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1
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Choi JH. Inflammatory Myofibroblastic Tumor: An Updated Review. Cancers (Basel) 2025; 17:1327. [PMID: 40282503 PMCID: PMC12026078 DOI: 10.3390/cancers17081327] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2025] [Revised: 04/12/2025] [Accepted: 04/12/2025] [Indexed: 04/29/2025] Open
Abstract
Inflammatory myofibroblastic tumor (IMT) is a rare neoplasm that is characterized by a proliferation of myofibroblastic and fibroblastic spindle cells, accompanied by an inflammatory infiltrate that is abundant in plasma cells, lymphocytes, and eosinophils. IMT can arise in various anatomical locations but most commonly occurs in the abdominal cavity, retroperitoneum, and lung, particularly in children and young adults. IMT typically demonstrates local invasion or recurrence, whereas metastasis is rare. IMTs pose a diagnostic challenge because of their overlapping morphological characteristics with a heterogeneous group of nonneoplastic and neoplastic lesions. Precise diagnosis is crucial for optimal management and accurate prognostication. Despite recent advancements in IMT diagnosis and treatment, its biological complexity and clinical management remain challenging due to significant histological heterogeneity and molecular genetic diversity. This review provides comprehensive updates on the clinical, molecular, and pathological characteristics of IMT, highlighting the diagnostic approaches and key differential diagnoses.
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Affiliation(s)
- Joon Hyuk Choi
- Department of Pathology, Yeungnam University College of Medicine, Daegu 42415, Republic of Korea
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2
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Min V, Corradini N, Macagno N, Orbach D, Reguerre Y, Petit P, Blay JY, Verschuur A. Gastrointestinal stromal tumours (GIST) in children: An update of this orphan disease. Bull Cancer 2025; 112:348-357. [PMID: 39455327 DOI: 10.1016/j.bulcan.2024.07.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Revised: 05/31/2024] [Accepted: 07/04/2024] [Indexed: 10/28/2024]
Abstract
BACKGROUND Gastrointestinal stromal tumours (GIST) are tumours of the digestive tract that mainly develop in adults. Recommendations for the management of GIST in pediatrics are limited. MATERIAL AND METHODS We performed an updated review of the literature serving as a basis for the development of diagnostic and therapeutic recommendations for GIST in children and young adults (YA). RESULTS GIST in pediatric population can have a sporadic presentation but occur more often in a syndromic and/or familial context. Currently more than 170 cases of sporadic GIST or in association with Carney-Stratakis syndrome or Carney's triad family cases of familial GIST have been described in children and YA. These syndromes are frequently associated with germline or somatic alterations in a sub-unit of Succinate Dehydrogenase (SDH). In contrast, the frequency of somatic KIT and PDGFRα oncogene mutations (±15%) is significantly lower as compared to adults with GIST. The recommendations for the management of children with GIST are generally comparable to those used for adult patients, although certain biological differences influence the therapeutic attitude. CONCLUSIONS International collaborations have been deployed in order to increase the clinical and biological knowledge of this orphan pathology in pediatrics.
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Affiliation(s)
- Victoria Min
- Pediatric Hematology Oncology Department, La Timone Children's Hospital, AP-HM, 264, rue St Pierre, 13385 Marseille cedex, France
| | - Nadège Corradini
- Pediatric Hematology Oncology Department, Institute of Pediatric Hematology and Oncology (IHOPe), Léon Bérard Cancer Centre, Lyon, France
| | | | - Daniel Orbach
- SIREDO Oncology Centre (Care, Innovation and Research for Children, Adolescents and Young Adults with Cancer), PSL University, Institut Curie, Paris, France
| | - Yves Reguerre
- Pediatric Oncology Department, University Hospital Center La Reunion, Saint-Denis, Reunion
| | - Philippe Petit
- Department of pediatric and prenatal radiology, La Timone Children's Hospital, Aix Marseille University, AP-HM, 264, rue St-Pierre, 13385 Marseille cedex, France
| | - Jean-Yves Blay
- Department of Medicine, Centre Leon Berard, UNICANCER & University Lyon I, Lyon, France
| | - Arnauld Verschuur
- Pediatric Hematology Oncology Department, La Timone Children's Hospital, AP-HM, 264, rue St Pierre, 13385 Marseille cedex, France.
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3
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Judson I, Jones RL, Wong NACS, Dileo P, Bulusu R, Smith M, Almond M. Gastrointestinal stromal tumour (GIST): British Sarcoma Group clinical practice guidelines. Br J Cancer 2025; 132:1-10. [PMID: 38840030 PMCID: PMC11723931 DOI: 10.1038/s41416-024-02672-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Revised: 03/21/2024] [Accepted: 03/25/2024] [Indexed: 06/07/2024] Open
Abstract
BACKGROUND British Sarcoma Group guidelines for the management of GIST were initially informed by those published by the European Society of Clinical Oncology. This update was written by a group of experts to includes a discussion of the highlight improvements in our knowledge of the disease and recent treatment developments. The guidelines include sections on Incidence, Aetiology, Diagnosis, including risk assessment, Treatment and Follow-up. METHODS A careful review of the literature was performed to ensure that wherever possible recommendations are supported by the results of clinical trials or substantive retrospective reports. Areas of uncertainty are indicated appropriately. CONCLUSION Guidelines represent a consensus view of current best clinical practice. Where appropriate, key recommendations are given and the levels of evidence and strength of recommendation gradings are those used by the European Society for Medical Oncology (ESMO).
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Affiliation(s)
- Ian Judson
- The Institute of Cancer Research, London, UK.
| | | | | | | | | | - Myles Smith
- Royal Marsden NHS Foundation Trust, London, UK
| | - Max Almond
- Birmingham University Hospitals, Birmingham, UK
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4
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Tsoy UA, Sokolnikova PS, Kravchuk EN, Ryazanov PA, Kozyreva AA, Fomicheva YV, Aramisova LS, Karonova TL, Kostareva AA, Grineva E. A Comprehensive Target Panel Allows to Extend the Genetic Spectrum of Neuroendocrine Tumors. Neuroendocrinology 2024:1-21. [PMID: 39536727 DOI: 10.1159/000542223] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Accepted: 09/17/2024] [Indexed: 11/16/2024]
Abstract
INTRODUCTION Neuroendocrine tumors (NETs) frequently have a genetic basis, and the range of genes implicated in NET development continues to expand. Application of targeted gene panels (TGPs) in next-generation sequencing is a central strategy for elucidating novel variants associated with NET development. METHODS In this study, we conducted comprehensive molecular genetic analyses using TGP on a cohort of 93 patients diagnosed with various NETs subtypes, mainly accompanied by various endocrine syndromes: insulinoma (n = 26), pheochromocytoma and paraganglioma (PPGL) (n = 38), parathyroid adenoma (n = 18, including three with insulinoma), and NETs of other locations (n = 14). The TGP encompassed genes linked to diverse NETs and other hereditary endocrine disorders, with subsequent variant classification according to the American College of Medical Genetics and Genomics guidelines. RESULTS Among the identified variants, 20 were found in genes previously linked to specific tumor types, and 10 were found in genes with a limited likelihood and unclear molecular mecanisms of association with observed NETs. Remarkably, 13 variants were discovered in genes not previously associated with the NETs observed in our patients. These genes, such as ABCC8, KCNJ11, KLF11, HABP2, and APC, were implicated in insulinoma; ZNRF3, GNAS, and KCNJ5 were linked with PPGL; parathyroid adenomas were related to variants in SDHB and TP53; while NETs of other locations displayed variants in APC and ABCC8. CONCLUSION Our study demonstrates that utilizing broad TGP in examining patients with various functioning NETs facilitates the identification of new germinal variants in genes that may contribute to the diseases. The verification of revealed findings requires research in vaster sample.
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Affiliation(s)
- Uliana A Tsoy
- World-Class Research Centre for Personalized Medicine, Almazov National Medical Research Centre, Saint Petersburg, Russian Federation
| | - Polina S Sokolnikova
- World-Class Research Centre for Personalized Medicine, Almazov National Medical Research Centre, Saint Petersburg, Russian Federation
| | - Ekaterina N Kravchuk
- World-Class Research Centre for Personalized Medicine, Almazov National Medical Research Centre, Saint Petersburg, Russian Federation
| | - Pavel A Ryazanov
- World-Class Research Centre for Personalized Medicine, Almazov National Medical Research Centre, Saint Petersburg, Russian Federation
| | - Alexandra A Kozyreva
- World-Class Research Centre for Personalized Medicine, Almazov National Medical Research Centre, Saint Petersburg, Russian Federation
| | - Yulia V Fomicheva
- World-Class Research Centre for Personalized Medicine, Almazov National Medical Research Centre, Saint Petersburg, Russian Federation
| | - Liana S Aramisova
- World-Class Research Centre for Personalized Medicine, Almazov National Medical Research Centre, Saint Petersburg, Russian Federation
| | - Tatiana L Karonova
- World-Class Research Centre for Personalized Medicine, Almazov National Medical Research Centre, Saint Petersburg, Russian Federation
| | - Anna A Kostareva
- World-Class Research Centre for Personalized Medicine, Almazov National Medical Research Centre, Saint Petersburg, Russian Federation
- Department of Women's and Children's Health, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden
| | - Elena Grineva
- World-Class Research Centre for Personalized Medicine, Almazov National Medical Research Centre, Saint Petersburg, Russian Federation
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5
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Mousavi S, Ono Y, VanderLaan PA, Guzmán-Arocho YD. Gastrointestinal stromal tumors in fine-needle aspiration biopsies. Diagn Cytopathol 2024; 52:575-581. [PMID: 38396207 DOI: 10.1002/dc.25285] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2024] [Revised: 01/24/2024] [Accepted: 01/29/2024] [Indexed: 02/25/2024]
Abstract
Gastrointestinal stromal tumors (GISTs), although rare, are the most common mesenchymal neoplasms of the gastrointestinal tract. Their potential for malignancy underscores the significance of identifying them through cytomorphologic findings and pertinent immunohistochemical markers. GISTs can emerge anywhere along the gastrointestinal tract with a predilection for the stomach. The clinical manifestations vary from nonspecific abdominal symptoms to incidental discovery during diagnostic interventions for unrelated signs and symptoms. Cytologically, GIST aspirates contain spindle or epithelioid cells with immunoreactivity for CD117/c-KIT, DOG-1, and CD34. Molecularly, KIT or PDGFRA mutations are prevalent, guiding targeted therapy with tyrosine kinase inhibitors. Distinct subtypes like succinate dehydrogenase-deficient GISTs pose challenges, often affecting younger individuals and displaying unique features. Histologically, GISTs are graded by mitotic rates, aiding prognostication. Distinguishing GISTs from similar entities is pivotal, necessitating attention to their immunostaining patterns for making an accurate diagnosis and molecular alterations for effectively planning treatment. Common differential diagnoses include leiomyoma, schwannoma, and solitary fibrous tumor. This article presents a classic GIST case and showcases relatively simple diagnostic clues for identifying similar lesions that may occur in diverse locations.
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Affiliation(s)
- Seyedreza Mousavi
- Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA
| | - Yuho Ono
- Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA
| | - Paul A VanderLaan
- Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA
| | - Yaileen D Guzmán-Arocho
- Department of Pathology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, USA
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6
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Wang XK, Shen LF, Yang X, Su H, Wu T, Tao PX, Lv HY, Yao TH, Yi L, Gu YH. Two different mutational types of familial gastrointestinal stromal tumors: Two case reports. World J Gastrointest Oncol 2024; 16:4028-4036. [PMID: 39350996 PMCID: PMC11438775 DOI: 10.4251/wjgo.v16.i9.4028] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2024] [Revised: 07/03/2024] [Accepted: 07/19/2024] [Indexed: 09/09/2024] Open
Abstract
BACKGROUND Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal (GI) tract, and cases of GISTs tend to be of the disseminated type, with a global incidence of 10 to 15 cases/million each year. The rarer familial GISTs, which often represent a population, differ in screening, diagnosis, and treatment. Familial GISTs include primary familial GISTs with predominantly KIT/PDGFRA mutations and wild-type GISTs. However, whether the same genetic family has different phenotypes has not been reported. CASE SUMMARY We report two cases of rare GISTs in the same family: A male patient with the V561D mutation in exon 12 of the PDGFRA gene, who has been taking the targeted drug imatinib since undergoing surgery, and a female patient diagnosed with wild-type GIST, who has been taking imatinib for 3 years since undergoing surgery. The favorable prognosis of these patients during the 7-year follow-up period validates the accuracy of our treatment strategy, and we have refined the entire process of diagnosis and treatment of familial GISTs in order to better manage this rare familial disease. CONCLUSION Different mutation types of familial GISTs in the same family are very rare, thus it is very important to make the correct diagnosis and treatment strategies according to the results of molecular detection for the management of familial GISTs.
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Affiliation(s)
- Xiao-Ke Wang
- The First School of Clinical Medical, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, China
| | - Lu-Fan Shen
- School of Traditional Chinese and Western Medicine, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, China
| | - Xin Yang
- The First School of Clinical Medical, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, China
| | - He Su
- Department of General Surgery, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China
| | - Tao Wu
- Department of General Surgery, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China
| | - Peng-Xian Tao
- Department of General Surgery, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China
| | - Hong-Ying Lv
- School of Traditional Chinese and Western Medicine, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, China
| | - Tong-Han Yao
- The First School of Clinical Medical, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, China
| | - Lin Yi
- School of Traditional Chinese and Western Medicine, Gansu University of Chinese Medicine, Lanzhou 730000, Gansu Province, China
| | - Yuan-Hui Gu
- Department of General Surgery, Gansu Provincial Hospital, Lanzhou 730000, Gansu Province, China
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7
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Trembath HE, Yeh JJ, Lopez NE. Gastrointestinal Malignancy: Genetic Implications to Clinical Applications. Cancer Treat Res 2024; 192:305-418. [PMID: 39212927 DOI: 10.1007/978-3-031-61238-1_15] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/04/2024]
Abstract
Advances in molecular genetics have revolutionized our understanding of the pathogenesis, progression, and therapeutic options for treating gastrointestinal (GI) cancers. This chapter provides a comprehensive overview of the molecular landscape of GI cancers, focusing on key genetic alterations implicated in tumorigenesis across various anatomical sites including GIST, colon and rectum, and pancreas. Emphasis is placed on critical oncogenic pathways, such as mutations in tumor suppressor genes, oncogenes, chromosomal instability, microsatellite instability, and epigenetic modifications. The role of molecular biomarkers in predicting prognosis, guiding treatment decisions, and monitoring therapeutic response is discussed, highlighting the integration of genomic profiling into clinical practice. Finally, we address the evolving landscape of precision oncology in GI cancers, considering targeted therapies and immunotherapies.
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Affiliation(s)
- Hannah E Trembath
- Division of Colon and Rectal Surgery, Department of Surgery, University of California San Diego, 4303 La Jolla Village Drive Suite 2110, San Diego, CA, 92122, USA
- Division of Surgical Oncology, Department of Surgery, University of North Carolina, 170 Manning Drive, CB#7213, 1150 Physician's Office Building, Chapel Hill, NC, 27599-7213, USA
| | - Jen Jen Yeh
- Division of Colon and Rectal Surgery, Department of Surgery, University of California San Diego, 4303 La Jolla Village Drive Suite 2110, San Diego, CA, 92122, USA
- Division of Surgical Oncology, Department of Surgery, University of North Carolina, 170 Manning Drive, CB#7213, 1150 Physician's Office Building, Chapel Hill, NC, 27599-7213, USA
| | - Nicole E Lopez
- Division of Colon and Rectal Surgery, Department of Surgery, University of California San Diego, 4303 La Jolla Village Drive Suite 2110, San Diego, CA, 92122, USA.
- Division of Surgical Oncology, Department of Surgery, University of North Carolina, 170 Manning Drive, CB#7213, 1150 Physician's Office Building, Chapel Hill, NC, 27599-7213, USA.
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8
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Zhao C, Jin L, Tan Y, Chen Y, Su Z, Li W, Yang Q. Case Report: Multiple gastrointestinal stromal tumors along with numerous cutaneous neurofibromas: a case description and literature analysis. Front Oncol 2023; 13:1206991. [PMID: 37909015 PMCID: PMC10615565 DOI: 10.3389/fonc.2023.1206991] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2023] [Accepted: 09/29/2023] [Indexed: 11/02/2023] Open
Abstract
Multiple gastrointestinal stromal tumors (GISTs) combined with cutaneous multiple neurofibromas are clinically rare. This paper presents a case of multiple gastrointestinal stromal tumors in the jejunum of a 68-year-old mother, along with her daughter who also had coexisting cutaneous multiple neurofibromas. The mother had been experiencing repeated melena for over 2 years and had previously been diagnosed with multiple small intestinal masses at other hospitals. Additionally, her 42-year-old daughter was admitted to our department due to recurrent abdominal pain caused by cholecystolithiasis. The mother and daughter both exhibited multiple nodular masses of varying sizes on their skin, including the truncus, limbs, and face, which were diagnosed as neurofibromas. The mother underwent a partial excision of the jejunum and a lateral jejunojejunal anastomosis side-to-side, as well as excision of skin lesions in our department. The final diagnosis of wild-type GISTs associated with neurofibromatosis type 1 (NF1) was confirmed through postoperative pathology, immunohistochemistry, and genetic testing results. During preoperative gastrointestinal endoscopy and intraoperative laparoscopic exploration of the gastrointestinal tract, no obvious tumors were found in her daughter. A combination of patient observations and a review of relevant literature in the field suggests that when patients present with gastrointestinal symptoms and multiple irregular painless swellings in the skin, it is important to consider the possibility of an association with NF1 and GIST. Additionally, obtaining a detailed family history can save time and improve the diagnosis of patients with both NF1 and GIST. We recommend that even if there are no gastrointestinal manifestations of GISTs in the offspring of newly mutated NF1 patients, regular review of gastroenteroscopy, imaging examination, and long-term follow-up after middle age are still crucial for the early diagnosis and treatment of NF1-related GISTs.
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Affiliation(s)
| | - Liquan Jin
- 1st Department of General Surgery, The First Affiliated Hospital of Dali University, Dali, Yunnan, China
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9
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Würtemberger J, Ripperger T, Vokuhl C, Bauer S, Teichert-von Lüttichau I, Wardelmann E, Niemeyer CM, Kratz CP, Schlegelberger B, Hettmer S. Genetic susceptibility in children, adolescents, and young adults diagnosed with soft-tissue sarcomas. Eur J Med Genet 2023; 66:104718. [PMID: 36764384 DOI: 10.1016/j.ejmg.2023.104718] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2021] [Revised: 10/30/2022] [Accepted: 01/29/2023] [Indexed: 02/11/2023]
Abstract
Soft tissue sarcomas (STS) may arise as a consequence of germline variants in cancer predisposition genes (CPGs). We believe that elucidating germline sarcoma predisposition is critical for understanding disease biology and therapeutic requirements. Participation in surveillance programs may allow for early tumor detection, early initiation of therapy and, ultimately, better outcomes. Among children, adolescents, and adults diagnosed with soft-tissue sarcomas and examined as part of published germline sequencing studies, pathogenic/likely pathogenic (P/LP) variants in CPGs were reported in 7-33% of patients. P/LP germline variants were detected most frequently in TP53, NF1 and BRCA1/2. In this review, we describe reported associations between soft tissue sarcomas and germline variants in CPGs, with mentioning of locally aggressive and benign soft tissue tumors that have important associations with cancer predisposition syndromes. We also discuss recommendations for diagnostic germline genetic testing. Testing for sarcoma-predisposing germline variants should be considered as part of the routine clinical workup and care of any child, adolescent, or adult diagnosed with STS and take into account consequences for the whole family.
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Affiliation(s)
- Julia Würtemberger
- Division of Pediatric Hematology and Oncology, Department of Pediatric and Adolescent Medicine, University Medical Center Freiburg, University of Freiburg, Germany
| | - Tim Ripperger
- Department of Human Genetics, Hannover Medical School, Hannover, Germany
| | - Christian Vokuhl
- Institute of Pathology, University Hospital Bonn, 53127, Bonn, Germany
| | - Sebastian Bauer
- Department of Oncology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Irene Teichert-von Lüttichau
- Technical University of Munich, School of Medicine, Department of Pediatrics and Children's Cancer Research Center, Kinderklinik München Schwabing, Munich, Germany
| | - Eva Wardelmann
- Gerhard Domagk Institute of Pathology, University Hospital Muenster, Muenster, Germany
| | - Charlotte M Niemeyer
- Division of Pediatric Hematology and Oncology, Department of Pediatric and Adolescent Medicine, University Medical Center Freiburg, University of Freiburg, Germany
| | - Christian P Kratz
- Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany
| | | | - Simone Hettmer
- Division of Pediatric Hematology and Oncology, Department of Pediatric and Adolescent Medicine, University Medical Center Freiburg, University of Freiburg, Germany.
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10
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Hornick JL, Webster F, Dei Tos AP, Hemmings C, Miettinen M, Oda Y, Raut CP, Rubin BP, Von Mehren M, Wardelmann E, Fletcher CDM. Dataset for reporting of gastrointestinal stromal tumours: recommendations from the International Collaboration on Cancer Reporting (ICCR). Histopathology 2023; 82:376-384. [PMID: 36073677 DOI: 10.1111/his.14791] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2022] [Revised: 09/04/2022] [Accepted: 09/05/2022] [Indexed: 01/20/2023]
Abstract
Gastrointestinal stromal tumours (GISTs) are the most common mesenchymal tumours of the gastrointestinal tract and are among the most frequent sarcomas. Accurate diagnosis, classification, and reporting are critical for prognostication and patient management, including selection of appropriate targeted therapy. Here we report on international consensus-based datasets for the pathology reporting of biopsy and resection specimens of GIST. The datasets were produced under the auspices of the International Collaboration on Cancer Reporting (ICCR), a global alliance of major international pathology and cancer organizations. An international expert panel consisting of pathologists, a surgical oncologist, and a medical oncologist produced a set of core and noncore data items for biopsy and resection specimens based on a critical review and discussion of current evidence. All professionals involved were subspecialized soft tissue tumour experts and affiliated with tertiary referral centres. Commentary was provided for each data item to explain its clinical relevance and the rationale for selection as a core or noncore element. Following international public consultation, the datasets, which include synoptic reporting guides, were finalized and ratified, and published on the ICCR website. These first international datasets for GIST are intended to promote high-quality, standardised pathology reporting. Their widespread adoption will improve consistency of reporting, facilitate multidisciplinary communication, and enhance comparability of data, all of which will ultimately help to improve the management of patients with GIST. All the ICCR datasets, including these on GIST, are freely available worldwide on the ICCR website (www.iccr-cancer.org/datasets).
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Affiliation(s)
- Jason L Hornick
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Fleur Webster
- International Collaboration on Cancer Reporting, Sydney, NSW, Australia
| | - Angelo Paolo Dei Tos
- Department of Pathology, Azienda Ospedaliera Universitaria di Padova, Padova, Italy.,Department of Medicine, University of Padua School of Medicine, Padua, Italy
| | - Chris Hemmings
- Department of Anatomic Pathology, Canterbury Health Laboratories, Christchurch, New Zealand.,Department of Pathology and Biomedical Science, Christchurch Clinical School, University of Otago School of Medicine, Christchurch, New Zealand
| | - Markku Miettinen
- Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health Bethesda, Bethesda, MD, USA
| | - Yoshinao Oda
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Chandrajit P Raut
- Department of Surgery, Brigham and Women's Hospital, Boston, MA, USA.,Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.,Harvard Medical School, Boston, MA, USA
| | - Brian P Rubin
- Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA
| | - Margaret Von Mehren
- Department of Hematology and Medical Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA
| | - Eva Wardelmann
- Gerhard-Domagk-Institute of Pathology, University of Münster, Münster, Germany
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11
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Mathias-Machado MC, de Jesus VHF, de Carvalho Oliveira LJ, Neumann M, Peixoto RD. Current Molecular Profile of Gastrointestinal Stromal Tumors and Systemic Therapeutic Implications. Cancers (Basel) 2022; 14:5330. [PMID: 36358751 PMCID: PMC9656487 DOI: 10.3390/cancers14215330] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2022] [Revised: 10/25/2022] [Accepted: 10/26/2022] [Indexed: 07/25/2023] Open
Abstract
Gastrointestinal stromal tumors (GISTs) are malignant mesenchymal tumors arising from the intestinal pacemaker cells of Cajal. They compose a heterogenous group of tumors due to a variety of molecular alterations. The most common gain-of-function mutations in GISTs are either in the KIT (60-70%) or platelet-derived growth factor receptor alpha (PDGFRA) genes (10-15%), which are mutually exclusive. However, a smaller subset, lacking KIT and PDGFRA mutations, is considered wild-type GISTs and presents distinct molecular findings with the activation of different proliferative pathways, structural chromosomal and epigenetic changes, such as inactivation of the NF1 gene, mutations in the succinate dehydrogenase (SDH), BRAF, and RAS genes, and also NTRK fusions. Currently, a molecular evaluation of GISTs is imperative in many scenarios, aiding in treatment decisions from the (neo)adjuvant to the metastatic setting. Here, we review the most recent data on the molecular profile of GISTs and highlight therapeutic implications according to distinct GIST molecular subtypes.
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Affiliation(s)
| | | | | | - Marina Neumann
- Centro Paulista de Oncologia (Oncoclínicas), São Paulo 04538-132, Brazil
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12
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Shi Y, Ding L, Mo C, Luo Y, Huang S, Cai S, Xia Y, Zhang X. Bladder paraganglioma, gastrointestinal stromal tumor, and SDHB germline mutation in a patient with Carney-Stratakis syndrome: A case report and literature review. Front Oncol 2022; 12:1030092. [PMID: 36387130 PMCID: PMC9650230 DOI: 10.3389/fonc.2022.1030092] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2022] [Accepted: 10/13/2022] [Indexed: 12/02/2022] Open
Abstract
Background Carney-Stratakis syndrome (CSS) is a rare dyad of paraganglioma (PGL)/pheochromocytoma (PHEO) and gastrointestinal stromal tumor (GIST). PGLs are neuroendocrine tumors of neural crest origin which are mostly found in the head, neck, and retroperitoneal space. GISTs are the most common mesenchymal tumors of the digestive tract, usually caused by KIT/PDGFRA mutations. Here, we reported a case of CSS with unusual bladder PGL and succinate dehydrogenase (SDH) deficient GIST due to a germline mutation in SDH-subunit B (SDHB) gene. Case presentation A 39-year-old female patient initially diagnosed with gastric GIST and isolated pelvic metastasis was eventually found to be CSS with bladder PGL and SDH-deficient GIST after surgery. This patient underwent resection of gastric and bladder tumors, and postoperative pathology confirmed the diagnosis of CSS. According to the next-generation sequencing (NGS), the patient carried a germline mutation in the SDHB gene, which was the cause of the disorder. The patient had no tumor recurrence with regular follow-up in 10 months. Conclusions CSS is an autosomal genetic disorder with no gender difference in incidence, and PGLs are more frequent than GISTs. SDH germline mutation is the molecular biological mechanism of CSS while the most common type is SDHB mutation. The unique mechanism of tumorigenesis including hypoxia and hypermethylation caused by SDH deficiency renders target therapy with tyrosine kinase inhibitors ineffective, therefore complete surgical resection is the optimal treatment in the absence of tumor metastases.
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Affiliation(s)
- Yihang Shi
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Li Ding
- Department of Pathology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Chengqiang Mo
- Department of Pharmacy, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yanji Luo
- Department of Urology Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Shaoqing Huang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Shirong Cai
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yanzhe Xia
- Department of Radiology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- *Correspondence: Xinhua Zhang, ; Yanzhe Xia,
| | - Xinhua Zhang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- *Correspondence: Xinhua Zhang, ; Yanzhe Xia,
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13
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Ding CKC, Chan S, Mak J, Umetsu SE, Simko J, Ruiz-Cordero R, Saunders T, Chan E. An exploration in pitfalls in interpreting SDHB immunohistochemistry. Histopathology 2022; 81:264-269. [PMID: 35546442 DOI: 10.1111/his.14681] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Revised: 05/09/2022] [Accepted: 05/10/2022] [Indexed: 11/28/2022]
Abstract
AIMS Mutations and epimutations in genes encoding the succinate dehydrogenase complex (SDHx) are associated with multiple tumor types in which identification of SDH-deficiency has significant management implications. Immunohistochemistry (IHC) for the SDHB subunit can help detect SDH-deficiency, which manifests as complete loss of staining in tumor cells. However, a subset of SDH-deficient tumors can show aberrant cytoplasmic SDHB-IHC staining patterns and be misinterpreted as "retained," a diagnostic pitfall complicating interpretation. Herein, we characterize in detail aberrant SDHB-IHC staining patterns in SDH-deficient tumors. METHODS AND RESULTS We identified 23 tumors from patients with known germline SDHx and/or molecularly confirmed SDHx pathogenic/likely-pathogenic variants in their tumor. Of these, 8 (35%) showed significant SDHB-IHC staining: 1 SDHA-, 1 SDHB-, 3 SDHC- and 3 SDHD-mutated cases. In all 8 cases, closer inspection revealed differences in intensity and intracellular distribution of SDHB-IHC staining in tumor cells compared to adjacent nonneoplastic cells: nonneoplastic cells showed intense cytoplasmic coarse granular staining; tumor cells in 7/8 cases showed weak to focally strong, cytoplasmic blush to fine granular staining, in >80% of cells. The remaining case on initial block showed variably strong nongranular cytoplasmic staining with globular perinuclear accentuation throughout, only subtly distinct from staining pattern of nonneoplastic cells. SDHB-IHC performed on two additional blocks in this latter case revealed significant intratumoral heterogeneity including convincing areas of complete loss. CONCLUSIONS When evaluating SDHB-IHC, care should be taken to distinguish true retained expression from aberrant cytoplasmic expression, which may be difficult to appreciate. Sometimes this may require additional molecular testing.
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Affiliation(s)
| | - Salina Chan
- Cancer Risk Program, Hellen Diller Family Comprehensive Cancer Center, University of California, San Francisco
| | - Julie Mak
- Cancer Risk Program, Hellen Diller Family Comprehensive Cancer Center, University of California, San Francisco
| | - Sarah E Umetsu
- Department of Pathology, University of California, San Francisco
| | - Jeffry Simko
- Department of Pathology, University of California, San Francisco
| | | | - Tara Saunders
- Department of Pathology, University of California, San Francisco
| | - Emily Chan
- Department of Pathology, University of California, San Francisco
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14
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Klug LR, Khosroyani HM, Kent JD, Heinrich MC. New treatment strategies for advanced-stage gastrointestinal stromal tumours. Nat Rev Clin Oncol 2022; 19:328-341. [PMID: 35217782 PMCID: PMC11488293 DOI: 10.1038/s41571-022-00606-4] [Citation(s) in RCA: 70] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/08/2022] [Indexed: 02/06/2023]
Abstract
When gastrointestinal stromal tumour (GIST), the most common form of sarcoma, was first recognized as a distinct pathological entity in the 1990s, patients with advanced-stage disease had a very poor prognosis owing to a lack of effective medical therapies. The discovery of KIT mutations as the first and most prevalent drivers of GIST and the subsequent development of the first KIT tyrosine kinase inhibitor (TKI), imatinib, revolutionized the treatment of patients with this disease. We can now identify the driver mutation in 99% of patients with GIST via molecular diagnostic testing, and therapies have been developed to treat many, but not all, molecular subtypes of the disease. At present, seven drugs are approved by the FDA for the treatment of advanced-stage GIST (imatinib, sunitinib, regorafenib, ripretinib, avapritinib, larotrectinib and entrectinib), all of which are TKIs. Although these agents can be very effective for treating certain GIST subtypes, challenges remain and new therapeutic approaches are needed. In this Review, we discuss the molecular subtypes of GIST and the evolution of current treatments, as well as their therapeutic limitations. We also highlight emerging therapeutic approaches that might overcome clinical challenges through novel strategies predicated on the biological features of the distinct GIST molecular subtypes.
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Affiliation(s)
- Lillian R Klug
- Portland VA Health Care System and Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA
| | - Homma M Khosroyani
- Portland VA Health Care System and Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA
| | - Jason D Kent
- Portland VA Health Care System and Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA
| | - Michael C Heinrich
- Portland VA Health Care System and Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA.
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15
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Foo T, Goldstein D, Segelov E, Shapiro J, Pavlakis N, Desai J, Yip D, Zalcberg J, Price TJ, Nagrial A, Chantrill L, Burge M, Karapetis CS, Tebbutt N, Roy AC. The Management of Unresectable, Advanced Gastrointestinal Stromal Tumours. Target Oncol 2022; 17:95-110. [PMID: 35290591 PMCID: PMC8995292 DOI: 10.1007/s11523-022-00869-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/23/2022] [Indexed: 12/11/2022]
Abstract
Gastrointestinal stromal tumours (GISTs) are the most common gastrointestinal tract mesenchymal tumours. Tyrosine kinase inhibitors (TKIs) have transformed the management of advanced GIST. Imatinib was the first TKI to gain approval as management for patients with advanced GIST, establishing a new standard of care. Since then, as a result of several trials including the GRID and INVICTUS studies, we now have five lines of approved targeted therapy, including imatinib, sunitinib, regorafenib, ripretinib and avapritinib for the treatment of unresectable, advanced GISTs. In this review, the Australasian Gastrointestinal Trials Group (AGITG) provide an overview of the key trials that have changed clinical practice, discuss the molecular drivers of GISTs, the importance of molecular testing and directing therapy according to molecular targets, as well as future strategies in the management of advanced GISTs.
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Affiliation(s)
- Tiffany Foo
- Flinders Centre for Innovation in Cancer/Flinders University, Bedford Park, SA, 5042, Australia
| | - David Goldstein
- Department of Medical Oncology, Prince of Wales Hospital, University of NSW, Sydney, NSW, Australia
| | - Eva Segelov
- Department of Medical Oncology, School of Clinical Sciences, Monash University and Monash Health, Melbourne, VIC, Australia
| | - Jeremy Shapiro
- Cabrini Health, Monash University, Melbourne, VIC, Australia
| | - Nick Pavlakis
- Department of Medical Oncology, Royal North Shore Hospital, University of Sydney, Sydney, NSW, Australia
| | - Jayesh Desai
- Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
| | - Desmond Yip
- Department of Medical Oncology, Canberra Region Cancer Centre, The Canberra Hospital, Canberra, ACT, Australia
| | - John Zalcberg
- Alfred Health, Monash University, Melbourne, VIC, Australia
| | - Timothy J Price
- The Queen Elizabeth Hospital/University of Adelaide, Adelaide, SA, Australia
| | - Adnan Nagrial
- Department of Medical Oncology, Westmead and Blacktown Hospitals, University of Sydney, Sydney, NSW, Australia
| | - Lorraine Chantrill
- Department of Medical Oncology, Wollongong Hospital, Illawarra Shoalhaven Local Health District, Illawarra, NSW, Australia
| | - Matt Burge
- Department of Cancer Care Services, Royal Brisbane Hospital, University of Queensland, Herston, QLD, Australia
| | - Christos S Karapetis
- Flinders Centre for Innovation in Cancer/Flinders University, Bedford Park, SA, 5042, Australia
| | - Niall Tebbutt
- Department of Medical Oncology, Olivia Newton-John Cancer Wellness and Research Centre, Austin Health, Heidelberg, VIC, Australia
| | - Amitesh C Roy
- Flinders Centre for Innovation in Cancer/Flinders University, Bedford Park, SA, 5042, Australia.
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16
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Casali PG, Blay JY, Abecassis N, Bajpai J, Bauer S, Biagini R, Bielack S, Bonvalot S, Boukovinas I, Bovee JVMG, Boye K, Brodowicz T, Buonadonna A, De Álava E, Dei Tos AP, Del Muro XG, Dufresne A, Eriksson M, Fedenko A, Ferraresi V, Ferrari A, Frezza AM, Gasperoni S, Gelderblom H, Gouin F, Grignani G, Haas R, Hassan AB, Hindi N, Hohenberger P, Joensuu H, Jones RL, Jungels C, Jutte P, Kasper B, Kawai A, Kopeckova K, Krákorová DA, Le Cesne A, Le Grange F, Legius E, Leithner A, Lopez-Pousa A, Martin-Broto J, Merimsky O, Messiou C, Miah AB, Mir O, Montemurro M, Morosi C, Palmerini E, Pantaleo MA, Piana R, Piperno-Neumann S, Reichardt P, Rutkowski P, Safwat AA, Sangalli C, Sbaraglia M, Scheipl S, Schöffski P, Sleijfer S, Strauss D, Strauss SJ, Hall KS, Trama A, Unk M, van de Sande MAJ, van der Graaf WTA, van Houdt WJ, Frebourg T, Gronchi A, Stacchiotti S. Gastrointestinal stromal tumours: ESMO-EURACAN-GENTURIS Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2022; 33:20-33. [PMID: 34560242 DOI: 10.1016/j.annonc.2021.09.005] [Citation(s) in RCA: 312] [Impact Index Per Article: 104.0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Revised: 09/01/2021] [Accepted: 09/04/2021] [Indexed: 02/06/2023] Open
Affiliation(s)
- P G Casali
- Department of Cancer Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy; Department of Oncology and Hemato-oncology University of Milan, Milan, Italy
| | - J Y Blay
- Centre Leon Berard and UCBL1, Lyon, France
| | - N Abecassis
- Instituto Portugues de Oncologia de Lisboa Francisco Gentil, EPE, Lisbon, Portugal
| | - J Bajpai
- Department of Medical Oncology, Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, India
| | - S Bauer
- Department of Medical Oncology, Interdisciplinary Sarcoma Center, West German Cancer Center, University of Duisburg-Essen, Essen, Germany
| | - R Biagini
- Department of Oncological Orthopedics, Musculoskeletal Tissue Bank, IFO, Regina Elena National Cancer Institute, Rome, Italy
| | - S Bielack
- Klinikum Stuttgart-Olgahospital, Stuttgart, Germany
| | - S Bonvalot
- Department of Surgery, Institut Curie, Paris, France
| | | | - J V M G Bovee
- Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands
| | - K Boye
- Department of Oncology, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway
| | - T Brodowicz
- Vienna General Hospital (AKH), Medizinische Universität Wien, Vienna, Austria
| | - A Buonadonna
- Centro di Riferimento Oncologico di Aviano, Aviano, Italy
| | - E De Álava
- Institute of Biomedicine of Sevilla (IBiS), Virgen del Rocio University Hospital/CSIC/University of Sevilla/CIBERONC, Seville, Spain; Department of Normal and Pathological Cytology and Histology, School of Medicine, University of Seville, Seville, Spain
| | - A P Dei Tos
- Department of Pathology, Azienda Ospedale Università Padova, Padova, Italy
| | - X G Del Muro
- Integrated Unit ICO Hospitalet, HUB, Barcelona, Spain
| | - A Dufresne
- Département d'Oncologie Médicale, Centre Leon Berard, Lyon, France
| | - M Eriksson
- Skane University Hospital-Lund, Lund, Sweden
| | - A Fedenko
- P. A. Herzen Cancer Research Institute, Moscow, Russian Federation
| | - V Ferraresi
- Sarcomas and Rare Tumors Unit, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - A Ferrari
- Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - A M Frezza
- Department of Cancer Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
| | - S Gasperoni
- Department of Oncology and Robotic Surgery, Azienda Ospedaliera Universitaria Careggi, Florence, Italy
| | - H Gelderblom
- Department of Medical Oncology, Leiden University Medical Centre, Leiden, The Netherlands
| | - F Gouin
- Centre Leon-Berard Lyon, Lyon, France
| | - G Grignani
- Candiolo Cancer Institute, FPO - IRCCS, Candiolo, Italy
| | - R Haas
- Department of Radiotherapy, The Netherlands Cancer Institute, Amsterdam, The Netherlands; Department of Radiotherapy, Leiden University Medical Centre, Leiden, The Netherlands
| | - A B Hassan
- Oxford University Hospitals NHS Foundation Trust and University of Oxford, Oxford, UK
| | - N Hindi
- Department of Medical Oncology, Fundación Jimenez Diaz, University Hospital, Advanced Therapies in Sarcoma Lab, Madrid, Spain
| | - P Hohenberger
- Mannheim University Medical Center, Mannheim, Germany
| | - H Joensuu
- Helsinki University Hospital (HUH) and University of Helsinki, Helsinki, Finland
| | - R L Jones
- Sarcoma Unit, Royal Marsden Hospital and Institute of Cancer Research, London, UK
| | - C Jungels
- Medical Oncology Clinic, Institut Jules Bordet, Université Libre de Bruxelles, Brussels, Belgium
| | - P Jutte
- University Medical Center Groningen, Groningen, The Netherlands
| | - B Kasper
- Mannheim University Medical Center, Mannheim, Germany
| | - A Kawai
- Department of Musculoskeletal Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - K Kopeckova
- University Hospital Motol, Prague, Czech Republic
| | - D A Krákorová
- Masaryk Memorial Cancer Institute, Brno, Czech Republic
| | - A Le Cesne
- Department of Cancer Medicine, Gustave Roussy, Villejuif, France
| | - F Le Grange
- Department of Oncology, University College London Hospitals NHS Foundation Trust (UCLH), London, UK
| | - E Legius
- Department for Human Genetics, University Hospitals Leuven, KU Leuven, Leuven, Belgium
| | - A Leithner
- Department of Orthopaedics and Trauma, Medical University of Graz, Graz, Austria
| | - A Lopez-Pousa
- Medical Oncology Department, Hospital Universitario Santa Creu i Sant Pau, Barcelona, Spain
| | - J Martin-Broto
- Department of Medical Oncology, Fundación Jimenez Diaz, University Hospital, Advanced Therapies in Sarcoma Lab, Madrid, Spain
| | - O Merimsky
- Aviv Sourasky Medical Center (Ichilov), Tel Aviv, Israel
| | - C Messiou
- Department of Radiology, Royal Marsden Hospital and Institute of Cancer Research, London, UK
| | - A B Miah
- Department of Oncology, Royal Marsden Hospital and Institute of Cancer Research, London, UK
| | - O Mir
- Department of Ambulatory Cancer Care, Gustave Roussy, Villejuif, France
| | - M Montemurro
- Department of Oncology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
| | - C Morosi
- Department of Radiology, IRCCS Foundation National Cancer Institute, Milan, Italy
| | - E Palmerini
- Department of Osteoncology, Bone and Soft Tissue Sarcomas and Innovative Therapies, IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy
| | - M A Pantaleo
- Division of Oncology, IRCCS Azienda Ospedaliero-Universitaria, di Bologna, Bologna, Italy
| | - R Piana
- Azienda Ospedaliero, Universitaria Città della Salute e della Scienza di Torino, Turin, Italy
| | | | - P Reichardt
- Helios Klinikum Berlin Buch, Berlin, Germany
| | - P Rutkowski
- Department of Soft Tissue/Bone Sarcoma and Melanoma, Maria Skłodowska-Curie National Research Institute of Oncology, Warsaw, Poland
| | - A A Safwat
- Aarhus University Hospital, Aarhus, Denmark
| | - C Sangalli
- Department of Radiotherapy, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - M Sbaraglia
- Department of Pathology, Azienda Ospedale Università Padova, Padova, Italy
| | - S Scheipl
- Department of Orthopaedics and Trauma, Medical University of Graz, Graz, Austria
| | - P Schöffski
- Department of General Medical Oncology, University Hospitals Leuven, Leuven Cancer Institute, Leuven, Belgium
| | - S Sleijfer
- Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - D Strauss
- Department of Surgery, Royal Marsden Hospital, London, UK
| | - S J Strauss
- Department of Oncology, University College London Hospitals NHS Foundation Trust (UCLH), London, UK
| | - K Sundby Hall
- Department of Oncology, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway
| | - A Trama
- Department of Research, Evaluative Epidemiology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - M Unk
- Institute of Oncology of Ljubljana, Ljubljana, Slovenia
| | - M A J van de Sande
- Department of Orthopedic Surgery, Leiden University Medical Center, Leiden, The Netherlands
| | - W T A van der Graaf
- Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands; Department of Medical Oncology, the Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - W J van Houdt
- Department of Surgical Oncology, the Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - T Frebourg
- Department of Genetics, Normandy Center for Genomic and Personalized Medicine, Normandie University, UNIROUEN, Inserm U1245 and Rouen University Hospital, Rouen, France
| | - A Gronchi
- Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori and University of Milan, Milan, Italy
| | - S Stacchiotti
- Department of Cancer Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
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17
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Dermawan JK, Rubin BP. Molecular Pathogenesis of Gastrointestinal Stromal Tumor: A Paradigm for Personalized Medicine. ANNUAL REVIEW OF PATHOLOGY-MECHANISMS OF DISEASE 2021; 17:323-344. [PMID: 34736340 DOI: 10.1146/annurev-pathol-042220-021510] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Over the past three to four decades, the molecular pathogenesis of gastrointestinal stromal tumors (GISTs) has been elucidated in great detail. In this review, we discuss the biological genesis of GISTs, identification of the various primary activating driver mutations (focusing on KIT and PDGFRA), oncogene addiction and targeted therapies with imatinib and other tyrosine kinase inhibitors, and the subsequent characterization of the various mechanisms of drug resistance. We illustrate how GIST has become a quintessential paradigm for personalized medicine. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease, Volume 17 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
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Affiliation(s)
- Josephine K Dermawan
- Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA; ,
| | - Brian P Rubin
- Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA; ,
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18
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Lim KT. Current surgical management of duodenal gastrointestinal stromal tumors. World J Gastrointest Surg 2021; 13:1166-1179. [DOI: https:/doi.org/10.4240/wjgs.v13.i10.1166] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 09/24/2023] Open
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19
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Lim KT. Current surgical management of duodenal gastrointestinal stromal tumors. World J Gastrointest Surg 2021; 13:1166-1179. [PMID: 34754385 PMCID: PMC8554720 DOI: 10.4240/wjgs.v13.i10.1166] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2021] [Revised: 06/30/2021] [Accepted: 08/09/2021] [Indexed: 02/06/2023] Open
Abstract
Duodenal gastrointestinal stromal tumors (D-GISTs) are uncommon mesenchymal tumors and are managed differently to common duodenal epithelial tumors. They may pose surgical challenges due to their unique but complex pancreaticoduodenal location of the gastrointestinal tract near the ampulla of Vater, pancreas, mesenteric blood vessels, biliary and pancreatic ducts. The surgical management of D-GISTs can be performed safely with good oncological outcomes provided an adequate resection margin can be achieved. The current surgical options of resectable primary D-GISTs varies with increasing complexity depending on the location, size and involvement of surrounding structures such as wedge resection with primary closure, segmental resection with small bowel anastomosis or radical pancreaticoduodenectomy. Laparoscopic approaches have been shown to be feasible and safe with good oncological outcomes in experienced hands. The minimally invasive techniques including robotic-assisted approach will likely increase in the future. D-GISTs have a prognosis comparable to gastric and other small bowel GISTs. However, the heterogeneity of different studies and the limited use of systemic tyrosine kinase inhibitor in the neoadjuvant and adjuvant settings may influence the overall survival of resected D-GISTs. The use of limited resection when condition allows is recommended due to lower surgical morbidity, less postoperative complications and better oncologic outcomes.
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Affiliation(s)
- Kheng Tian Lim
- Department of Surgery, Khoo Teck Puat Hospital, Singapore 768828, Singapore
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20
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Daumova M, Svajdler M, Fabian P, Kren L, Babankova I, Jezova M, Sedivcova M, Vanecek T, Behenska K, Michal M, Daum O. SDHC Methylation Pattern in Patients With Carney Triad. Appl Immunohistochem Mol Morphol 2021; 29:599-605. [PMID: 33624983 DOI: 10.1097/pai.0000000000000920] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2020] [Accepted: 01/26/2021] [Indexed: 11/26/2022]
Abstract
Carney triad is a multitumor syndrome affecting almost exclusively young women in a nonfamilial setting, which manifests by multifocal gastric gastrointestinal stromal tumors, paragangliomas, and pulmonary chondroma. The Carney triad-associated tumors are characterized by a deficiency of the mitochondrial succinate dehydrogenase enzymatic complex. Recently, it has been observed that the deficiency results from epigenetic silencing of the SDHC gene by its promoter hypermethylation. To elucidate anatomic distribution of SDHC promoter methylation in Carney triad patients and thus to shed some light on the possible natural development of this epigenetic change, both neoplastic and available non-neoplastic tissues of 3 patients with Carney triad were tested for hypermethylation at the SDHC promoter site. SDHC promoter hypermethylation was proven in all tumors studied. Lack of SDHC epigenetic silencing in the non-neoplastic lymphoid and duodenal tissue (ie, tissues not involved in the development of Carney triad-associated tumors) together with the finding of SDHC promoter hypermethylation in the non-neoplastic gastric wall favors the hypothesis of postzygotic somatic mosaicism as the biological background of Carney triad; it also offers an explanation of the multifocality of gastrointestinal stromal tumors of the stomach occurring in this scenario as well. However, the precise mechanism responsible for the peculiar organ-specific distribution of Carney triad-associated tumors is still unknown.
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Affiliation(s)
- Magdalena Daumova
- Sikl's Institute of Pathology, Faculty of Medicine and Teaching Hospital in Plzen, Charles University
- Bioptical Laboratory Ltd, Plzen
| | - Marian Svajdler
- Sikl's Institute of Pathology, Faculty of Medicine and Teaching Hospital in Plzen, Charles University
- Bioptical Laboratory Ltd, Plzen
| | - Pavel Fabian
- Department of Oncological Pathology, Masaryk Memorial Cancer Institute
| | - Leos Kren
- Department of Pathology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Iva Babankova
- Department of Oncological Pathology, Masaryk Memorial Cancer Institute
| | - Marta Jezova
- Department of Pathology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | | | - Tomas Vanecek
- Sikl's Institute of Pathology, Faculty of Medicine and Teaching Hospital in Plzen, Charles University
- Bioptical Laboratory Ltd, Plzen
| | - Kristyna Behenska
- Sikl's Institute of Pathology, Faculty of Medicine and Teaching Hospital in Plzen, Charles University
| | - Michal Michal
- Sikl's Institute of Pathology, Faculty of Medicine and Teaching Hospital in Plzen, Charles University
| | - Ondrej Daum
- Sikl's Institute of Pathology, Faculty of Medicine and Teaching Hospital in Plzen, Charles University
- Bioptical Laboratory Ltd, Plzen
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21
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Ceausu M, Socea B, Ciobotaru VP, Constantin VD, Enache S, Enache V, Bancu A, Socea LI, Șerban D, Predescu D, Smarandache CG, Ceausu Z. A multidisciplinary approach in the diagnostic challenge of GIST. Exp Ther Med 2021; 22:1063. [PMID: 34434277 PMCID: PMC8353641 DOI: 10.3892/etm.2021.10497] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Accepted: 06/30/2021] [Indexed: 12/12/2022] Open
Abstract
Gastrointestinal stromal tumors (GISTs) are the most common malignant mesenchymal lesions of the gastrointestinal tract. They originate from the interstitial cells of Cajal and are characterized by overexpression of the tyrosine kinase receptor, protein product of c-KIT gene (KIT). In this retrospective study, conducted over a period of 10 years, we retrieved from our database, a total number of 57 patients, admitted and operated in the surgical department of ‘Sf. Pantelimon’ Emergency Clinical Hospital, Bucharest, for digestive tumors, histopathologically confirmed as GISTs. More than half of the cases presented as surgical emergencies and the tumors found during the surgical procedures, which proved to be GISTs, were sometimes difficult to differentiate from other mesenchymal tumors, both for the clinician and the pathologist. The diagnosis of GIST relies mostly on pathology and immunohistochemistry, but also on clinical and imagistic data. The most common emergencies were digestive hemorrhage (associated with gastric location), followed by intestinal obstruction (especially for the ileal localization). The largest dimensions corresponded to gastric location. For selected indications (upper digestive sites), upper digestive endoscopy approaches 100% sensitivity. This study focuses on diagnosis of GISTs sustained by both clinical and imagistic methods, along with histopathology and immunohistochemistry techniques, according to the World Health Organization 2019 criteria. Even though the differential diagnosis of these tumors is challenging, an interdisciplinary cooperation with a multiple approach increases the odds of a correct positive diagnosis.
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Affiliation(s)
- Mihai Ceausu
- Department of Pathology, 'Carol Davila' University of Medicine and Pharmacy, 020021 Bucharest, Romania
| | - Bogdan Socea
- Department of Surgery, 'Carol Davila' University of Medicine and Pharmacy, 020021 Bucharest, Romania.,Department of Surgery, 'Sf. Pantelimon' Emergency Clinical Hospital, 021659 Bucharest, Romania
| | - Vladimir Paul Ciobotaru
- Department of Surgery, 'Carol Davila' University of Medicine and Pharmacy, 020021 Bucharest, Romania.,Department of Surgery, 'Sf. Pantelimon' Emergency Clinical Hospital, 021659 Bucharest, Romania
| | - Vlad Denis Constantin
- Department of Surgery, 'Carol Davila' University of Medicine and Pharmacy, 020021 Bucharest, Romania.,Department of Surgery, 'Sf. Pantelimon' Emergency Clinical Hospital, 021659 Bucharest, Romania
| | - Simona Enache
- Pathology Department, University Emergency Hospital, 050098 Bucharest, Romania
| | - Valentin Enache
- Pathology Department, University Emergency Hospital, 050098 Bucharest, Romania
| | - Alice Bancu
- Pathology Department, 'Victor Babeş' Institute of Bucharest, 050096 Bucharest, Romania
| | - Laura Ileana Socea
- Department of Organic Chemistry, Faculty of Pharmacy, 'Carol Davila' University of Medicine and Pharmacy, 020956 Bucharest, Romania
| | - Dragoș Șerban
- Department of Surgery, 'Carol Davila' University of Medicine and Pharmacy, 020021 Bucharest, Romania.,Department of Surgery, University Emergency Hospital, 050098 Bucharest, Romania
| | - Dragoș Predescu
- Department of Surgery, 'Carol Davila' University of Medicine and Pharmacy, 020021 Bucharest, Romania.,Department of Surgery, 'Sf. Maria' Hospital, 011172 Bucharest, Romania
| | - Cătălin G Smarandache
- Department of Surgery, 'Carol Davila' University of Medicine and Pharmacy, 020021 Bucharest, Romania.,Department of Surgery, University Emergency Hospital, 050098 Bucharest, Romania
| | - Zenaida Ceausu
- Pathology Department, 'Sf. Pantelimon' Emergency Hospital, 021659 Bucharest, Romania
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22
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Al-Share B, Alloghbi A, Al Hallak MN, Uddin H, Azmi A, Mohammad RM, Kim SH, Shields AF, Philip PA. Gastrointestinal stromal tumor: a review of current and emerging therapies. Cancer Metastasis Rev 2021; 40:625-641. [PMID: 33876372 DOI: 10.1007/s10555-021-09961-7] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Accepted: 03/29/2021] [Indexed: 02/07/2023]
Abstract
Gastrointestinal stromal tumors (GIST) are rare neoplasms arising from the interstitial cell of Cajal in the gastrointestinal tract. Two thirds of GIST in adult patients have c-Kit mutation and smaller fractions have platelet derived growth factor receptor alpha (PDGFRA) mutation. Surgery is the only curative treatment for localized disease. Imatinib improves survival when used adjuvantly and in advanced disease. Several targeted therapies have also improved survival in GIST patients after progression on imatinib including sunitinib and regorafenib. Recently, United States Federal and Drug Administration (FDA) approved two new tyrosine kinase inhibitors for the treatment of heavily pretreated advanced/unresectable GIST including avapritinib (a selective inhibitor for PDGFRA exon 18 mutation including D842V mutations) and ripretinib (a broad-spectrum kinase inhibitor of c-Kit and PDGFRA). In this article, we will provide a comprehensive review of GIST including the current standard of care treatment and exploring future paradigm shifts in therapy.
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Affiliation(s)
- Bayan Al-Share
- Department of Oncology, Karmanos Cancer Institute, School of Medicine, Wayne State University, Detroit, MI, USA
| | - Abdulrahman Alloghbi
- Department of Oncology, Karmanos Cancer Institute, School of Medicine, Wayne State University, Detroit, MI, USA
| | - Mohammed Najeeb Al Hallak
- Department of Oncology, Karmanos Cancer Institute, School of Medicine, Wayne State University, Detroit, MI, USA
| | - Hafiz Uddin
- Department of Oncology, Karmanos Cancer Institute, School of Medicine, Wayne State University, Detroit, MI, USA
| | - Asfar Azmi
- Department of Oncology, Karmanos Cancer Institute, School of Medicine, Wayne State University, Detroit, MI, USA
| | - Ramzi M Mohammad
- Department of Oncology, Karmanos Cancer Institute, School of Medicine, Wayne State University, Detroit, MI, USA
| | - Steve H Kim
- Department of Oncology, Karmanos Cancer Institute, School of Medicine, Wayne State University, Detroit, MI, USA
| | - Anthony F Shields
- Department of Oncology, Karmanos Cancer Institute, School of Medicine, Wayne State University, Detroit, MI, USA
| | - Philip A Philip
- Department of Oncology, Karmanos Cancer Institute, School of Medicine, Wayne State University, Detroit, MI, USA.
- Department of Pharmacology, School of Medicine, Wayne State University, Detroit, MI, USA.
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23
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Brčić I, Argyropoulos A, Liegl-Atzwanger B. Update on Molecular Genetics of Gastrointestinal Stromal Tumors. Diagnostics (Basel) 2021; 11:194. [PMID: 33525726 PMCID: PMC7912114 DOI: 10.3390/diagnostics11020194] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Revised: 01/21/2021] [Accepted: 01/23/2021] [Indexed: 12/14/2022] Open
Abstract
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. The majority are sporadic, solitary tumors that harbor mutually exclusive KIT or PDGFRA gain-of-function mutations. The type of mutation in addition to risk stratification corresponds to the biological behavior of GIST and response to treatment. Up to 85% of pediatric GISTs and 10-15% of adult GISTs are devoid of these (KIT/PDGFRA) mutations and are referred to as wild-type GISTs (wt-GIST). It has been shown that these wt-GISTs are a heterogeneous tumor group with regard to their clinical behavior and molecular profile. Recent advances in molecular pathology helped to further sub-classify the so-called "wt-GISTs". Based on their significant clinical and molecular heterogeneity, wt-GISTs are divided into a syndromic and a non-syndromic (sporadic) subgroup. Recently, the use of succinate dehydrogenase B (SDHB) by immunohistochemistry has been used to stratify GIST into an SDHB-retained and an SDHB-deficient group. In this review, we focus on GIST sub-classification based on clinicopathologic, and molecular findings and discuss the known and yet emerging prognostic and predictive genetic alterations. We also give insights into the limitations of targeted therapy and highlight the mechanisms of secondary resistance.
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Affiliation(s)
| | | | - Bernadette Liegl-Atzwanger
- Diagnostic and Research Institute of Pathology, Medical University of Graz, 8010 Graz, Austria; (I.B.); (A.A.)
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24
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Pitsava G, Settas N, Faucz FR, Stratakis CA. Carney Triad, Carney-Stratakis Syndrome, 3PAS and Other Tumors Due to SDH Deficiency. Front Endocrinol (Lausanne) 2021; 12:680609. [PMID: 34012423 PMCID: PMC8126684 DOI: 10.3389/fendo.2021.680609] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Accepted: 04/12/2021] [Indexed: 12/20/2022] Open
Abstract
Succinate dehydrogenase (SDH) is a key respiratory enzyme that links Krebs cycle and electron transport chain and is comprised of four subunits SDHA, SDHB, SDHC and SDHD. All SDH-deficient tumors are caused by or secondary to loss of SDH activity. As many as half of the familial cases of paragangliomas (PGLs) and pheochromocytomas (PHEOs) are due to mutations of the SDHx subunits. Gastrointestinal stromal tumors (GISTs) associated with SDH deficiency are negative for KIT/PDGFRA mutations and present with distinctive clinical features such as early onset (usually childhood or adolescence) and almost exclusively gastric location. SDH-deficient GISTs may be part of distinct clinical syndromes, Carney-Stratakis syndrome (CSS) or dyad and Carney triad (CT). CSS is also known as the dyad of GIST and PGL; it affects both genders equally and is inherited in an autosomal dominant manner with incomplete penetrance. CT is a very rare disease; PGL, GIST and pulmonary chondromas constitute CT which shows female predilection and may be a mosaic disorder. Even though there is some overlap between CT and CSS, as both are due to SDH deficiency, CSS is caused by inactivating germline mutations in genes encoding for the SDH subunits, while CT is mostly caused by a specific pattern of methylation of the SDHC gene and may be due to germline mosaicism of the responsible genetic defect.
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Affiliation(s)
- Georgia Pitsava
- Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institutes of Child Health and Human Development, National Institutes of Health, Bethesda, MD, United States
- Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, United States
| | - Nikolaos Settas
- Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, United States
| | - Fabio R. Faucz
- Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, United States
- *Correspondence: Fabio R. Faucz,
| | - Constantine A. Stratakis
- Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, United States
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25
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PDGFRA mutant gastrointestinal stromal tumor with composite sclerosing and inflammatory myofibroblastic tumor-like morphology, a case report. HUMAN PATHOLOGY: CASE REPORTS 2020. [DOI: 10.1016/j.ehpc.2020.200453] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
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26
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Genetic Testing for Cancer Predisposition Syndromes in Adolescents and Young Adults (AYAs). CURRENT GENETIC MEDICINE REPORTS 2020. [DOI: 10.1007/s40142-020-00187-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
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27
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Gao X, Ma C, Sun X, Zhao Q, Fang Y, Jiang Y, Shen K, Shen X. Upregulation of ZNF148 in SDHB-deficient gastrointestinal stromal tumor potentiates Forkhead box M1-mediated transcription and promotes tumor cell invasion. Cancer Sci 2020; 111:1266-1278. [PMID: 32060966 PMCID: PMC7156819 DOI: 10.1111/cas.14348] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Revised: 01/18/2020] [Accepted: 02/03/2020] [Indexed: 12/18/2022] Open
Abstract
Succinate dehydrogenase (SDH) deficiency is associated with gastrointestinal stromal tumor (GIST) oncogenesis, but the underlying molecular mechanism remains to be further investigated. Here, we show that succinate accumulation induced by SDHB loss of function increased the expression of zinc finger protein 148 (ZNF148, also named ZBP-89) in GIST cells. Meanwhile, ZNF148 is found to be phosphorylated by ERK at Ser306, and this phosphorylation results in ZNF148 binding to Forkhead box M1 (FOXM1). Through the complex formation at the promoter, ZNF148 facilitates Histone H3 acetylation and FOXM1-mediated Snail transcription, which eventually promotes cell invasion and tumor growth. The clinical analysis indicates that SDHB deficiency is associated with elevated ZNF148 levels, and ZNF148-S306 phosphorylation level displays a positive correlation with poor prognosis in GIST patients. These findings illustrate an unidentified molecular mechanism underlying FOXM1-regulated gene transcription related to GIST cell invasion, which highlights the physiological effects of SDHB deficiency on the invasiveness of GIST.
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Affiliation(s)
- Xiaodong Gao
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Chunmin Ma
- The Institute of Cell Metabolism, School of Medicine, Shanghai General Hospital, Shanghai Jiaotong University, Shanghai, China
| | - Xiangwei Sun
- Department of General Surgery, Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Qin Zhao
- The Institute of Cell Metabolism, School of Medicine, Shanghai General Hospital, Shanghai Jiaotong University, Shanghai, China
| | - Yong Fang
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yuhui Jiang
- The Institute of Cell Metabolism, School of Medicine, Shanghai General Hospital, Shanghai Jiaotong University, Shanghai, China
| | - Kuntang Shen
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xian Shen
- Department of General Surgery, Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang, China
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28
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A Huge Pelvic-Abdominal Malignant GIST Tumour in a Patient with Neurofibromatosis Type 1: Case Report and Literature Review. Case Rep Oncol Med 2020; 2020:6590307. [PMID: 31984144 PMCID: PMC6964723 DOI: 10.1155/2020/6590307] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2019] [Revised: 08/25/2019] [Accepted: 12/23/2019] [Indexed: 11/18/2022] Open
Abstract
Gastrointestinal stromal tumours are rare tumours of the gastrointestinal tract (GIT) accounting for 0.1%–3% of all gastrointestinal tumours. The most common location is the stomach (55%) followed by the small bowel (31.8%), colon (6%), other various locations (5.5%), and the oesophagus (0.7%). They may also occur in extraintestinal locations. The signs and symptoms of GIST depend on the tumour's location and size. Gastrointestinal bleeding is one of the most common symptoms. Other signs and symptoms include abdominal discomfort, pain or distention; intestinal obstruction, and weight loss. The association between the development of GISTs and neurofibromatosis 1 (NF1) has been established. NF1-associated GISTs tend to have a distinct phenotype, and the absence of KIT/PDGRFα mutations in turn has implications on further management when they do not respond well to imatinib treatment. Here, we present one of the largest GISTs reported in the literature with a total volume of 25.3 × 20 × 14 cm + 27.9 × 23 × 8 cm and an overall weight of 7.3 kg, which developed in a 43-year-old female patient with NF1 and was resected on an emergency basis due to the rapid deterioration and development of abdominal compartment syndrome. Pathology assessment showed a malignant GIST composed of spindle cells with elongated nuclei with necrosis, marked pleomorphism and numerous giant cell. The mitotic count was >15/50 HPF, Ki 67 was 80%, and the lymphovascular invasion was clear. Immunohistochemistry investigations showed that Vimentin, CD117, and DOG1 were positive, while BCL-2 and CD99 were focal positives. Pan-CK, S-100, CD34, Desmin, SMA, and HMB-45 were negatives.
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29
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Ngo QD, Pham QT, Phan DAT, Hoang AV, Hua TNH, Nguyen ST. Molecular and Clinicopathological Features of Gastrointestinal Stromal Tumors in Vietnamese Patients. J Pathol Transl Med 2019; 53:361-368. [PMID: 31525834 PMCID: PMC6877433 DOI: 10.4132/jptm.2019.08.27] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2019] [Revised: 07/07/2019] [Accepted: 08/27/2019] [Indexed: 01/10/2023] Open
Abstract
BACKGROUND Gastrointestinal stromal tumors (GISTs) are the most frequent mesenchymal neoplasms of the gastrointestinal tract. Management of GIST patients is currently based on clinicopathological features and associated genetic changes. However, the detailed characteristics and molecular genetic features of GISTs have not yet been described in the Vietnamese population. METHODS We first identified 155 patients with primary GIST who underwent surgery with primary curative intent between 2011 and 2014 at University Medical Center at Ho Chi Minh City, Vietnam. We evaluated the clinicopathological features and immunohistochemical reactivity to p53 and Ki-67 in these patients. Additionally, KIT genotyping was performed in 100 cases. RESULTS The largest proportion of GISTs was classified as high-risk (43.2%). Of the 155 GISTs, 52 (33.5%) were positive for Ki-67, and 58 (37.4%) were positive for p53. The expression of Ki-67 and p53 were correlated with mitotic rate, tumor size, risk assessment, and tumor stage. Out of 100 GIST cases, KIT mutation was found in 68%, of which 62 (91.2%) were found in exon 11, two (2.9%) in exon 9, and four (5.8%) in exon 17. No mutation in exon 13 was identified. Additionally, KIT mutations did not correlate with any clinicopathological features. CONCLUSIONS The expression of Ki-67 and p53 were associated with high-risk tumors. Mutations in exon 11 were the most commonly found, followed by exon 17 and exon 9. Additionally, KIT mutation status was not correlated with any recognized clinicopathological features.
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Affiliation(s)
- Quoc Dat Ngo
- Department of Pathology, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City, Vietnam
| | - Quoc Thang Pham
- Department of Pathology, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City, Vietnam
| | - Dang Anh Thu Phan
- Department of Pathology, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City, Vietnam
| | - Anh Vu Hoang
- Center for Molecular Biomedicine, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City, Vietnam
| | - Thi Ngoc Ha Hua
- Department of Pathology, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City, Vietnam
| | - Sao Trung Nguyen
- Department of Pathology, University of Medicine and Pharmacy at Ho Chi Minh City, Ho Chi Minh City, Vietnam
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30
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Chatzopoulos K, Fritchie KJ, Aubry M, Carney JA, Folpe AL, Boland JM. Loss of succinate dehydrogenase B immunohistochemical expression distinguishes pulmonary chondromas from hamartomas. Histopathology 2019; 75:825-832. [DOI: 10.1111/his.13945] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2019] [Accepted: 06/23/2019] [Indexed: 12/26/2022]
Affiliation(s)
| | | | | | - J Aiden Carney
- Division of Anatomic Pathology Mayo Clinic Rochester MN USA
| | - Andrew L Folpe
- Division of Anatomic Pathology Mayo Clinic Rochester MN USA
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31
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Huda T, Singh MP. Gastrointestinal Stromal Tumors of Small Intestine. Surg J (N Y) 2019; 5:e92-e95. [PMID: 31475241 PMCID: PMC6713571 DOI: 10.1055/s-0039-1694704] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2019] [Accepted: 07/01/2019] [Indexed: 12/18/2022] Open
Abstract
Gastrointestinal stromal tumor (GIST) is defined as mesenchymal tumors of the gastrointestinal tract expressing proto-oncogene protein CD117. They are the most common sarcomatous tumors of the gastrointestinal tract. GISTs are presumed to arise from interstitial cells of Cajal or gastrointestinal pacemaker cells which control gut motility. They have unpredictable biological behavior. Prognosis is dependent on tumor size as well as mitotic count. Radical surgical excision is the treatment of choice. They rarely metastasize to lymph nodes. Imatinib therapy is used as an adjuvant therapy. The follow-up of patients postsurgery is not standardized.
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Affiliation(s)
- Tanweerul Huda
- Department of General Surgery, All India Institute of Medical Sciences (AIIMS), Bhopal, Madhya Pradesh, India
| | - Mahendra Pratap Singh
- Department of General Surgery, All India Institute of Medical Sciences (AIIMS), Bhopal, Madhya Pradesh, India
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32
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Abstract
Carney-Stratakis Syndrome (CSS) comprises of paragangliomas (PGLs) and gastrointestinal stromal tumors (GISTs). Several of its features overlap with Carney Triad (CT) - PGLs, GISTs, and pulmonary chondromas. CSS has autosomal dominant inheritance, incomplete penetrance, and greater relative frequency of PGL over GISTs. The PGLs in CSS are multicentric and GISTs are multifocal in all the patients, suggesting an inherited susceptibility and associating the two manifestations. In this review, we highlight the clinical, pathological, and molecular characteristics of CSS, along with its diagnostic and therapeutic implications.
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Affiliation(s)
- Arushi Khurana
- VCU Massey Cancer Center - Hematology Oncology, Richmond, Virginia, USA
| | - Lin Mei
- VCU Massey Cancer Center - Hematology Oncology, Richmond, Virginia, USA
| | - Anthony C Faber
- Virginia Commonwealth University - Philips Institute for Oral Health Research, Richmond, Virginia, USA
| | - Steven C Smith
- Virginia Commonwealth University - Pathology, Richmond, Virginia, USA
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33
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Oudijk L, Gaal J, Koopman K, de Krijger RR. An Update on the Histology of Pheochromocytomas: How Does it Relate to Genetics? Horm Metab Res 2019; 51:403-413. [PMID: 30142639 DOI: 10.1055/a-0672-1266] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Pheochromocytomas are rare neuroendocrine tumors of the adrenal gland, whereas any extra-adrenal tumor with similar histology is designated as paraganglioma. These tumors have a very high rate of germline mutations in a large number of genes, up to 35% to 40%, frequently predisposing for other tumors as well. Therefore, they represent a phenomenal challenge for treating physicians. This review focuses on pheochromocytomas only, with special attention to gross and microscopic clues to the diagnosis of genetic syndromes, including the role of succinate dehydrogenase subunit A and subunit B immunohistochemistry as surrogate markers for genetic analysis in the field of succinate dehydrogenase subunit gene mutations.
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Affiliation(s)
- Lindsey Oudijk
- Department of Pathology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
| | - José Gaal
- Department of Pathology, Isala Clinics, Zwolle, The Netherlands
| | - Karen Koopman
- Department of Pathology, Isala Clinics, Zwolle, The Netherlands
| | - Ronald R de Krijger
- Department of Pathology, University Medical Center/Princess Maxima Center for Pediatric Oncology, Utrecht and Reinier de Graaf Hospital, Delft, The Netherlands
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34
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[Tumors of the adrenal glands : Update]. DER PATHOLOGE 2019; 40:467-492. [PMID: 31250089 DOI: 10.1007/s00292-019-0618-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
Nodular hyperplasias and adenomas are by far the most frequently resected tumors of the adrenal cortex followed by pheochromocytomas, which are either discovered incidentally or become conspicuous due to hormonal hypersecretions. Cortical nodes and adenomas are easy to diagnose using simple staining methods. Uncertain cortical carcinomas, pheochromocytomas and other tumors of the adrenal region require additional immunohistochemical staining methods. Determination of the dignity of tumors of the adrenal cortex necessitates at least the Weiss score (possibly in its modified form), for oncocytic tumors the Bisceglia score and for pediatric tumors the Wieneke score. The Ki-67 index must also be taken into consideration. For pheochromocytomas the PASS and the GAPP systeme are used.
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35
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Wu CE, Tzen CY, Wang SY, Yeh CN. Clinical Diagnosis of Gastrointestinal Stromal Tumor (GIST): From the Molecular Genetic Point of View. Cancers (Basel) 2019; 11:cancers11050679. [PMID: 31100836 PMCID: PMC6563074 DOI: 10.3390/cancers11050679] [Citation(s) in RCA: 54] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2019] [Revised: 05/13/2019] [Accepted: 05/15/2019] [Indexed: 02/06/2023] Open
Abstract
Gastrointestinal stromal tumors (GISTs) originating from the interstitial cells of Cajal are mesenchymal tumors of the gastrointestinal tract and have been found to harbor c-KIT mutations and KIT (CD117) expression since 1998. Later, PDGFRA mutations, SDH alterations, and other drive mutations were identified in GISTs. In addition, more and more protein markers such as DOG1, PKCθ were found to be expressed in GISTs which might help clinicians diagnose CD117-negative GISTs. Therefore, we plan to comprehensively review the molecular markers and genetics of GISTs and provide clinicians useful information in diagnostic and therapeutic strategies of GISTs. Twenty years after the discovery of KIT in GISTs, the diagnosis of GISTs became much more accurate by using immunohistochemical (IHC) panel (CD117/DOG1) and molecular analysis (KIT/PDGFRA), both of which constitute the gold standard of diagnosis in GISTs. The accurately molecular diagnosis of GISTs guides clinicians to precision medicine and provides optimal treatment for the patients with GISTs. Successful treatment in GISTs prolongs the survival of GIST patients and causes GISTs to become a chronic disease. In the future, the development of effective treatment for GISTs resistant to imatinib/sunitinib/regorafenib and KIT/PDGFRA-WT GISTs will be the challenge for GISTs.
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Affiliation(s)
- Chiao-En Wu
- GIST Team, Division of Hematology-Oncology, Department of Internal Medicine, Chang Gung Memorial Hospital, Linkou branch, Chang Gung University, Taoyuan 333, Taiwan.
| | - Chin-Yuan Tzen
- Forlab Clinic, F2, No 14, Sec 2, Zhongxiao East Rd, Taipei 100, Taiwan.
| | - Shang-Yu Wang
- GIST Team, Department of Surgery, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan 333, Taiwan.
| | - Chun-Nan Yeh
- GIST Team, Department of Surgery, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan 333, Taiwan.
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36
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Stanley K, Friehling E, Davis A, Ranganathan S. Succinate Dehydrogenase-Deficient Gastrointestinal Stromal Tumor With SDHC Germline Mutation and Bilateral Renal and Neck Cysts. Pediatr Dev Pathol 2019; 22:265-268. [PMID: 30301441 DOI: 10.1177/1093526618805354] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Gastrointestinal stromal tumors (GISTs) are rare in children. Succinate dehydrogenase (SDH)-deficient GISTs are wild type and lack KIT proto-oncogene receptor tyrosine kinase and platelet-derived growth factor receptor A ( KIT or PDGFRA) mutations. These tumors result from germline SDH mutations, somatic SDH mutations, or SDH epimutants. Germline mutations in SDH genes ( SDHA, SDHB, SDHC, or SDHD) suggest Carney-Stratakis syndrome, a paraganglioma syndrome with predisposition for GIST. Negative immunohistochemistry for SDHB indicates dysfunction of the mitochondrial complex regardless of the subunit affected. We present an adolescent male with an SDH-deficient GIST and SDHC germline mutation who developed bilateral renal cysts and neck cysts, not previously described in children with this mutation. Germline testing is critical when SDH mutations are discovered due to treatment and surveillance implications. Further investigations are necessary to fully define the phenotypic expression of this mutation.
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Affiliation(s)
- Kaitlin Stanley
- 1 Division of Pediatric Hematology/Oncology, Department of Pediatrics, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania
| | - Erika Friehling
- 1 Division of Pediatric Hematology/Oncology, Department of Pediatrics, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania
| | - Amy Davis
- 2 Department of Pathology, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania
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Orbital Paraganglioma. J Craniofac Surg 2019; 30:e503-e506. [PMID: 30896513 DOI: 10.1097/scs.0000000000005408] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
BACKGROUND Paragangliomas are groups of neuroendocrine neoplasms originating from neural crest cells throughout the body, but are rarely observed within the orbit. CASE REPORT Two patients, a 4-year-old male and 27-year-old female, presented with a slow-growing proptosis. Well-defined masses were located in the superomedial (male) and temporal (female) portion of the right orbit and involved the entire bodies of either the superior (male) or lateral (female) rectus muscles. B-mode ultrasound scan revealed a homogeneous, well-defined, hypoechoic mass, with rich blood flow signals inside the mass on CDI. CT scans indicated a well-defined, homogeneous mass with moderate enhancement, while MRI showed a well-defined mass with a salt and pepper appearance due to the prominence of blood vessels in the form of flow-void areas. Anterior orbitotomy and total tumor excision were performed on both patients. Subsequent histological and immunohistochemistry assays confirmed the diagnosis of orbital paraganglioma. The male patient is currently at 14 years of follow-up without recurrence or metastasis. The female patient developed recurrence at 3 months post-surgery. After a second surgery and local radiotherapy, there were no signs of the recurrence as assessed at 13 years of follow-up in this female patient. CONCLUSION Orbital paraganglioma is an extremely rare benign tumor. The salt-and-pepper appearance as observed with MRI scan represents a relatively salient characteristic of this condition. Total excision of the lesion by orbitotomy is the treatment of choice and the possibility of tumor recurrence warrants diligent consideration. Radiotherapy is useful in patients with tumor recurrence or subtotal surgical excision.
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Bernardo-Castiñeira C, Sáenz-de-Santa-María I, Valdés N, Astudillo A, Balbín M, Pitiot AS, Jiménez-Fonseca P, Scola B, Tena I, Molina-Garrido MJ, Sevilla MA, Beristein E, Forga L, Villabona C, Oriola J, Halperin I, Suarez C, Chiara MD. Clinical significance and peculiarities of succinate dehydrogenase B and hypoxia inducible factor 1α expression in parasympathetic versus sympathetic paragangliomas. Head Neck 2018; 41:79-91. [PMID: 30549360 DOI: 10.1002/hed.25386] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2017] [Revised: 02/22/2018] [Accepted: 05/31/2018] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND Succinate dehydrogenase subunit B (SDHB) immunohistochemistry was considered a valuable tool to identify patients with inherited paraganglioma/pheochromocytoma (PGL/PCC). However, previous studies jointly analyzed 2 related but clinically distinct entities, parasympathetic head and neck paragangliomas (HNPGLs) and sympathetic PCCs/PGLs. Additionally, a role for hypoxia inducible factor-1α (HIF-1α) as a biomarker for succinate dehydrogenase (SDHx)-mutated tumors has not been studied. Here, we evaluated the utility of SDHB/HIF-1α proteins in HNPGLs and PCCs/PGLs as clinically useful biomarkers. METHODS The SDHB/succinate dehydrogenase subunit A (SDHA)/HIF-1α immunohistochemistry analysis was performed in 158 genetically defined patients. RESULTS Similarly to PCCs/PGLs, SDHB immune-negativity correlated with SDHx-mutations in HNPGLs (P < .0001). The HIF-1α stabilization was associated with SDHx-mutations in HNPGLs (P = .020), not in PCCs/PGLs (P = .319). However, 25% of SDHx-HNPGLs lacked HIF-1α positive cells. CONCLUSION As in PCCs/PGLs, SDHB immunohistochemistry in HNPGLs is a valuable method for identification of candidates for SDHx-genetic testing. On the contrary, although SDHx mutations may favor HIF-1α stabilization in HNPGLs, this is not a clinically useful biomarker.
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Affiliation(s)
- Cristóbal Bernardo-Castiñeira
- Institute of Sanitary Research of Asturias, Institute of Oncology of Asturias (IUOPA), CIBERONC, Hospital Central de Asturias, Universidad de Oviedo, Oviedo, Spain
| | - Inés Sáenz-de-Santa-María
- Institute of Sanitary Research of Asturias, Institute of Oncology of Asturias (IUOPA), CIBERONC, Hospital Central de Asturias, Universidad de Oviedo, Oviedo, Spain
| | - Nuria Valdés
- Service of Endocrinology and Nutrition, Hospital Central de Asturias, Oviedo, Spain
| | - Aurora Astudillo
- Service of Pathology, Hospital Central de Asturias, Oviedo, Spain
| | - Milagros Balbín
- Service of Molecular Oncology, Hospital Central de Asturias, Oviedo, Spain
| | - Ana S Pitiot
- Service of Molecular Oncology, Hospital Central de Asturias, Oviedo, Spain
| | | | - Bartolomé Scola
- Service of Otorhinolaryngology, Hospital Gregorio Marañón, Madrid, Spain
| | - Isabel Tena
- Service of Medical Oncology, Hospital Provincial de Castellón, Castellón, Spain
| | | | | | - Elena Beristein
- Laboratory of Molecular Genetic, Hospital Universitario Araba-Txagorritxu, Vitoria-Gasteiz, Spain
| | - Lluís Forga
- Service of Endocrinology and Nutrition, Complejo Hospitalario de Navarra, Pamplona, Spain
| | - Carles Villabona
- Service of Endocrinology and Nutrition, Hospital Universitario de Bellvitge, Barcelona, Spain
| | - Josep Oriola
- Laboratory of Biochemistry and Molecular Genetics and Endocrinology and Nutrition Service, Hospital Clinic, Barcelona, Spain
| | - Irene Halperin
- Laboratory of Biochemistry and Molecular Genetics and Endocrinology and Nutrition Service, Hospital Clinic, Barcelona, Spain
| | - Carlos Suarez
- Service of Otorhinolaryngology, Hospital Central de Asturias, Oviedo, Spain
| | - María-Dolores Chiara
- Institute of Sanitary Research of Asturias, Institute of Oncology of Asturias (IUOPA), CIBERONC, Hospital Central de Asturias, Universidad de Oviedo, Oviedo, Spain
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Kays JK, Sohn JD, Kim BJ, Goze K, Koniaris LG. Approach to wild-type gastrointestinal stromal tumors. Transl Gastroenterol Hepatol 2018; 3:92. [PMID: 30603728 DOI: 10.21037/tgh.2018.10.13] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2018] [Accepted: 10/29/2018] [Indexed: 12/24/2022] Open
Abstract
Gastrointestinal stromal tumors (GISTs) arise from the intestinal pacemaker cells of Cajal. Wild-type gastrointestinal stromal tumors (WT-GIST) are a unique and uncommon subtype of GISTs that lack activating mutations in the tyrosine kinase c-KIT or platelet derived growth factor receptor alpha (PDGFRA) receptors. The lack of these growth-stimulating mutations renders tyrosine kinase receptor inhibitors, such as imatinib mesylate, relatively ineffective against these tumors. WT-GIST arises most commonly due to underlying alternate proliferative signals associated with germ-line, genetic mutations. WT-GIST frequently arises in patients with BRAF mutations, Carney's Triad or neurofibromatosis type-1 (NF-1). All patients with WT-GIST require a careful examination for germ-line mutations and very close observation for recurrent tumors. Surgery remains a mainstay therapy for these patients. This review aims to discuss the most recent data available on the diagnosis and treatment of WT-GIST.
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Affiliation(s)
- Joshua K Kays
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Jeffrey D Sohn
- Monmouth Medical Center, Robert Wood Johnson Barnabas Health, Long Branch, NJ, USA
| | - Bradford J Kim
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Katherine Goze
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Leonidas G Koniaris
- Department of Surgery, Indiana University School of Medicine, Indianapolis, IN, USA
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Fostira F, Koutsodontis G, Vagia E, Economopoulou P, Kotsantis I, Sasaki C, Rontogianni D, Perisanidis C, Psyrri A. Predisposing Germline Mutations in Young Patients With Squamous Cell Cancer of the Oral Cavity. JCO Precis Oncol 2018; 2:1-8. [PMID: 35135152 DOI: 10.1200/po.18.00022] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Affiliation(s)
- Florentia Fostira
- Florentia Fostira, National Center for Scientific Research "Demokritos"; George Koutsodontis, Elena Vagia, Panagiota Economopoulou, Ioannis Kotsantis, and Amanda Psyrri, National and Kapodistrian University of Athens; Dimitra Rontogianni, Evangelismos Hospital, Athens, Greece; Clarence Sasaki, Yale University School of Medicine, New Haven, CT; and Christos Perisanidis, Medical University of Vienna, Vienna, Austria
| | - George Koutsodontis
- Florentia Fostira, National Center for Scientific Research "Demokritos"; George Koutsodontis, Elena Vagia, Panagiota Economopoulou, Ioannis Kotsantis, and Amanda Psyrri, National and Kapodistrian University of Athens; Dimitra Rontogianni, Evangelismos Hospital, Athens, Greece; Clarence Sasaki, Yale University School of Medicine, New Haven, CT; and Christos Perisanidis, Medical University of Vienna, Vienna, Austria
| | - Elena Vagia
- Florentia Fostira, National Center for Scientific Research "Demokritos"; George Koutsodontis, Elena Vagia, Panagiota Economopoulou, Ioannis Kotsantis, and Amanda Psyrri, National and Kapodistrian University of Athens; Dimitra Rontogianni, Evangelismos Hospital, Athens, Greece; Clarence Sasaki, Yale University School of Medicine, New Haven, CT; and Christos Perisanidis, Medical University of Vienna, Vienna, Austria
| | - Panagiota Economopoulou
- Florentia Fostira, National Center for Scientific Research "Demokritos"; George Koutsodontis, Elena Vagia, Panagiota Economopoulou, Ioannis Kotsantis, and Amanda Psyrri, National and Kapodistrian University of Athens; Dimitra Rontogianni, Evangelismos Hospital, Athens, Greece; Clarence Sasaki, Yale University School of Medicine, New Haven, CT; and Christos Perisanidis, Medical University of Vienna, Vienna, Austria
| | - Ioannis Kotsantis
- Florentia Fostira, National Center for Scientific Research "Demokritos"; George Koutsodontis, Elena Vagia, Panagiota Economopoulou, Ioannis Kotsantis, and Amanda Psyrri, National and Kapodistrian University of Athens; Dimitra Rontogianni, Evangelismos Hospital, Athens, Greece; Clarence Sasaki, Yale University School of Medicine, New Haven, CT; and Christos Perisanidis, Medical University of Vienna, Vienna, Austria
| | - Clarence Sasaki
- Florentia Fostira, National Center for Scientific Research "Demokritos"; George Koutsodontis, Elena Vagia, Panagiota Economopoulou, Ioannis Kotsantis, and Amanda Psyrri, National and Kapodistrian University of Athens; Dimitra Rontogianni, Evangelismos Hospital, Athens, Greece; Clarence Sasaki, Yale University School of Medicine, New Haven, CT; and Christos Perisanidis, Medical University of Vienna, Vienna, Austria
| | - Dimitra Rontogianni
- Florentia Fostira, National Center for Scientific Research "Demokritos"; George Koutsodontis, Elena Vagia, Panagiota Economopoulou, Ioannis Kotsantis, and Amanda Psyrri, National and Kapodistrian University of Athens; Dimitra Rontogianni, Evangelismos Hospital, Athens, Greece; Clarence Sasaki, Yale University School of Medicine, New Haven, CT; and Christos Perisanidis, Medical University of Vienna, Vienna, Austria
| | - Christos Perisanidis
- Florentia Fostira, National Center for Scientific Research "Demokritos"; George Koutsodontis, Elena Vagia, Panagiota Economopoulou, Ioannis Kotsantis, and Amanda Psyrri, National and Kapodistrian University of Athens; Dimitra Rontogianni, Evangelismos Hospital, Athens, Greece; Clarence Sasaki, Yale University School of Medicine, New Haven, CT; and Christos Perisanidis, Medical University of Vienna, Vienna, Austria
| | - Amanda Psyrri
- Florentia Fostira, National Center for Scientific Research "Demokritos"; George Koutsodontis, Elena Vagia, Panagiota Economopoulou, Ioannis Kotsantis, and Amanda Psyrri, National and Kapodistrian University of Athens; Dimitra Rontogianni, Evangelismos Hospital, Athens, Greece; Clarence Sasaki, Yale University School of Medicine, New Haven, CT; and Christos Perisanidis, Medical University of Vienna, Vienna, Austria
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Casali PG, Abecassis N, Aro HT, Bauer S, Biagini R, Bielack S, Bonvalot S, Boukovinas I, Bovee JVMG, Brodowicz T, Broto JM, Buonadonna A, De Álava E, Dei Tos AP, Del Muro XG, Dileo P, Eriksson M, Fedenko A, Ferraresi V, Ferrari A, Ferrari S, Frezza AM, Gasperoni S, Gelderblom H, Gil T, Grignani G, Gronchi A, Haas RL, Hassan B, Hohenberger P, Issels R, Joensuu H, Jones RL, Judson I, Jutte P, Kaal S, Kasper B, Kopeckova K, Krákorová DA, Le Cesne A, Lugowska I, Merimsky O, Montemurro M, Pantaleo MA, Piana R, Picci P, Piperno-Neumann S, Pousa AL, Reichardt P, Robinson MH, Rutkowski P, Safwat AA, Schöffski P, Sleijfer S, Stacchiotti S, Sundby Hall K, Unk M, Van Coevorden F, van der Graaf WTA, Whelan J, Wardelmann E, Zaikova O, Blay JY. Gastrointestinal stromal tumours: ESMO-EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2018; 29:iv68-iv78. [PMID: 29846513 DOI: 10.1093/annonc/mdy095] [Citation(s) in RCA: 287] [Impact Index Per Article: 41.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/08/2023] Open
Affiliation(s)
- P G Casali
- Fondazione IRCCS Istituto Nazionale dei Tumori and University of Milan, Milan, Italy
| | - N Abecassis
- Instituto Portugues de Oncologia de Lisboa Francisco Gentil, EPE, Lisbon, Portugal
| | - H T Aro
- Turku University Hospital (Turun Yliopistollinen Keskussairaala), Turlu, Finland
| | - S Bauer
- University Hospital Essen, Essen Germany
| | - R Biagini
- Department of Oncological Orthopedics, Musculoskeletal Tissue Bank, IFO, Regina Elena National Cancer Institute, Rome, Italy
| | - S Bielack
- Klinikum Stuttgart-Olgahospital, Stuttgart, Germany
| | | | | | - J V M G Bovee
- Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands
| | - T Brodowicz
- Vienna General Hospital (AKH), Medizinische Universität Wien, Vienna, Austria
| | - J M Broto
- Hospital Universitario Virgen del Rocio-CIBERONC, Seville, Spain
| | - A Buonadonna
- Centro di Riferimento Oncologico di Aviano, Aviano
| | - E De Álava
- Hospital Universitario Virgen del Rocio-CIBERONC, Seville, Spain
| | - A P Dei Tos
- Ospedale Regionale di Treviso 'S.Maria di Cà Foncello', Treviso, Italy
| | - X G Del Muro
- Integrated Unit ICO Hospitalet, HUB, Barcelona, Spain
| | - P Dileo
- Sarcoma Unit, University College London Hospitals, London, UK
| | - M Eriksson
- Skane University Hospital-Lund, Lund, Sweden
| | - A Fedenko
- N. N. Blokhin Russian Cancer Research Center, Moscow, Russian Federation
| | - V Ferraresi
- Institute of Scientific Hospital Care (IRCCS), Regina Elena National Cancer Institute, Rome
| | - A Ferrari
- Pediatric Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan
| | - S Ferrari
- Istituto Ortopedico Rizzoli, Bologna
| | - A M Frezza
- Fondazione IRCCS Istituto Nazionale dei Tumori and University of Milan, Milan, Italy
| | - S Gasperoni
- Azienda Ospedaliera Universitaria Careggi Firenze, Florence, Italy
| | - H Gelderblom
- Department of Medical Oncology, Leiden University Medical Centre, Leiden, The Netherlands
| | - T Gil
- Institut Jules Bordet, Brussels, Belgium
| | - G Grignani
- Candiolo Cancer Institute, FPO IRCCS, Candiolo, Italy
| | - A Gronchi
- Fondazione IRCCS Istituto Nazionale dei Tumori and University of Milan, Milan, Italy
| | - R L Haas
- Department of Radiotherapy, The Netherlands Cancer Institute, Amsterdam and Department of Radiotherapy, Leiden University Medical Centre, Leiden, The Netherlands
| | - B Hassan
- Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | | | - R Issels
- Department of Medicine III, University Hospital, Ludwig-Maximilians-University Munich, Munich, Germany
| | - H Joensuu
- Helsinki University Central Hospital (HUCH), Helsinki, Finland
| | | | - I Judson
- The Institute of Cancer Research, London, UK
| | - P Jutte
- University Medical Center Groningen, Groningen
| | - S Kaal
- Radboud University Medical Center, Nijmegen, The Netherlands
| | - B Kasper
- Mannheim University Medical Center, Mannheim
| | | | - D A Krákorová
- Masaryk Memorial Cancer Institute, Brno, Czech Republic
| | - A Le Cesne
- Gustave Roussy Cancer Campus, Villejuif, France
| | - I Lugowska
- Maria Sklodowska Curie Institute, Oncology Centre, Warsaw, Poland
| | - O Merimsky
- Tel Aviv Sourasky Medical Center (Ichilov), Tel Aviv, Israel
| | - M Montemurro
- Medical Oncology, University Hospital of Lausanne, Lausanne, Switzerland
| | - M A Pantaleo
- Azienda Ospedaliera, Universitaria, Policlinico S Orsola-Malpighi Università di Bologna, Bologna
| | - R Piana
- Azienda Ospedaliero, Universitaria Cita della Salute e della Scienza di Torino, Turin, Italy
| | - P Picci
- Istituto Ortopedico Rizzoli, Bologna
| | | | - A L Pousa
- Fundacio de Gestio Sanitaria de L'hospital de la Santa Creu I Sant Pau, Barcelona, Spain
| | - P Reichardt
- Helios Klinikum Berlin Buch, Berlin, Germany
| | - M H Robinson
- YCRC Department of Clinical Oncology, Weston Park Hospital NHS Trust, Sheffield, UK
| | - P Rutkowski
- Maria Sklodowska Curie Institute, Oncology Centre, Warsaw, Poland
| | - A A Safwat
- Aarhus University Hospital, Aarhus, Finland
| | | | - S Sleijfer
- Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - S Stacchiotti
- Fondazione Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale dei Tumori, Milan, Italy
| | - K Sundby Hall
- Department of Oncology, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway
| | - M Unk
- Institute of Oncology of Ljubljana, Ljubljana, Slovenia
| | - F Van Coevorden
- Netherlands Cancer Institute Antoni van Leeuwenhoek, Amsterdam, The Netherlands
| | | | - J Whelan
- University College Hospital, London, UK
| | - E Wardelmann
- Gerhard-Domagk-Institut für Pathologie, Universitätsklinikum Münster, Münster, Germany
| | - O Zaikova
- Oslo University Hospital, Norwegian Radium Hospital, Oslo, Norway
| | - J Y Blay
- Centre Leon Bernard and UCBL1, Lyon, France
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Herzberg M, Beer M, Anupindi S, Vollert K, Kröncke T. Imaging pediatric gastrointestinal stromal tumor (GIST). J Pediatr Surg 2018; 53:1862-1870. [PMID: 29685489 DOI: 10.1016/j.jpedsurg.2018.03.022] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2018] [Revised: 03/18/2018] [Accepted: 03/20/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND Gastrointestinal stromal tumors (GIST) are extremely rare in children. Imaging plays a key role in staging and monitoring therapy (surgical and with tyrosine kinase inhibitors). The vast majority of articles addressing imaging of GIST base on adults and are based on CT. The subtype "pediatric GIST" - if at all - is only mentioned in a dependent clause. Although the imaging features in children and adults are similar, histology, clinical course and thus imaging approach are different. METHODS A PubMed search using the search terms "Gastrointestinal stromal tumor, GIST, WT GIST, children, pediatric, carney's triad, imaging, staging, follow-up, MRI, CEUS, ultrasonography, Positron emission tomography" was conducted. Studies that reported on laparoscopy, endoscopy and surgical techniques only were excluded. RESULTS Based on our selective literature review, we present alternative radiological imaging strategies using MRI, contrast enhanced ultrasound (CEUS) and PET-CT to stage and follow-up pediatric GIST patients. As pediatric GIST often is a chronic disease, minimizing exposure to ionizing radiation is mandatory. CONCLUSION MRI, contrast enhanced ultrasound and PET-CT instead of CT are the imaging modalities to evaluate pediatric GIST. TYPE OF STUDY Systematic review LEVEL OF EVIDENCE: III.
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Affiliation(s)
- Moriz Herzberg
- Department of Diagnostic and Interventional Radiology and Neuroradiology, Klinikum Augsburg, Stenglinstraße 2, 86156, Germany.
| | - Meinrad Beer
- Department of Diagnostic and Interventional Radiology and Neuroradiology, University Ulm, Albert-Einstein-Allee 23, 89081, Germany.
| | - Sudha Anupindi
- Department of Radiology at The Children's Hospital of Philadelphia, 3401 Civic Center Blvd, Philadelphia, PA 19104, USA.
| | - Kurt Vollert
- Department of Diagnostic and Interventional Radiology and Neuroradiology, Klinikum Augsburg, Stenglinstraße 2, 86156, Germany.
| | - Thomas Kröncke
- Department of Diagnostic and Interventional Radiology and Neuroradiology, Klinikum Augsburg, Stenglinstraße 2, 86156, Germany.
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Goudie C, Hannah-Shmouni F, Kavak M, Stratakis CA, Foulkes WD. 65 YEARS OF THE DOUBLE HELIX: Endocrine tumour syndromes in children and adolescents. Endocr Relat Cancer 2018; 25:T221-T244. [PMID: 29986924 DOI: 10.1530/erc-18-0160] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2018] [Accepted: 05/31/2018] [Indexed: 12/16/2022]
Abstract
As medicine is poised to be transformed by incorporating genetic data in its daily practice, it is essential that clinicians familiarise themselves with the information that is now available from more than 50 years of genetic discoveries that continue unabated and increase by the day. Endocrinology has always stood at the forefront of what is called today 'precision medicine': genetic disorders of the pituitary and the adrenal glands were among the first to be molecularly elucidated in the 1980s. The discovery of two endocrine-related genes, GNAS and RET, both identified in the late 1980s, contributed greatly in the understanding of cancer and its progression. The use of RET mutation testing for the management of medullary thyroid cancer was among the first and one of most successful applications of genetics in informing clinical decisions in an individualised manner, in this case by preventing cancer or guiding the choice of tyrosine kinase inhibitors in cancer treatment. New information emerges every day in the genetics or system biology of endocrine disorders. This review goes over most of these discoveries and the known endocrine tumour syndromes. We cover key genetic developments for each disease and provide information that can be used by the clinician in daily practice.
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Affiliation(s)
- Catherine Goudie
- Division of Hematology-OncologyDepartment of Pediatrics, The Hospital for Sick Children, Toronto, Canada
| | - Fady Hannah-Shmouni
- Section on Endocrinology and Genetics The Eunice Kennedy Shriver Institute of Child Health and Human DevelopmentNational Institutes of Health, Bethesda, Maryland, USA
| | - Mahmure Kavak
- Department of Pharmacology and ToxicologyUniversity of Toronto, Toronto, Canada
| | - Constantine A Stratakis
- Section on Endocrinology and Genetics The Eunice Kennedy Shriver Institute of Child Health and Human DevelopmentNational Institutes of Health, Bethesda, Maryland, USA
| | - William D Foulkes
- Department of Human GeneticsResearch Institute of the McGill University Health Centre, and Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, Canada
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Gopie P, Mei L, Faber AC, Grossman SR, Smith SC, Boikos SA. Classification of gastrointestinal stromal tumor syndromes. Endocr Relat Cancer 2018; 25:R49-R58. [PMID: 29170162 DOI: 10.1530/erc-17-0329] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2017] [Accepted: 11/23/2017] [Indexed: 12/12/2022]
Abstract
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract, thought to derive from neoplastic outgrowth of the interstitial cells of Cajal. Building on recent advances in recognition, classification and diagnosis, the past two decades have seen a changing paradigm with molecular diagnostics and targeted therapies. KIT and PDGFRA mutations account for 85-90% of GIST carcinogenesis. However, the remaining 10-15% of GISTs, which until recently were called KIT/PDGFRA wild-type GISTs, have been found to have one of the several mutations, including in the SDHA, B, C, D, BRAF and NF1 genes. Though most of such GISTs are sporadic, a number of families with high incidence rates of GISTs and other associated clinical manifestations have been reported and found to harbor germline mutations in KIT, PDGFRA, SDH subunits and NF1 The goal of this review is to describe the mutations, clinical manifestations and therapeutic implications of syndromic and inherited GISTs in light of recent studies of their clinicopathologic range and pathogenesis.
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Affiliation(s)
- Priya Gopie
- Massey Cancer CenterVCU School of Medicine, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Lin Mei
- Massey Cancer CenterVCU School of Medicine, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Anthony C Faber
- Phillips Institute for Oral Health ResearchVCU School of Dentistry and Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Steven R Grossman
- Massey Cancer CenterVCU School of Medicine, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Steven C Smith
- Departments of Pathology and SurgeryVCU School of Medicine, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Sosipatros A Boikos
- Massey Cancer CenterVCU School of Medicine, Virginia Commonwealth University, Richmond, Virginia, USA
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Niinuma T, Suzuki H, Sugai T. Molecular characterization and pathogenesis of gastrointestinal stromal tumor. Transl Gastroenterol Hepatol 2018; 3:2. [PMID: 29441367 DOI: 10.21037/tgh.2018.01.02] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2017] [Accepted: 01/04/2018] [Indexed: 12/11/2022] Open
Abstract
Most gastrointestinal stromal tumors (GISTs) harbor activating mutations in the receptor tyrosine kinase gene KIT or platelet-derived growth factor receptor alpha (PDGFRA), and the resultant activation of downstream signals plays a pivotal role in the development of GISTs. The sites of the tyrosine kinase gene mutations are associated with the biological behavior of GISTs, including risk category, clinical outcome and drug response. Mutations in RAS signaling pathway genes, including KRAS and BRAF, have also been reported in KIT/PDGFRA wild-type GISTs, though they are rare. Neurofibromin 1 (NF1) is a tumor suppressor gene mutated in neurofibromatosis type 1. Patients with NF1 mutations are at high risk of developing GISTs. Recent findings suggest that altered expression or mutation of members of succinate dehydrogenase (SDH) heterotetramer are causally associated with GIST development through induction of aberrant DNA methylation. At present, GISTs with no alterations in KIT, PDGFRA, RAS signaling genes or SDH family genes are referred to as true wild-type GISTs. KIT and PDGFRA mutations are thought as the earliest events in GIST development, and subsequent accumulation of chromosomal aberrations and other molecular alterations are required for malignant progression. In addition, recent studies have shown that epigenetic alterations and noncoding RNAs also play key roles in the pathogenesis of GISTs.
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Affiliation(s)
- Takeshi Niinuma
- Department of Molecular Biology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Hiromu Suzuki
- Department of Molecular Biology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Tamotsu Sugai
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, Morioka, Japan
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Mannelli M, Canu L, Ercolino T, Rapizzi E, Martinelli S, Parenti G, De Filpo G, Nesi G. DIAGNOSIS of ENDOCRINE DISEASE: SDHx mutations: beyond pheochromocytomas and paragangliomas. Eur J Endocrinol 2018; 178:R11-R17. [PMID: 28924001 DOI: 10.1530/eje-17-0523] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2017] [Revised: 09/06/2017] [Accepted: 09/18/2017] [Indexed: 01/10/2023]
Abstract
Mutations in one of the five genes encoding the succinate dehydrogenase (SDHx) or mitochondrial complex II cause the corresponding family syndromes characterized by the occurrence of pheochromocytomas (PHEO) and paragangliomas (PGL). Recently, other solid growths, such as gastrointestinal stromal tumors (GISTs), renal cell carcinomas (RCCs) and pituitary adenomas (PAs) have been associated with these syndromes. In the absence of prospective studies assessing their frequency, at present, their occurrence seems too infrequent to suggest systematic screening for SDHx mutation carriers. However, SDHB immunohistochemistry (IHC) on tumor tissues or SDHx genetic testing on blood or tumor samples should be performed in patients affected by GISTs, RCCs or PAs with clinicopathologic phenotypes suggesting an etiologic role of SDHx genes.
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Affiliation(s)
| | - Letizia Canu
- Department of Experimental and Clinical Biomedical Sciences
| | | | - Elena Rapizzi
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | | | | | | | - Gabriella Nesi
- Department of Surgery and Translational Medicine, University of Florence, Florence, Italy
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Mei L, Smith SC, Faber AC, Trent J, Grossman SR, Stratakis CA, Boikos SA. Gastrointestinal Stromal Tumors: The GIST of Precision Medicine. Trends Cancer 2017; 4:74-91. [PMID: 29413424 DOI: 10.1016/j.trecan.2017.11.006] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2017] [Revised: 11/06/2017] [Accepted: 11/14/2017] [Indexed: 02/07/2023]
Abstract
The discovery of activated KIT mutations in gastrointestinal (GI) stromal tumors (GISTs) in 1998 triggered a sea change in our understanding of these tumors and has ushered in a new paradigm for the use of molecular genetic diagnostics to guide targeted therapies. KIT and PDGFRA mutations account for 85-90% of GISTs; subsequent genetic studies have led to the identification of mutation/epimutation of additional genes, including the succinate dehydrogenase (SDH) subunit A, B, C, and D genes. This review focuses on integrating findings from clinicopathologic, genetic, and epigenetic studies, which classify GISTs into two distinct clusters: an SDH-competent group and an SDH-deficient group. This development is important since it revolutionizes our current management of affected patients and their relatives, fundamentally, based on the GIST genotype.
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Affiliation(s)
- Lin Mei
- VCU Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA
| | - Steven C Smith
- Departments of Pathology and Surgery, VCU School of Medicine, Richmond, VA, USA
| | - Anthony C Faber
- VCU Phillips Institute for Oral Health Research, School of Dentistry and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA
| | | | - Steven R Grossman
- VCU Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA
| | - Constantine A Stratakis
- Eunice Kennedy Shriver National Institute of Child Health and Human Development, Rockville, MD, USA
| | - Sosipatros A Boikos
- VCU Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA.
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Affiliation(s)
- Anthony J Gill
- Department of Anatomical Pathology; Royal North Shore Hospital; St Leonards NSW Australia
- Cancer Diagnosis and Pathology Research Group; Kolling Institute of Medical Research; Royal North Shore Hospital; St Leonards NSW Australia
- University of Sydney; Sydney NSW Australia
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Lim KT. Surgical treatment of gastrointestinal stromal tumors of the stomach: current status and future perspective. Transl Gastroenterol Hepatol 2017; 2:104. [PMID: 29354761 PMCID: PMC5762995 DOI: 10.21037/tgh.2017.12.01] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2017] [Accepted: 11/27/2017] [Indexed: 02/05/2023] Open
Abstract
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract, with the majority found in the stomach. Surgical resection of the primary gastric GISTs with complete resection margin has been the forefront of curative treatment. The indications for surgical resection are usually related to symptomatic gastric GISTs at presentation. Primary gastric GISTs resection performed conventionally through an open surgery can now be frequently achieved by minimal invasive surgery with similar oncological outcome. Surgeon's selection of the type of surgical techniques such as open, laparoscopic and endoscopic resections depends on the site, size and local invasion of gastric GISTs to the adjacent organ. Similarly those factors dictate the extent of gastric resections in the form of wedge, partial or total gastrectomy. All these inherent tumor factors (size and mitotic index), patient factors (older age, male) and surgical factors (incomplete resection margin, tumor rupture or spillage) play an important role in stratifying the malignant potential risk of primary gastric GISTs and their chances of recurrence. The understanding of gene mutation driving the growth of GISTs and the discovery of tyrosine kinase inhibitors (TKIs) has altered the surgical management of advanced and metastatic GISTs. Multi-modal therapy incorporating the surgical resection of GISTs and utilizing the molecular targeted therapy in the adjuvant, neoadjuvant and palliative settings can offer optimal personalized outcome and prolong patient's overall survival (OS).
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Affiliation(s)
- Kheng Tian Lim
- Department of Surgery, Khoo Teck Puat Hospital, Singapore
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Rutkowski P, Magnan H, Chou AJ, Benson C. Treatment of gastrointestinal stromal tumours in paediatric and young adult patients with sunitinib: a multicentre case series. BMC Cancer 2017; 17:717. [PMID: 29110655 PMCID: PMC5674814 DOI: 10.1186/s12885-017-3727-1] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2016] [Accepted: 10/30/2017] [Indexed: 01/24/2023] Open
Abstract
Background Gastrointestinal stromal tumours (GIST) are rarely encountered mesenchymal tumours of the gastrointestinal tract (1.5 people per 100,000/year) that are even more rarely seen in paediatric patients (1–2% of all cases). The standard treatment for advanced adult GIST is imatinib with sunitinib as a second-line option. Although the efficacy and tolerability of sunitinib in adults with GIST has been established, little is known of the profile of sunitinib in paediatric/young adult patients with GIST given the rarity of this disease. Methods Paediatric/young adult patients aged up to 21 years with diagnosis of GIST who were treated with sunitinib were identified from retrospective records from three centres in Europe and the US. Most patients commenced sunitinib in a 6-week cycle, however, dosing could be reduced, delayed, changed to (or initiated with) a continuous schedule. Objective response (Response Evaluation Criteria In Solid Tumours [RECIST]) and adverse events were recorded. Results We identified 9 paediatric/young adult patients (aged 11–21 years) with GIST who were treated with sunitinib de novo (n = 1) or following failure of imatinib (n = 8). Progressive disease was previously documented for all patients including 7 patients during imatinib therapy. Baseline patient and tumour profile characteristics showed a distinct profile (notably all were wild-type KIT/PDGFR) compared to that established for adults. Sunitinib treatment was associated with a best response of stable disease for 7 patients, with disease stabilisation lasting from 1 month to >73 months and a median progression free survival time of 15 months. There was some evidence of better disease control for sunitinib when compared to prior imatinib. Most adverse events with sunitinib were manageable and all were consistent with the known profile of the agent. Conclusion The ability to draw firm conclusions from this case series is limited by the small number of patients and the use of retrospective data which is largely reflective of the rarity of this condition. However, our findings provide initial evidence of clinical benefit and a generally manageable toxicity profile for sunitinib when administered to paediatric/young adult patients with GIST, most of whom had documented progressive disease during prior imatinib treatment.
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Affiliation(s)
- Piotr Rutkowski
- Maria Skłodowska-Curie Institute - Oncology Center, Roentgena 5, 02-781, Warsaw, Poland.
| | - Heather Magnan
- Memorial Sloan Kettering Cancer Center, New York, NY, USA
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