acromegaly, pheochromocytoma and thyroid follicular adenoma without clear association with multiple endocrine &
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neoplasia syndromes or familial GIST syndromes. Although KIT and PDGFRa mutations were not described in that report, the cooccurrence of acromegaly and GIST raises the possibility of PDGFRa pathway involvement given the large hands seen in patients with germline mutations of PDGFRa.
NEUROFIBROMATOSIS TYPE 1 NF-1, von Reckinghausen’s disease, is a disorder classically characterized by cutaneous (i.e. cafe´ au lait spots, axillary/inguinal freckling, and dermal neurofibromas) and ocular (i.e. iris hamartomas and Lisch nodules) manifestations, as well as nervous system tumors (i.e. gliomas, plexiform neurofibromas, ganglioneuromas and malignant peripheral nerve sheath tumors) and GISTs. In recent years, there is a growing body of literature demonstrating that additional gastrointestinal tumors (i.e. periampullary neuroendocrine tumors, pancreatic neuroendocrine tumors including somatostatinomas, and juvenilelike inflammatory/hyperplastic mucosal polyps), sarcomas (i.e. leiomyosarcoma and osteosarcoma) and pheochromocytomas are associated with NF-1 [46 ,47–51]. Regarding GISTs, they are not uncommon in NF-1 patients. A Swedish Cancer Registry study revealed that 7% of NF-1 patients had GISTs [52]. These NF-1-associated GISTs are more frequent in the small bowel than the stomach and account for 1.5% of all GISTs [53]. Underlying this phenotype, NF-1 is an autosomal dominant disease that results from germline mutations in the NF-1 gene, which encodes neurofibromin. Because the NF-1 gene has a high rate of de-novo mutations, approximately half of NF-1 cases occur in the absence of a family history [54]. Given that the interstitial cell of Cajal (ICC) is the cellular origin of GIST, it is not surprising that ICC hyperplasia is common in NF-1 patients [53]. In contrast to familial GISTs, wherein ICC hyperplasia is believed to be a direct consequence of constitutive KIT or PDGFRa activation, ICC hyperplasia in NF-1 patients it is thought to be secondary to NF-1 haploinsufficiency [55]. The emergence of GIST is likely due to subsequent loss of heterozygosity at NF-1 and accumulation of additional chromosomal alterations. In turn, GIST represents the most common gastrointestinal manifestation of NF-1 [46 ]. In this patient population, GISTs tend to be diagnosed in the fifth or sixth decade of life with a slight female predominance [53,56]. NF-1-associated GISTs mostly present asymptomatically as multiple small tumors with low mitotic activity. As a result, they typically have a relatively indolent biology. However, recent reports have suggested that some patients can present symptomatically with bleeding and anemia, perforation, obstruction or pain with invasion into
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adjacent structures, suggesting that the risk of complications and aggressive disease biology should not be underestimated in NF-1 patients [57–60]. Neurofibromin is a tumor suppressor protein that negatively regulates Ras signal transduction and downstream mitogen-activated protein kinase (MAPK) pathway activation. As a result, NF-1 inactivation results in constitutive mitogenic MAPK signal transduction, which leads to tumorigenesis [61]. Similarly, MAPK pathway activation occurs in sporadic GISTs due to gain-of-function mutations in KIT or PDGFRa. Moreover, the NF-1-associated GISTs have several other similarities to the various subsets of sporadic GISTs. Like many KIT and PDGFRamutated GISTs, they are uniformly KIT positive by immunohistochemistry [46 ], as well as retain mitochondrial expression of SDH subunit B (SDHB) [62,63]. However, similar to sporadic wild-type GISTs lacking KIT and PDGFRa mutations, NF-1associated GISTs rarely harbor somatic KIT/PDGFRa mutations [64] and have variable imatinib sensitivity [65,66]. &&
CARNEY–STRATAKIS SYNDROME Classically, Carney–Stratakis syndrome results from a germline mutation in the B, C and D subunits of SDH. This appears to be an autosomal dominant syndrome with incomplete penetrance and variable manifestations. Affected patients develop paragangliomas, GISTs or the dyad of both [67–69]. These SDH-deficient GISTs are characterized by gastric location, frequent lymph node metastases and an indolent metastatic disease [70]. The GISTs in these individuals do not have KIT or PDGFRa mutations, but rather show loss of SDHB expression by immunohistochemistry with an underlying SDH gene mutation [71]. This SDHB deficiency signals the loss of function of the SDH complex consisting of mitochondrial inner membrane proteins. More recently, germline mutations in SDH subunit A (SDHA) have been identified in 30% of SDHdeficient GISTs [72 ,73 ]. These SDHA mutations also correlated with loss of SDHA expression. Thus, germline mutations in SDH subunits A, B, C and D must be considered when an SDH-deficient GIST is encountered. Analogous to Carney–Stratakis syndrome, GISTs associated with Carney’s triad lack KIT/ PDGFRa mutations and are SDH-deficient by immunohistochemistry. However, unlike Carney–Stratakis syndrome, associated SDH gene mutations have not been identified in Carney’s triad patients [5,74]. Apart from the clinical and genomic distinctions between the dyad (Carney–Stratakis syndrome) and Carney’s triad (quadrad),a recent study has also &
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described their distinction based upon the differential expression of 34 miRNAs [75]. However, a larger cohort of patients is needed to confirm this finding and determine its significance. Taken together, Carney–Stratakis syndrome and Carney’s triad represent distinct disease entities with inherent differences in their heritability, molecular pathogenesis and clinical presentations.
CONCLUSION We continue to gain further insight into the nonrandom association between GIST and other malignancies, as well as the underlying biology of hereditary GIST syndromes. In turn, this knowledge can be utilized to shape the clinical management of these patients, including: cancer screening recommendations; prevention strategies; familial genetic counseling and screening; and development of anticancer therapies against unappreciated targets in patients with GIST multiple tumor syndromes. Acknowledgements Authors’ Contributions Acquisition of data, A.M.B., N.S., J.K.S., Conception and design, A.M.B., N.S., J.K.S., Analysis of data, A.M.B., N.S., J.K.S., Interpretation of data, A.M.B., N.S., J.K.S., Drafting of article, A.M.B., N.S., J.K.S., Critical revision of article: A.M.B., N.S., J.K.S. Final approval of the version to be published: A.M.B., N.S., J.K.S. Grant Support: This work was supported by the Jack Kiel Wolf Memorial Research Fund (J.K.S.), the Stuart Manroel Memorial Research Fund (J.K.S.), the UCSD GIST Research Fund (J.K.S.), as well as funding provided by UCSD Moores Cancer Center. Conflicts of interest J.K.S. received honoraria from Novartis Pharmaceuticals Corporation for advisory board consultancy and speaking, as well as reimbursement for travel, lodging, and meals. J.K.S. received honoraria from Genentech Inc. for speaking. No additional authors have conflicts of interest to declare.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Agaimy A, Hartmann A. Hereditary and nonhereditary syndromic gastointestinal stromal tumours. Pathologe 2010; 31:430–437. 2. Neuhann TM, Mansmann V, Merkelbach-Bruse S, et al. A novel germline KIT & mutation (p.L576P) in a family presenting with juvenile onset of multiple gastrointestinal stromal tumors, skin hyperpigmentations, and esophageal stenosis. Am J Surg Pathol 2013; 37:898–905. This is an excellent review of 24 reported kindreds with germline KIT mutations and associated familial GIST.
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Gastrointestinal stromal tumor syndromes Burgoyne et al. 3. Kuroda N, Tanida N, Hirota S, et al. Familial gastrointestinal stromal tumor with germ line mutation of the juxtamembrane domain of the KIT gene observed in relatively young women. Ann Diagn Pathol 2011; 15:358–361. 4. Ponti G, Luppi G, Martorana D, et al. Gastrointestinal stromal tumor and other primary metachronous or synchronous neoplasms as a suspicion criterion for syndromic setting. Oncol Rep 2010; 23:437–444. 5. Stratakis CA, Carney JA. The triad of paragangliomas, gastric stromal tumours and pulmonary chondromas (Carney triad), and the dyad of paragangliomas and gastric stromal sarcomas (Carney-Stratakis syndrome): molecular genetics and clinical implications. J Intern Med 2009; 266:43–52. 6. Pandurengan RK, Dumont AG, Araujo DM, et al. Survival of patients with multiple primary malignancies: a study of 783 patients with gastrointestinal stromal tumor. Ann Oncol 2010; 21:2107–2111. 7. Agaimy A, Wunsch PH, Sobin LH, et al. Occurrence of other malignancies in patients with gastrointestinal stromal tumors. Semin Diagn Pathol 2006; 23:120–129. 8. Miettinen M, Kraszewska E, Sobin LH, Lasota J. A nonrandom association between gastrointestinal stromal tumors and myeloid leukemia. Cancer 2008; 112:645–649. 9. Rheingold S, Neugut A, Meadows A. Secondary cancers: incidence, risk factors, and management. In: Bast RC Jr, Kufe D, Pollock R, editors. HollandFrei cancer medicine. 5th ed. Hamilton, Ontario, British Columbia: Decker; 2000. Chapter 156. 10. Kosary C, Lag R, Miller B. SEER Cancer statistics review 1973-1992: tables and graphs, N. National Cancer Institute, Editor 1995: Bethesda, MD. 11. Liu YJ, Yang Z, Hao LS, et al. Synchronous incidental gastrointestinal stromal and epithelial malignant tumors. World J Gastroenterol 2009; 15:2027– 2031. 12. Chan CH, Cools-Lartigue J, Marcus VA, et al. The impact of incidental gastrointestinal stromal tumours on patients undergoing resection of upper gastrointestinal neoplasms. Can J Surg 2012; 55:366–370. 13. AbdullGaffar B. Gastrointestinal stromal tumors and extra-gastrointestinal tract neoplasms. South Med J 2010; 103:1004–1008. 14. Kakkar A, Gupta RK, Dash NR, et al. Lymphoepithelioma-like carcinoma of the stomach with incidental gastrointestinal stromal tumor (GIST)-a rare synchrony of two tumors. J Gastrointest Cancer 2014. [Epub ahead of print] 15. Dumont AG, Rink L, Godwin AK, et al. A nonrandom association of gastrointestinal stromal tumor (GIST) and desmoid tumor (deep fibromatosis): case series of 28 patients. Ann Oncol 2012; 23:1335–1340. 16. Pitini V, Arrigo C, Sauta MG, Altavilla G. Myelodysplastic syndrome appearing during imatinib mesylate therapy in a patient with GIST. Leuk Res 2009; 33:e143–e144. 17. Del Biondo E, De Raeva H, Huysmans G, et al. Concomitant JAK2 V617F positive essential thrombocytemia and BCR-ABL1 positive chronic myeloid leukaemia masked by imatinib therapy for a gastrointestinal stromal tumour. Belgian J Hematol 2012; 3:105–107. 18. Schoeler D, Klu¨hs C, Pink D, et al. Polycythemia vera in GIST patients. J Clin Oncol 2010; 28:. 2010 (suppl; abstr e20520). 19. Campbell PJ, Green AR. The myeloproliferative disorders. N Engl J Med 2006; 355:2452–2466. 20. Pikman Y, Lee BH, Mercher T, et al. MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia. PLoS Med 2006; 3:e270. 21. Rubin BP, Heinrich MC, Corless CL. Gastrointestinal stromal tumour. Lancet 2007; 369:1731–1741. 22. Corless CL, Barnett CM, Heinrich MC. Gastrointestinal stromal tumours: origin and molecular oncology. Nat Rev Cancer 2011; 11:865–878. 23. Liegl-Atzwanger B, Fletcher JA, Fletcher CD. Gastrointestinal stromal tumors. Virchows Arch 2010; 456:111–127. 24. Agaram NP, Wong GC, Guo T, et al. Novel V600E BRAF mutations in imatinib-naive and imatinib-resistant gastrointestinal stromal tumors. Genes Chromosomes Cancer 2008; 47:853–859. 25. Mehta J, Wang H, Iqbal SU, Mesa R. Epidemiology of myeloproliferative neoplasms in the United States. Leuk Lymphoma 2014; 55:595–600. 26. Landgren O, Goldin LR, Kristinsson SY, et al. Increased risks of polycythemia vera, essential thrombocythemia, and myelofibrosis among 24,577 firstdegree relatives of 11,039 patients with myeloproliferative neoplasms in Sweden. Blood 2008; 112:2199–2204. 27. Hemminki K, Sundquist J, Bermejo JL. Associated cancers in parents and offspring of polycythaemia vera and myelofibrosis patients. Br J Haematol 2009; 147:526–530. 28. Cario H, Goerttler PS, Steimle C, et al. The JAK2V617F mutation is acquired secondary to the predisposing alteration in familial polycythaemia vera. Br J Haematol 2005; 130:800–801. 29. Bellanne-Chantelot C, Chaumarel I, Labopin M, et al. Genetic and clinical implications of the Val617Phe JAK2 mutation in 72 families with myeloproliferative disorders. Blood 2006; 108:346–352. 30. Rumi E, Passamonti F, Pietra D, et al. JAK2 (V617F) as an acquired somatic mutation and a secondary genetic event associated with disease progression in familial myeloproliferative disorders. Cancer 2006; 107:2206– 2211. 31. Pardanani A, Lasho T, McClure R, et al. Discordant distribution of JAK2V617F mutation in siblings with familial myeloproliferative disorders. Blood 2006; 107:4572–4573.
32. Kralovics R, Stockton DW, Prchal JT. Clonal hematopoiesis in familial polycythemia vera suggests the involvement of multiple mutational events in the early pathogenesis of the disease. Blood 2003; 102:3793–3796. 33. Carney JA, Sheps SG, Go VL, Gordon H. The triad of gastric leiomyosarcoma, functioning extra-adrenal paraganglioma and pulmonary chondroma. N Engl J Med 1977; 296:1517–1518. 34. Carney JA. Carney triad. Front Horm Res 2013; 41:92–110. 35. Carney JA, Stratakis CA, Young WF Jr. Adrenal cortical adenoma: the fourth & component of the Carney triad and an association with subclinical Cushing syndrome. Am J Surg Pathol 2013; 37:1140–1149. This report describes 14 patients with a fourth component of Carney’s triad, namely benign unilateral or bilateral adrenal adenomas. 36. Belinsky MG, Rink L, Flieder DB, et al. Overexpression of insulin-like growth & factor 1 receptor and frequent mutational inactivation of SDHA in wild-type SDHB-negative gastrointestinal stromal tumors. Genes Chromosomes Cancer 2013; 52:214–224. Similar to wild-type GISTs, this recent report describes overexpression of IGF1R in three patients with Carney’s triad. 37. Tarn C, Rink L, Merkel E, et al. Insulin-like growth factor 1 receptor is a potential therapeutic target for gastrointestinal stromal tumors. Proc Natl Acad Sci U S A 2008; 105:8387–8392. 38. Marshall JB, Diaz-Arias AA, Bochna GS, Vogele KA. Achalasia due to diffuse esophageal leiomyomatosis and inherited as an autosomal dominant disorder. Report of a family study. Gastroenterology 1990; 98 (5 Pt 1):1358– 1365. 39. Nishida T, Hirota S, Taniguchi M, et al. Familial gastrointestinal stromal tumours with germline mutation of the KIT gene. Nat Genet 1998; 19:323–324. 40. Campbell T, Felsten L, Moore J. Disappearance of lentigines in a patient receiving imatinib treatment for familial gastrointestinal stromal tumor syndrome. Arch Dermatol 2009; 145:1313–1316. 41. Postow MA, Robson ME. Inherited gastrointestinal stromal tumor syndromes: && mutations, clinical features, and therapeutic implications. Clin Sarcoma Res 2012; 2:16. This report reviews three reports of germline PDGFRa mutations in familial GIST kindreds. 42. de Raedt T, Cools J, Debiec-Rychter M, et al. Intestinal neurofibromatosis is a subtype of familial GIST and results from a dominant activating mutation in PDGFRA. Gastroenterology 2006; 131:1907–1912. 43. Pasini B, Matyakhina L, Bei T, et al. Multiple gastrointestinal stromal and other tumors caused by platelet-derived growth factor receptor alpha gene mutations: a case associated with a germline V561D defect. J Clin Endocrinol Metab 2007; 92:3728–3732. 44. Chompret A, Kannengiesser C, Barrois M, et al. PDGFRA germline mutation in a family with multiple cases of gastrointestinal stromal tumor. Gastroenterology 2004; 126:318–321. 45. Boguszewski CL, Fighera TM, Bornschein A, et al. Genetic studies in a coexistence of acromegaly, pheochromocytoma, gastrointestinal stromal tumor (GIST) and thyroid follicular adenoma. Arq Bras Endocrinol Metabol 2012; 56:507–512. 46. Agaimy A, Vassos N, Croner RS. Gastrointestinal manifestations of && neurofibromatosis type 1 (Recklinghausen’s disease): clinicopathological spectrum with pathogenetic considerations. Int J Clin Exp Pathol 2012; 5:852–862. This excellent review summarizes the growing body of literature demonstrating gastrointestinal tumors (i.e. GISTs, periampullary neuroendocrine tumors, pancreatic neuroendocrine tumors including somatostatinomas, and juvenile-like inflammatory/hyperplastic mucosal polyps) in NF-1 patients. 47. Agaimy A, Schaefer IM, Kotzina L, et al. Juvenile-like (inflammatory/hyperplastic) mucosal polyps of the gastrointestinal tract in neurofibromatosis type 1. Histopathology 2014; 64:777–786. 48. Afsar CU, Kara IO, Kozat BK, et al. Neurofibromatosis type 1, gastrointestinal stromal tumor, leiomyosarcoma and osteosarcoma: four cases of rare tumors and a review of the literature. Crit Rev Oncol Hematol 2013; 86:191–199. 49. Tavares AB, Viveiros FA, Cidade CN, Maciel J. Gastric GIST with synchronous neuroendocrine tumour of the pancreas in a patient without neurofibromatosis type 1. BMJ Case Rep 2012; 2012. 50. Cavallaro G, Basile U, Polistena A, et al. Surgical management of abdominal manifestations of type 1 neurofibromatosis: experience of a single center. Am Surg 2010; 76:389–396. 51. Haugvik SP, Røsok BI, Edwin B, et al. Concomitant nonfunctional pancreatic neuroendocrine tumor and gastric GIST in a patient without neurofibromatosis type 1. J Gastrointest Cancer 2011. [Epub ahead of print] 52. Zoller ME, Rembeck B, Ode´n A, et al. Malignant and benign tumors in patients with neurofibromatosis type 1 in a defined Swedish population. Cancer 1997; 79:2125–2131. 53. Miettinen M, Fetsch JF, Sobin LH, Lasota J. Gastrointestinal stromal tumors in patients with neurofibromatosis 1: a clinicopathologic and molecular genetic study of 45 cases. Am J Surg Pathol 2006; 30:90–96. 54. Ferner RE. Neurofibromatosis 1 and neurofibromatosis 2: a twenty first century perspective. Lancet Neurol 2007; 6:340–351. 55. Maertens O, Prenen H, Debiec-Rychter M, et al. Molecular pathogenesis of multiple gastrointestinal stromal tumors in NF1 patients. Hum Mol Genet 2006; 15:1015–1023.
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Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Sarcomas 56. Takazawa Y, Sakurai S, Sakuma Y, et al. Gastrointestinal stromal tumors of neurofibromatosis type I (von Recklinghausen’s disease). Am J Surg Pathol 2005; 29:755–763. 57. Saha SB, Parmar RA. Mandal, small bowel obstruction in a neurofibromatosis patient-a rare presentation of gastro-intestinal stromal tumors (GISTs): case report and literature review. Indian J Surg 2013; 75 (Suppl 1):415–417. 58. Swain SK, Smile R, Arul T, David D. Unusual presentation of gastrointestinal stromal tumor of stomach in neurofibromatosis type 1: a case report. Indian J Surg 2013; 75 (Suppl 1):398–400. 59. Sawalhi S, Al-Harbi K, Raghib Z, et al. Behavior of advanced gastrointestinal stromal tumor in a patient with von-Recklinghausen disease: Case report. World J Clin Oncol 2013; 4:70–74. 60. Kitagawa M, Koh T, Nakagawa N, et al. Gastrointestinal stromal tumor in a patient with neurofibromatosis: abscess formation in the tumor leading to bacteremia and seizure. Case Rep Gastroenterol 2010; 4:435–442. 61. Gottfried ON, Viskochil DH, Couldwell WT. Neurofibromatosis type 1 and tumorigenesis: molecular mechanisms and therapeutic implications. Neurosurg Focus 2010; 28:E8. 62. Gill AJ, Chou A, Vilain R, et al. Immunohistochemistry for SDHB divides gastrointestinal stromal tumors (GISTs) into 2 distinct types. Am J Surg Pathol 2010; 34:636–644. 63. Wang JH, Lasota J, Miettinen M. Succinate dehydrogenase subunit B (SDHB) is expressed in neurofibromatosis 1-associated gastrointestinal stromal tumors (GISTs): implications for the SDHB expression based classification of GISTs. J Cancer 2011; 2:90–93. 64. Kinoshita K, Hirota S, Isozaki K, et al. Absence of c-kit gene mutations in gastrointestinal stromal tumours from neurofibromatosis type 1 patients. J Pathol 2004; 202:80–85. 65. Lee JL, Kim JY, Ryu MH, et al. Response to imatinib in KIT- and PDGFRA-wild type gastrointestinal stromal associated with neurofibromatosis type 1. Dig Dis Sci 2006; 51:1043–1046. 66. Mussi C, Schildhaus HU, Gronchi A, et al. Therapeutic consequences from molecular biology for gastrointestinal stromal tumor patients affected by neurofibromatosis type 1. Clin Cancer Res 2008; 14:4550–4555.
414
www.co-oncology.com
67. Carney JA, Stratakis CA. Familial paraganglioma and gastric stromal sarcoma: a new syndrome distinct from the Carney triad. Am J Med Genet 2002; 108:132–139. 68. McWhinney SR, Pasini B, Stratakis CA, et al. Familial gastrointestinal stromal tumors and germ-line mutations. N Engl J Med 2007; 357:1054– 1056. 69. Pasini B, McWhinney SR, Bei T, et al. Clinical and molecular genetics of patients with the Carney-Stratakis syndrome and germline mutations of the genes coding for the succinate dehydrogenase subunits SDHB, SDHC, and SDHD. Eur J Hum Genet 2008; 16:79–88. 70. Miettinen M, Wang ZF, Sarlomo-Rikala M, et al. Succinate dehydrogenasedeficient GISTs: a clinicopathologic, immunohistochemical, and molecular genetic study of 66 gastric GISTs with predilection to young age. Am J Surg Pathol 2011; 35:1712–1721. 71. Gaal J, Stratakis CA, Carney JA, et al. SDHB immunohistochemistry: a useful tool in the diagnosis of Carney-Stratakis and Carney triad gastrointestinal stromal tumors. Mod Pathol 2011; 24:147–151. 72. Dwight T, Benn DE, Clarkson A, et al. Loss of SDHA expression identifies & SDHA mutations in succinate dehydrogenase-deficient gastrointestinal stromal tumors. Am J Surg Pathol 2013; 37:226–233. Back-to-back report first demonstrating the presence of germline SDHA mutations in Carney–Stratakis patients. 73. Miettinen M, Killian JK, Wang ZF, et al. Immunohistochemical loss of succinate & dehydrogenase subunit A (SDHA) in gastrointestinal stromal tumors (GISTs) signals SDHA germline mutation. Am J Surg Pathol 2013; 37:234–240. Back-to-back report first demonstrating the presence of germline SDHA mutations in Carney–Stratakis patients. 74. Matyakhina L, Bei TA, McWhinney SR, et al. Genetics of carney triad: recurrent losses at chromosome 1 but lack of germline mutations in genes associated with paragangliomas and gastrointestinal stromal tumors. J Clin Endocrinol Metab 2007; 92:2938–2943. 75. Kelly L, Bryan K, Ki SY, et al. Posttranscriptional dysregulation by miRNAs is implicated in the pathogenesis of gastrointestinal stromal tumor [GIST]. PLoS One 2013; 8:e64102.
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