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Freitas-Castro F, Santana LS, Fagundes GFC, Lobato EC, Afonso ACF, Nakamura IT, Ledesma FL, Soares IC, Mendonca BB, Latronico AC, Stratakis CA, Almeida MQ. SLC25A11, a Novel Gene Associated With Carney-Stratakis Syndrome. J Endocr Soc 2025; 9:bvaf052. [PMID: 40242210 PMCID: PMC12000648 DOI: 10.1210/jendso/bvaf052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Indexed: 04/18/2025] Open
Abstract
Background Carney-Stratakis syndrome (CSS), a rare condition characterized by paragangliomas and/or pheochromocytomas and gastrointestinal stromal tumors (GIST), is caused by germline heterozygous pathogenic variants in the succinate dehydrogenase subunit genes (SDHB, SDHC, SDHD). Methods Histological, genetic, and functional analyses were conducted in a 59-year-old female with CSS (9 cm left pheochromocytoma, 4.8 cm paraganglioma, and 9.3 cm GIST). Whole-exome sequencing (WES) of germline DNA paired with tumor DNA was performed. Results WES identified a rare heterozygous germline variant (c.293G>A/p.Arg98His) in the mitochondrial 2-oxoglutarate/malate carrier gene (SLC25A11). This variant, located in a highly conserved residue of the SLC25A11 mitochondrial carrier domain, is predicted to be deleterious in silico (REVEL score = 0.81). WES of pheochromocytoma, paraganglioma, and GIST did not reveal somatic pathogenic variants in genes previously associated with these tumors. A significant reduction in SLC25A11 expression was observed in the tumors of this patient with the SLC25A11 c.293G>A variant (0.69 ± 0.003) compared to tumors from cluster 1 (1.39 ± 0.45; P = 0.0229) and cluster 2 (1.79 ± 0.71; P = .0154). Consistent with the mRNA findings, SLC25A11 protein levels were markedly reduced in the pheochromocytoma and paraganglioma compared to other tumors. Negative staining for 5-hydroxymethylcytosine in all 3 tumors suggests a DNA hypermethylation profile characteristic of cluster 1A, despite normal SDHB expression levels. However, genome-wide copy number variation analysis did not reveal any loss of heterozygosity at the SLC25A11 locus. Conclusion The loss of SLC25A11 expression in tumors, the absence of somatic drivers, and the hypermethylation status strongly support the role of SLC25A11 in CSS pathogenesis.
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Affiliation(s)
- Felipe Freitas-Castro
- Unidade de Adrenal, Laboratório de Endocrinologia Molecular e Celular LIM25, Divisão de Endocrinologia e Metabologia, Hospital das Clínicas HCFMUSP, Faculdade de Medicina da Universidade de São Paulo, São Paulo 01246-903, Brasil
| | - Lucas S Santana
- Unidade de Adrenal, Laboratório de Endocrinologia Molecular e Celular LIM25, Divisão de Endocrinologia e Metabologia, Hospital das Clínicas HCFMUSP, Faculdade de Medicina da Universidade de São Paulo, São Paulo 01246-903, Brasil
| | - Gustavo F C Fagundes
- Unidade de Adrenal, Laboratório de Endocrinologia Molecular e Celular LIM25, Divisão de Endocrinologia e Metabologia, Hospital das Clínicas HCFMUSP, Faculdade de Medicina da Universidade de São Paulo, São Paulo 01246-903, Brasil
| | - Eduardo C Lobato
- Unidade de Adrenal, Laboratório de Endocrinologia Molecular e Celular LIM25, Divisão de Endocrinologia e Metabologia, Hospital das Clínicas HCFMUSP, Faculdade de Medicina da Universidade de São Paulo, São Paulo 01246-903, Brasil
| | - Ana Caroline F Afonso
- Laboratório de Hormônios e Genética Molecular LIM42 e Laboratório de Sequenciamento em Larga Escala (SELA), Divisão de Endocrinologia e Metabologia, Hospital das Clínicas HCFMUSP, Faculdade de Medicina da Universidade de São Paulo, São Paulo 01246-903, Brasil
| | - Izabel T Nakamura
- Unidade de Adrenal, Laboratório de Endocrinologia Molecular e Celular LIM25, Divisão de Endocrinologia e Metabologia, Hospital das Clínicas HCFMUSP, Faculdade de Medicina da Universidade de São Paulo, São Paulo 01246-903, Brasil
| | - Felipe L Ledesma
- Divisão de Anatomia Patológica, Hospital das Clínicas HCFMUSP & Instituto do Câncer do Estado de São Paulo (ICESP), Faculdade de Medicina da Universidade de São Paulo, São Paulo 01246-903, Brasil
| | - Ibere C Soares
- Divisão de Anatomia Patológica, Hospital das Clínicas HCFMUSP & Instituto do Câncer do Estado de São Paulo (ICESP), Faculdade de Medicina da Universidade de São Paulo, São Paulo 01246-903, Brasil
| | - Berenice B Mendonca
- Laboratório de Hormônios e Genética Molecular LIM42 e Laboratório de Sequenciamento em Larga Escala (SELA), Divisão de Endocrinologia e Metabologia, Hospital das Clínicas HCFMUSP, Faculdade de Medicina da Universidade de São Paulo, São Paulo 01246-903, Brasil
| | - Ana Claudia Latronico
- Unidade de Adrenal, Laboratório de Endocrinologia Molecular e Celular LIM25, Divisão de Endocrinologia e Metabologia, Hospital das Clínicas HCFMUSP, Faculdade de Medicina da Universidade de São Paulo, São Paulo 01246-903, Brasil
| | - Constantine A Stratakis
- Human Genetics & Precision Medicine, IMBB, FORTH, Heraklion, Crete & ASTREA Health, Athens 11528, Greece
| | - Madson Q Almeida
- Unidade de Adrenal, Laboratório de Endocrinologia Molecular e Celular LIM25, Divisão de Endocrinologia e Metabologia, Hospital das Clínicas HCFMUSP, Faculdade de Medicina da Universidade de São Paulo, São Paulo 01246-903, Brasil
- Unidade de Oncologia Endócrina, Instituto do Câncer do Estado de São Paulo (ICESP), Faculdade de Medicina da Universidade de São Paulo, São Paulo 01246-000, Brasil
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Popoiu TA, Pîrvu CA, Popoiu CM, Iacob ER, Talpai T, Voinea A, Albu RS, Tãban S, Bãlãnoiu LM, Pantea S. Gastrointestinal Stromal Tumors (GISTs) in Pediatric Patients: A Case Report and Literature Review. CHILDREN (BASEL, SWITZERLAND) 2024; 11:1040. [PMID: 39334573 PMCID: PMC11429550 DOI: 10.3390/children11091040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Revised: 08/18/2024] [Accepted: 08/23/2024] [Indexed: 09/30/2024]
Abstract
Gastrointestinal stromal tumors (GISTs) are rare mesenchymal neoplasms that primarily affect adults, with pediatric cases constituting only 0.5-2.7% of the total. Pediatric GISTs present unique clinical, genetic, and pathological features that distinguish them from adult cases. This literature review aims to elucidate these differences, emphasizing diagnostic and therapeutic challenges. We discuss the resistance of pediatric GISTs to conventional chemotherapy and highlight the importance of surgical intervention, especially in emergency situations involving intra-abdominal bleeding. The review also explores the molecular characteristics of pediatric GISTs, including rare mutations such as quadruple-negative wild-type GIST with an FGF3 gene gain mutation. To illustrate these points, we conclude with a case from our clinic involving a 15-year-old female with multiple CD117-positive gastric GISTs and a quadruple-negative wild-type genetic profile who required urgent surgical intervention following a failed tumor embolization. This case underscores the critical need for early diagnosis and individualized therapeutic strategies combining oncologic and surgical care to improve outcomes in pediatric GIST patients.
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Affiliation(s)
- Tudor-Alexandru Popoiu
- Department of General Surgery, "Victor Babeş" University of Medicine and Pharmacy, 300041 Timisoara, Romania
- Department III of Functional Sciences, Discipline of Medical Informatics and Biostatistics, "Victor Babeş" University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Cãtãlin-Alexandru Pîrvu
- Department of General Surgery, "Victor Babeş" University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Cãlin-Marius Popoiu
- Department of Pediatric Surgery, "Victor Babes" University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Emil Radu Iacob
- Department of Pediatric Surgery, "Victor Babes" University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Tamas Talpai
- Department of General Surgery, "Victor Babeş" University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Amalia Voinea
- Department of General Surgery, "Victor Babeş" University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Rãzvan-Sorin Albu
- Department of General Surgery, "Victor Babeş" University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Sorina Tãban
- Department of Pathology, "Victor Babeş" University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Larisa-Mihaela Bãlãnoiu
- Department of General Surgery, "Victor Babeş" University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Stelian Pantea
- Department of General Surgery, "Victor Babeş" University of Medicine and Pharmacy, 300041 Timisoara, Romania
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Lao A, Silva J, Chiu B, Sergi CM. Carney complex: A clinicopathologic study on a single family from several Canadian provinces. Cardiovasc Pathol 2024; 69:107599. [PMID: 38072094 DOI: 10.1016/j.carpath.2023.107599] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Revised: 12/01/2023] [Accepted: 12/04/2023] [Indexed: 12/26/2023] Open
Abstract
Carney syndrome is an autosomal dominant complex involving endocrinopathy, mucocutaneous hyperpigmentation, and different tumors, including cardiac myxomas. We report on a single family with several members affected with Carney syndrome. Family and individual medical histories were investigated in several Canadian provinces. The histology slides were also reviewed. Four family members (two young women, both sisters, their mother, and maternal grandmother) were found to harbor Carney syndrome. Everyone was presented with multiple and recurrent atrial myxomas of the heart, requiring multiple open cardiac surgeries. Breast myxomas and cutaneous hyperpigmentation were also revealed in one of the sisters and their mother. Interestingly, genetic testing was positive for the female family members and negative for the father and brother. We cannot rule out that the brother may have had a new mutation or harboring a mosaic. The young woman's brother did not have cardiac myxoma but developed a unilateral Sertoli cell tumor of testis. Carney syndrome is a rare complex multisystemic genetic disorder, including multiple and recurrent cardiac myxomas. We strongly suggest that reporting familial Carney syndrome is still critical in the 21st century to augment the awareness of this situation among clinicians and pathologists.
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Affiliation(s)
- Alexandra Lao
- Department of Laboratory Medicine and Pathology, Hôpital de Saint-Georges; CISSS - Chaudière-Appalaches, Quebec, Canada
| | - Julio Silva
- Medicine Hat Regional Hospital, Alberta Precision Laboratories Ltd. (APL) - South Sector, Alberta, Canada
| | - Brian Chiu
- Department of Laboratory Medicine and Pathology, University of Alberta Hospital, Edmonton, Alberta, Canada
| | - Consolato M Sergi
- Department of Laboratory Medicine and Pathology, University of Alberta Hospital, Edmonton, Alberta, Canada; Anatomic Pathology, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, Ontario, Canada.
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Schipani A, Nannini M, Astolfi A, Pantaleo MA. SDHA Germline Mutations in SDH-Deficient GISTs: A Current Update. Genes (Basel) 2023; 14:genes14030646. [PMID: 36980917 PMCID: PMC10048394 DOI: 10.3390/genes14030646] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Revised: 02/17/2023] [Accepted: 03/01/2023] [Indexed: 03/08/2023] Open
Abstract
Loss of function of the succinate dehydrogenase complex characterizes 20–40% of all KIT/PDGFRA-negative GIST. Approximately half of SDH-deficient GIST patients lack SDHx mutations and are caused by a hypermethylation of the SDHC promoter, which causes the repression of SDHC transcription and depletion of SDHC protein levels through a mechanism described as epimutation. The remaining 50% of SDH-deficient GISTs have mutations in one of the SDH subunits and SDHA mutations are the most common (30%), with consequent loss of SDHA and SDHB protein expression immunohistochemically. SDHB, SDHC, and SDHD mutations in GIST occur in only 20–30% of cases and most of these SDH mutations are germline. More recently, germline mutations in SDHA have also been described in several patients with loss of function of the SDH complex. SDHA-mutant patients usually carry two mutational events at the SDHA locus, either the loss of the wild type allele or a second somatic event in compound heterozygosis. This review provides an overview of all data in the literature regarding SDHA-mutated GIST, especially focusing on the prevalence of germline mutations in SDH-deficient GIST populations who harbor SDHA somatic mutations, and offers a view towards understanding the importance of genetic counselling for SDHA-variant carriers and relatives.
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Affiliation(s)
- Angela Schipani
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, 40138 Bologna, Italy
- Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CS Utrecht, The Netherlands
| | - Margherita Nannini
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, 40138 Bologna, Italy
- Division of Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
| | - Annalisa Astolfi
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, 40138 Bologna, Italy
- Correspondence: ; Tel.: +39-051-2144520
| | - Maria A. Pantaleo
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, 40138 Bologna, Italy
- Division of Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
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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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Schaefer IM, DeMatteo RP, Serrano C. The GIST of Advances in Treatment of Advanced Gastrointestinal Stromal Tumor. Am Soc Clin Oncol Educ Book 2022; 42:1-15. [PMID: 35522913 DOI: 10.1200/edbk_351231] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Gastrointestinal stromal tumor (GIST) is the most common malignant neoplasm of mesenchymal origin and a compelling clinical and biologic model for the rational development of molecularly targeted agents. This is because the majority of GISTs are driven by gain-of-function mutations in KIT or PDGFRA receptor tyrosine kinases. Specific GIST mutations circumscribe well-defined molecular subgroups that must be determined during the diagnostic work-up to guide clinical management, including therapeutic decisions. Surgery is the cornerstone treatment in localized disease and can also be clinically relevant in the metastatic setting. The correct combination and sequence of targeted agents and surgical procedures improves outcomes for patients with GIST and should be discussed individually within multidisciplinary expert teams. All currently approved agents for the treatment of GIST are based on orally available tyrosine kinase inhibitors targeting KIT and PDGFRA oncogenic activation. Although first-line imatinib achieves remarkable prolonged disease control, the benefit of subsequent lines of treatment is more modest. Novel therapeutic strategies focus on overcoming the heterogeneity of KIT or PDGFRA secondary mutations and providing more potent inhibition of specific challenging mutations. This article reviews the current understanding and treatment of GIST, with an emphasis on recent advances.
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Affiliation(s)
- Inga-Marie Schaefer
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
| | | | - César Serrano
- Sarcoma Translational Research Program, Vall d'Hebron Institute of Oncology, Barcelona, Spain.,Medical Oncology Department, Vall d'Hebron University Hospital, Barcelona, Spain
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Sugiyama Y, Sasaki M, Kouyama M, Tazaki T, Takahashi S, Nakamitsu A. Current treatment strategies and future perspectives for gastrointestinal stromal tumors. World J Gastrointest Pathophysiol 2022; 13:15-33. [PMID: 35116177 PMCID: PMC8788163 DOI: 10.4291/wjgp.v13.i1.15] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Revised: 05/23/2021] [Accepted: 11/15/2021] [Indexed: 02/06/2023] Open
Abstract
Gastrointestinal stromal tumors (GISTs) are mesenchymal tumors that originate from the gastrointestinal tract, mostly from the stomach. GISTs are derived from the myenteric interstitial cells of Cajal and are caused by several mutations in the c-kit and platelet-derived growth factor receptor genes. Clinically, GISTs are detected by endoscopic and imaging findings and are diagnosed by immunostaining. Surgery is the first line of treatment, and if the tumor is relatively small, minimally invasive surgery such as laparoscopy is performed. In recent years, neoadjuvant therapy has been administered to patients with GISTs that are suspected of having a large size or infiltration to other organs. Postoperative adjuvant imatinib is the standard therapy for high-risk GISTs. It is important to assess the risk of recurrence after GIST resection. However, the effect of tyrosine kinase inhibitor use will vary by the mutation of c-kit genes and the site of mutation. Furthermore, information regarding gene mutation is indispensable when considering the treatment policy for recurrent GISTs. This article reviews the clinicopathological characteristics of GISTs along with the minimally invasive and multidisciplinary treatment options available for these tumors. The future perspectives for diagnostic and treatment approaches for these tumors have also been discussed.
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Affiliation(s)
- Yoichi Sugiyama
- Department of Gastrointestinal Surgery, JA Hiroshima General Hospital, Hatsukaichi 738-8503, Hiroshima, Japan
| | - Masaru Sasaki
- Department of Gastrointestinal Surgery, JA Hiroshima General Hospital, Hatsukaichi 738-8503, Hiroshima, Japan
| | - Mohei Kouyama
- Department of Gastrointestinal Surgery, JA Hiroshima General Hospital, Hatsukaichi 738-8503, Hiroshima, Japan
| | - Tatsuya Tazaki
- Department of Gastrointestinal Surgery, JA Hiroshima General Hospital, Hatsukaichi 738-8503, Hiroshima, Japan
| | - Shinya Takahashi
- Department of Surgery, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734-8551, Japan
| | - Atsushi Nakamitsu
- Department of Gastrointestinal Surgery, JA Hiroshima General Hospital, Hatsukaichi 738-8503, Hiroshima, Japan
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Tansir G, Dash NR, Galodha S, Das P, Shamim SA, Rastogi S. Carney's triad in an adult male from a tertiary care center in India: a case report. J Med Case Rep 2021; 15:559. [PMID: 34782012 PMCID: PMC8594125 DOI: 10.1186/s13256-021-03149-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Accepted: 09/28/2021] [Indexed: 11/16/2022] Open
Abstract
BACKGROUND Carney's triad is a rare syndrome comprising gastrointestinal stromal tumor, extra-adrenal paraganglioma, and pulmonary chondroma along with newer additions of adrenal adenoma and esophageal leiomyoma. The triad is completely manifest in only 25-30% cases, with most patients presenting with two out of three parts of the syndrome. Wild-type succinate-dehydrogenase-deficient gastric gastrointestinal stromal tumor forms the most common component of Carney's triad and is usually multicentric and multifocal. It usually demonstrates indolent behavior and resistance to imatinib; hence, the management remains predominantly surgical. Pulmonary chondromas are commonly unilateral and multiple with slow-growing nature, which allows for conservative management. Adrenocortical adenomas are found in 20% of patients and are usually detected as incidentalomas. CASE PRESENTATION A 49-year-old Asian male presented with upper gastrointestinal bleed and was diagnosed with multiple gastric succinate-dehydrogenase-deficient gastrointestinal stromal tumors. On evaluation, he was found to have left pulmonary chondroma and non-secretory adrenal adenoma, thus completing the Carney's triad. He underwent surgery with sleeve gastrectomy and excision of the antral tumor nodule, while the adrenal and pulmonary tumors have been under close follow-up. CONCLUSION Literature regarding Carney's triad is scarce, especially from the Indian setting. Our report aims to highlight the various manifestations of this syndrome with emphasis on management of wild-type succinate-dehydrogenase-deficient gastrointestinal stromal tumor. Radical gastric surgeries do not offer a survival advantage in this condition; hence, more conservative modalities of resection can be adopted.
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Affiliation(s)
- Ghazal Tansir
- Department of Medical Oncology, BRA IRCH, All India Institute of Medical Sciences, New Delhi, India
| | - Nihar Ranjan Dash
- Department of Gastrointestinal Surgery, All India Institute of Medical Sciences, New Delhi, India
| | - Saurabh Galodha
- Department of Gastrointestinal Surgery, All India Institute of Medical Sciences, New Delhi, India
| | - Prasenjit Das
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
| | - Shamim Ahmed Shamim
- Department of Nuclear Medicine, All India Institute of Medical Sciences, New Delhi, India
| | - Sameer Rastogi
- Sarcoma Medical Oncology Clinic, BRA IRCH, All India Institute of Medical Sciences, New Delhi, India.
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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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Genetics of Acromegaly and Gigantism. J Clin Med 2021; 10:jcm10071377. [PMID: 33805450 PMCID: PMC8036715 DOI: 10.3390/jcm10071377] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Revised: 03/18/2021] [Accepted: 03/19/2021] [Indexed: 12/11/2022] Open
Abstract
Growth hormone (GH)-secreting pituitary tumours represent the most genetically determined pituitary tumour type. This is true both for germline and somatic mutations. Germline mutations occur in several known genes (AIP, PRKAR1A, GPR101, GNAS, MEN1, CDKN1B, SDHx, MAX) as well as familial cases with currently unknown genes, while somatic mutations in GNAS are present in up to 40% of tumours. If the disease starts before the fusion of the epiphysis, then accelerated growth and increased final height, or gigantism, can develop, where a genetic background can be identified in half of the cases. Hereditary GH-secreting pituitary adenoma (PA) can manifest as isolated tumours, familial isolated pituitary adenoma (FIPA) including cases with AIP mutations or GPR101 duplications (X-linked acrogigantism, XLAG) or can be a part of systemic diseases like multiple endocrine neoplasia type 1 or type 4, McCune-Albright syndrome, Carney complex or phaeochromocytoma/paraganglioma-pituitary adenoma association. Family history and a search for associated syndromic manifestations can help to draw attention to genetic causes; many of these are now tested as part of gene panels. Identifying genetic mutations allows appropriate screening of associated comorbidities as well as finding affected family members before the clinical manifestation of the disease. This review focuses on germline and somatic mutations predisposing to acromegaly and gigantism.
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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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12
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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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13
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Papke DJ, Hornick JL. Recent developments in gastroesophageal mesenchymal tumours. Histopathology 2020; 78:171-186. [PMID: 33382494 DOI: 10.1111/his.14164] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2020] [Revised: 05/26/2020] [Accepted: 05/27/2020] [Indexed: 12/19/2022]
Abstract
The pathologist's approach to gastroesophageal mesenchymal tumours has changed dramatically during the last 25 years. In particular, gastrointestinal stromal tumour (GIST) has evolved from a wastebasket mesenchymal tumour category to a precisely defined entity with an increasingly detailed genetic subclassification. This subclassification has brought gastrointestinal mesenchymal neoplasia into the realm of precision medicine, with specific treatments optimised for particular genetic subtypes. Molecular genetic data have also greatly improved our understanding of oesophageal mesenchymal tumours, including the discovery that so-called 'giant fibrovascular polyps' in fact represent a clinically distinctive presentation of well-differentiated liposarcoma. Here, we will focus on gastroesophageal mesenchymal tumours for which there have been recent developments in classification, molecular genetics or tumour biology: granular cell tumour, 'giant fibrovascular polyp'/well-differentiated liposarcoma, plexiform fibromyxoma, gastroblastoma and, of course, GIST.
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Affiliation(s)
- David J Papke
- Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
| | - Jason L Hornick
- Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA
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14
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Shen YY, Ma XL, Yang LX, Zhao WY, Tu L, Zhuang C, Ni B, Liu Q, Wang M, Cao H. Clinicopathologic characteristics, diagnostic clues, and prognoses of patients with multiple sporadic gastrointestinal stromal tumors: a case series and review of the literature. Diagn Pathol 2020; 15:56. [PMID: 32408889 PMCID: PMC7222320 DOI: 10.1186/s13000-020-00939-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2019] [Accepted: 02/11/2020] [Indexed: 12/28/2022] Open
Abstract
Background Most sporadic gastrointestinal stromal tumors (GISTs) occur as solitary tumors, while multiple sporadic GISTs are extremely rare and often misdiagnosed as metastatic GISTs, leading to inappropriate treatment. This study aimed to investigate the clinicopathological characteristics, diagnostic clues, and prognoses of multiple sporadic GISTs. Methods Twenty-seven patients with multiple sporadic GISTs and 11 patients with metastatic GISTs mimicking sporadic GISTs were analyzed. The clinicopathological characteristics, genetic mutation types, and prognoses were summarized. In addition, 1066 cases of primary GISTs with a single lesion diagnosed at the same hospital were included as controls. Results Compared with 1066 cases of primary GIST with a single lesion, multiple sporadic GISTs occurred at an older age, were more common in women than in men, and were located mainly in the stomach. They were generally small in size, had a low mitotic index and were more often rated as very low risk/low risk. Mutation analysis of all available lesions revealed different KIT/PDGFRA mutation patterns among tumors from the same patients. No patient relapsed during the follow-up period. Among 11 patients with metastatic GISTs that mimicked multiple sporadic GISTs, multiple lesions from the same patient always had concordant pathological and mutational characteristics; namely, they carried an identical KIT/PDGFRA mutation, and the mitotic index was usually high. Conclusions The prognoses of patients with multiple sporadic GISTs were not worse than those of patients with a single lesion of the same risk under the same treatment. When it was difficult to distinguish multiple sporadic GISTs from metastatic GISTs, multiple lesions in the same patient carried different KIT/PDGFRA mutation patterns, which supported tumor multiplicity, while the concordant hypermitotic phase in multiple lesions of GISTs suggested that the tumor was metastatic.
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Affiliation(s)
- Yan-Ying Shen
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, 160 Pujian Road, Shanghai, 200127, People's Republic of China.,Department of Pathology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, People's Republic of China
| | - Xin-Li Ma
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, 160 Pujian Road, Shanghai, 200127, People's Republic of China
| | - Lin-Xi Yang
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, 160 Pujian Road, Shanghai, 200127, People's Republic of China
| | - Wen-Yi Zhao
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, 160 Pujian Road, Shanghai, 200127, People's Republic of China
| | - Lin Tu
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, 160 Pujian Road, Shanghai, 200127, People's Republic of China
| | - Chun Zhuang
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, 160 Pujian Road, Shanghai, 200127, People's Republic of China
| | - Bo Ni
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, 160 Pujian Road, Shanghai, 200127, People's Republic of China
| | - Qiang Liu
- Department of Pathology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, People's Republic of China
| | - Ming Wang
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, 160 Pujian Road, Shanghai, 200127, People's Republic of China.
| | - Hui Cao
- Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong University, 160 Pujian Road, Shanghai, 200127, People's Republic of China.
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15
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Neppala P, Banerjee S, Fanta PT, Yerba M, Porras KA, Burgoyne AM, Sicklick JK. Current management of succinate dehydrogenase-deficient gastrointestinal stromal tumors. Cancer Metastasis Rev 2020; 38:525-535. [PMID: 31773431 DOI: 10.1007/s10555-019-09818-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Gastrointestinal stromal tumors (GISTs) are increasingly recognized as having diverse biology. With the development of tyrosine kinase inhibitors molecularly matched to oncogenic KIT and PDGFRA mutations, GISTs have become a quintessential model for precision oncology. However, about 5-10% of GIST lack these driver mutations and are deficient in succinate dehydrogenase (SDH), an enzyme that converts succinate to fumarate. SDH deficiency leads to accumulation of succinate, an oncometabolite that promotes tumorigenesis. SDH-deficient GISTs are clinically unique in that they generally affect younger patients and are associated with GIST-paraganglioma hereditary syndrome, also known as Carney-Stratakis Syndrome. SDH-deficient GISTs are generally resistant to tyrosine-kinase inhibitors, the standard treatment for advanced or metastatic GIST. Thus, surgical resection is the mainstay of treatment for localized disease, but recurrence is common. Clinical trials are currently underway investigating systemic agents for treatment of advanced SDH-deficient GIST. However, further studies are warranted to improve our understanding of SDH-deficient GIST disease biology, natural history, surgical approaches, and novel therapeutics.
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Affiliation(s)
- Pushpa Neppala
- UC San Diego School of Medicine, University of California, San Diego, La Jolla, CA, USA
| | - Sudeep Banerjee
- Division of Surgical Oncology, Department of Surgery, UC San Diego Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA.,Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Paul T Fanta
- Center for Personalized Cancer Therapy, UC San Diego Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA.,Division of Hematology-Oncology, Department of Medicine, UC San Diego Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA
| | - Mayra Yerba
- Division of Surgical Oncology, Department of Surgery, UC San Diego Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA
| | - Kevin A Porras
- UC San Diego School of Medicine, University of California, San Diego, La Jolla, CA, USA
| | - Adam M Burgoyne
- Division of Hematology-Oncology, Department of Medicine, UC San Diego Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA.
| | - Jason K Sicklick
- Division of Surgical Oncology, Department of Surgery, UC San Diego Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA. .,Center for Personalized Cancer Therapy, UC San Diego Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA.
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16
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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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17
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Witt RG, Baldini EH, Raut CP. Screening populations at high risk for soft tissue sarcoma and surveillance following soft tissue sarcoma resection. J Surg Oncol 2019; 120:882-890. [PMID: 31432526 DOI: 10.1002/jso.25676] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2019] [Accepted: 08/07/2019] [Indexed: 11/12/2022]
Abstract
Soft tissue sarcomas (STS) are a rare and diverse group of tumors that affect both adult and pediatric populations. This review discusses current screening recommendations for populations at increased risk for STS, including those with genetic predispositions. We also review surveillance guidelines for those at risk for recurrence following curative-intent surgery.
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Affiliation(s)
- Russell G Witt
- Department of Surgery, Brigham and Women's Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
| | - Elizabeth H Baldini
- Department of Radiation Oncology, Brigham and Women's Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
| | - Chandrajit P Raut
- Department of Surgery, Brigham and Women's Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
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18
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Li K, Tjhoi W, Shou C, Yang W, Zhang Q, Liu X, Yu J. Multiple gastrointestinal stromal tumors: analysis of clinicopathologic characteristics and prognosis of 20 patients. Cancer Manag Res 2019; 11:7031-7038. [PMID: 31413638 PMCID: PMC6662863 DOI: 10.2147/cmar.s197560] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2018] [Accepted: 06/18/2019] [Indexed: 12/16/2022] Open
Abstract
Purpose Multiple gastrointestinal stromal tumors (GISTs) are rare. The aim of this study was to investigate the clinicopathologic characteristics and prognosis of multiple GISTs. Patients and methods Between May 2003 and June 2018, patients who underwent surgery for multiple GISTs were retrospectively analyzed. Exons 9, 11, 13, and 17 of the KIT gene, and exons 12, and 18 of the PDGFRA gene were examined in 34 tumors from 20 patients. Results A total of 20 patients with multiple GISTs were enrolled. There were 11 females and nine males with a median age of 59 years (range: 37–80 years). Of these cases, 16 were sporadic cases and four were associated with GIST syndromes (two cases of Carney triad and two cases of neurofibromatosis type 1 [NF1]). The most common presentation was gastrointestinal bleeding. Carney triad GISTs did not exhibit KIT/PDGFRA mutations. One of the NF1 patients was a KIT/PDGFRA wild-type, and the other patient had a PDGFRA mutation. Of the sporadic cases, one shared the same KIT gene mutation within each GIST and one had two lesions that were both wild-type for KIT and PDGFRA. Different KIT mutations among individual tumors were detected in seven patients. During the median follow-up period of 66 months (range: 3–183 months), four patients developed liver or abdominal metastases, three of whom expired due to the disease. The rates of recurrence-free survival and overall surviva at 5 years were 65.8% and 76.7%, respectively. Conclusion Multiple GISTs may occur as sporadic tumors or as an additional component of specific syndromes (eg, Carney triad and NF1) that display different clinicopathologic characteristics based on their particular underlying mechanisms. The overall prognosis of patients with multiple GISTs is comparable to that of patients with only a single GIST.
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Affiliation(s)
- Kai Li
- Department of Gastrointestinal Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China
| | - Weh Tjhoi
- Department of Gastrointestinal Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China
| | - Chunhui Shou
- Department of Gastrointestinal Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China
| | - Weili Yang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China
| | - Qing Zhang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China
| | - Xiaosun Liu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China
| | - Jiren Yu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China
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19
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Ibrahim A, Chopra S. Succinate Dehydrogenase–Deficient Gastrointestinal Stromal Tumors. Arch Pathol Lab Med 2019; 144:655-660. [DOI: 10.5858/arpa.2018-0370-rs] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Succinate dehydrogenase (SDH)–deficient gastrointestinal stromal tumor (GIST) is a subset of wild-type GIST that constitutes approximately 10% of gastric GISTs. SDH-mutated GISTs lack mutations in the proto-oncogene receptor tyrosine kinase (also known as KIT, c-KIT, or CD117) or platelet-derived growth factor receptor α (PDGFR-α). These tumors have female predilection, affect children and young adults, and have a spectrum of behavior from indolent to progressive. These tumors have characteristic morphologic features including multinodular architecture, multiple tumors, lymphovascular involvement, and occasional lymph node metastasis. They can be seen in patients with Carney triad or Carney-Stratakis syndrome. Although a mutation in any one of the SDH subunits can be pathogenic, deficiency of a single subunit leads to loss of detectable SDH subunit B by immunohistochemistry, enabling a convenient, tissue-based screening method. The prognosis and the clinical course of these tumors is different from that of KIT- or PDGFR-α–mutated GISTs. Surgical management is considered the main line of treatment. SDH-mutated GISTs do not respond well to the common targeted therapy, with no objective tumor response to imatinib. The role of the pathologist in diagnosing these cases is imperative in management and subsequent follow-up.
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Affiliation(s)
- Ahmad Ibrahim
- From the Department of Pathology, LAC + USC Medical Center, University of Southern California, Keck School of Medicine, Los Angeles (Dr Ibrahim); and the Department of Pathology, University of Southern California, Keck School of Medicine, Los Angeles (Dr Chopra)
| | - Shefali Chopra
- From the Department of Pathology, LAC + USC Medical Center, University of Southern California, Keck School of Medicine, Los Angeles (Dr Ibrahim); and the Department of Pathology, University of Southern California, Keck School of Medicine, Los Angeles (Dr Chopra)
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20
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Kamilaris CDC, Stratakis CA. An update on adrenal endocrinology: significant discoveries in the last 10 years and where the field is heading in the next decade. Hormones (Athens) 2018; 17:479-490. [PMID: 30456751 PMCID: PMC6294814 DOI: 10.1007/s42000-018-0072-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2018] [Revised: 08/28/2018] [Accepted: 09/20/2018] [Indexed: 02/07/2023]
Abstract
The last 10 years have produced an amazing number of significant discoveries in the field of adrenal endocrinology. The development of the adrenal gland was linked to specific molecules. Cortisol-producing lesions were associated mostly with defects of the cyclic AMP (cAMP) signaling pathway, whereas aldosterone-producing lesions were found to be the result of defects in aldosterone biosynthesis or the potassium channel KCNJ5 and related molecules. Macronodular adrenal hyperplasia was linked to ARMC5 defects and new genes were found to be involved in adrenocortical cancer (ACC). The succinate dehydrogenase (SDH) enzyme was proven to be the most important molecular pathway involved in pheochromocytomas, along with several other genes. Adrenomedullary tumors are now largely molecularly elucidated. Unfortunately, most of these important discoveries have yet to produce new therapeutic tools for our patients with adrenal diseases: ACC in its advanced stages remains largely an untreatable disorder and malignant pheochromocytomas are equally hard to treat. Thus, the challenge for the next 10 years is to translate the important discoveries of the previous decade into substantial advances in the treatment of adrenal disorders and tumors.
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Affiliation(s)
- Crystal D C Kamilaris
- Section on Endocrinology and Genetics & Inter-Institute Endocrinology Training Program, Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), National Institutes of Health (NIH), NIH-Clinical Research Center, 10 Center Drive, Building 10, Room 1-3330, MSC1103, Bethesda, MD, 20892, USA
| | - Constantine A Stratakis
- Section on Endocrinology and Genetics & Inter-Institute Endocrinology Training Program, Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), National Institutes of Health (NIH), NIH-Clinical Research Center, 10 Center Drive, Building 10, Room 1-3330, MSC1103, Bethesda, MD, 20892, USA.
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21
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De Palma A, Lorusso M, Di Gennaro F, Quercia R, Pizzuto O, Garofalo G, Fiorella A, Maiolino E, Nex G, Schiavone M, De Iaco G, Gentile A, Lastilla G, Loizzi M, Resta L. Pulmonary and mediastinal paragangliomas: rare endothoracic malignancies with challenging diagnosis and treatment. J Thorac Dis 2018; 10:5318-5327. [PMID: 30416779 DOI: 10.21037/jtd.2018.09.01] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Background Pulmonary and mediastinal paragangliomas are rare tumors that may have neuroendocrine activity or be non-functional, incidental, in asymptomatic patients, or causing mass effect symptoms. Although being low-grade tumors, they can display an aggressive behaviour, developing local infiltration and distant metastases. We report our experience with three endothoracic paragangliomas and a Literature review, to point out diagnostic difficulties and problems related to surgical treatment. Methods From 2009 to 2017, we treated 3 patients with histological diagnosis of paraganglioma: 2 pulmonary, 1 mediastinal. No one presented catecholamine-secreting syndromes; pulmonary cases were asymptomatic, while the mediastinal one had aspecific cough and dyspnea. Imaging diagnosis was based on chest computerized tomography (CT) and magnetic resonance imaging (MRI) scan. No patient had preoperative histological diagnosis. Intraoperative pathological examination was suggestive for malignancy: in pulmonary cases, wedge resection and lobectomy were performed; the middle mediastinal mass was completely removed after challenging dissection, isolation and section of numerous vascular pedicles. Results Postoperative course was uneventful in all cases. No patient received adjuvant treatments. At a median follow-up of 47 months (range, 6-102 months), two patients are alive, without local or distant recurrence; one patient died 6 months after surgery, due to disease progression. Conclusions Endothoracic paragangliomas, rare and often asymptomatic tumors, are of difficult diagnosis and should be considered malignant tumors, due to the potential aggressive behaviour of cases with high mitotic index and the frequent possibility of recurrence and metastases. Surgical resection is the treatment of choice and careful intraoperative manipulation is recommended, due to the high vascularity of these tumors, to prevent complications. After complete excision, long-term prognosis is generally good. However, even after surgical removal, a close, periodical and life-long follow-up is mandatory.
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Affiliation(s)
- Angela De Palma
- Section of Thoracic Surgery, Department of Emergency and Organ Transplantation, University of Bari "Aldo Moro", Bari, Italy
| | - Mariagrazia Lorusso
- Section of Thoracic Surgery, Department of Emergency and Organ Transplantation, University of Bari "Aldo Moro", Bari, Italy
| | - Francesco Di Gennaro
- Section of Thoracic Surgery, Department of Emergency and Organ Transplantation, University of Bari "Aldo Moro", Bari, Italy
| | - Rosatea Quercia
- Section of Thoracic Surgery, Department of Emergency and Organ Transplantation, University of Bari "Aldo Moro", Bari, Italy
| | - Ondina Pizzuto
- Section of Thoracic Surgery, Department of Emergency and Organ Transplantation, University of Bari "Aldo Moro", Bari, Italy
| | - Giuseppe Garofalo
- Section of Thoracic Surgery, Department of Emergency and Organ Transplantation, University of Bari "Aldo Moro", Bari, Italy
| | - Angela Fiorella
- Section of Thoracic Surgery, Department of Emergency and Organ Transplantation, University of Bari "Aldo Moro", Bari, Italy
| | - Elena Maiolino
- Section of Thoracic Surgery, Department of Emergency and Organ Transplantation, University of Bari "Aldo Moro", Bari, Italy
| | - Giulia Nex
- Section of Thoracic Surgery, Department of Emergency and Organ Transplantation, University of Bari "Aldo Moro", Bari, Italy
| | - Marcella Schiavone
- Section of Thoracic Surgery, Department of Emergency and Organ Transplantation, University of Bari "Aldo Moro", Bari, Italy
| | - Giulia De Iaco
- Section of Thoracic Surgery, Department of Emergency and Organ Transplantation, University of Bari "Aldo Moro", Bari, Italy
| | - Antonia Gentile
- Division of Pathology, Department of Emergency and Organ Transplantation, University of Bari "Aldo Moro", Bari, Italy
| | - Gaetano Lastilla
- Division of Pathology, Department of Emergency and Organ Transplantation, University of Bari "Aldo Moro", Bari, Italy
| | - Michele Loizzi
- Section of Thoracic Surgery, Department of Emergency and Organ Transplantation, University of Bari "Aldo Moro", Bari, Italy
| | - Leonardo Resta
- Division of Pathology, Department of Emergency and Organ Transplantation, University of Bari "Aldo Moro", Bari, Italy
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22
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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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Settas N, Faucz FR, Stratakis CA. Succinate dehydrogenase (SDH) deficiency, Carney triad and the epigenome. Mol Cell Endocrinol 2018; 469:107-111. [PMID: 28739378 PMCID: PMC5776069 DOI: 10.1016/j.mce.2017.07.018] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2017] [Revised: 07/13/2017] [Accepted: 07/20/2017] [Indexed: 12/29/2022]
Abstract
In this report, we review the relationship between succinate dehydrogenase (SDH) deficiency and the epigenome, especially with regards to two clinical conditions. Carney triad (CT) is a very rare disease with synchronous or metachronous occurrence of at least three different tumor entities; gastric gastrointestinal stromal tumor (GIST), paraganglioma (PGL), and pulmonary chondroma. This condition affects mostly females and it is never inherited. Another disease that shares two of the tumor components of CT, namely GIST and PGL is the Carney-Stratakis syndrome (CSS) or dyad. CSS affects both genders during childhood and adolescence. We review herein the main clinical features and molecular mechanisms behind those two syndromes that share quite a bit of similarities, but one is non-hereditary (CT) whereas the other shows an autosomal-dominant, with incomplete penetrance, inheritance pattern (CSS). Both CT and CSS are caused by the deficiency of the succinate dehydrogenase (SDH) enzyme. The key difference between the two syndromes is the molecular mechanism that causes the SDH deficiency. Most cases of CT show down-regulation of SDH through site-specific hyper-methylation of the SDHC gene, whereas CSS cases carry inactivating germline mutations within one of the genes coding for the SDH subunits A, B, C, or D (SDHA, SDHB, SDHC, and SDHD). There is only partial overlap between the two conditions (there are a few patients with CT that have SDH subunit mutations) but both lead to increased methylation of the entire genome in the tumors associated with them. Other tumors (outside CT and CSS) that have SDH deficiency are associated with increased methylation of the entire genome, but only in CT there is site-specific methylation of the SDHC gene. These findings have implications for diagnostics and the treatment of patients with these, often metastatic tumors.
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Affiliation(s)
- Nikolaos Settas
- Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, USA.
| | - Fabio R Faucz
- Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, USA
| | - Constantine A Stratakis
- Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, USA
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The role of metabolic enzymes in mesenchymal tumors and tumor syndromes: genetics, pathology, and molecular mechanisms. J Transl Med 2018; 98:414-426. [PMID: 29339836 DOI: 10.1038/s41374-017-0003-6] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2017] [Revised: 11/01/2017] [Accepted: 11/21/2017] [Indexed: 02/07/2023] Open
Abstract
The discovery of mutations in genes encoding the metabolic enzymes isocitrate dehydrogenase (IDH), succinate dehydrogenase (SDH), and fumarate hydratase (FH) has expanded our understanding not only of altered metabolic pathways but also epigenetic dysregulation in cancer. IDH1/2 mutations occur in enchondromas and chondrosarcomas in patients with the non-hereditary enchondromatosis syndromes Ollier disease and Maffucci syndrome and in sporadic tumors. IDH1/2 mutations result in excess production of the oncometabolite (D)-2-hydroxyglutarate. In contrast, SDH and FH act as tumor suppressors and genomic inactivation results in succinate and fumarate accumulation, respectively. SDH deficiency may result from germline SDHA, SDHB, SDHC, or SDHD mutations and is found in autosomal-dominant familial paraganglioma/pheochromocytoma and Carney-Stratakis syndrome, describing the combination of paraganglioma and gastrointestinal stromal tumor (GIST). In contrast, patients with the non-hereditary Carney triad, including paraganglioma, GIST, and pulmonary chondroma, usually lack germline SDH mutations and instead show epigenetic SDH complex inactivation through SDHC promoter methylation. Inactivating FH germline mutations are found in patients with hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome comprising benign cutaneous/uterine leiomyomas and renal cell carcinoma. Mutant IDH, SDH, and FH share common inhibition of α-ketoglutarate-dependent oxygenases such as the TET family of 5-methylcytosine hydroxylases preventing DNA demethylation, and Jumonji domain histone demethylases increasing histone methylation, which together inhibit cell differentiation. Ongoing studies aim to better characterize these complex alterations in cancer, the different clinical phenotypes, and variable penetrance of inherited and sporadic cancer predisposition syndromes. A better understanding of the roles of metabolic enzymes in cancer may foster the development of therapies that specifically target functional alterations in tumor cells in the future. Here, the physiologic functions of these metabolic enzymes, the mutational spectrum, and associated functional alterations will be discussed, with a focus on mesenchymal tumor predisposition syndromes.
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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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26
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Schaefer IM, Cote GM, Hornick JL. Contemporary Sarcoma Diagnosis, Genetics, and Genomics. J Clin Oncol 2018; 36:101-110. [DOI: 10.1200/jco.2017.74.9374] [Citation(s) in RCA: 65] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Sarcomas include diverse mesenchymal neoplasms with widely varied prognosis, clinical behavior, and treatment. Owing to their rarity and histologic overlap, accurate diagnosis of sarcomas can be challenging. Our approach has evolved dramatically in the past few decades, where novel insights into the molecular pathogenetic basis for sarcomas has dramatically (re)shaped contemporary diagnosis, building on a largely morphology- and clinical presentation–based strategy. Examples include the introduction of novel immunohistochemical markers that serve as surrogates for molecular genetic alterations and identification of characteristic molecular alterations. Accordingly, cytogenetic and molecular genetic analyses, such as conventional karyotyping, fluorescence in situ hybridization, reverse transcription–polymerase chain reaction, and targeted sequencing, have increasingly been incorporated into the routine diagnostic work-up of these neoplasms. For those sarcomas with complex cytogenetic changes that lack specific alterations, additional testing is often directed toward identifying lines of differentiation and excluding pathognomonic (cyto-)genetic alterations. Although some gene rearrangements are diagnostic of particular sarcoma types, certain fusion partners, most notably EWSR1, are not tumor specific (and may, in fact, also be found in benign tumors). Correlation with clinical, radiologic, morphologic, and immunohistochemical findings is particularly important in tumors with such rearrangements to establish the correct diagnosis, acknowledging the inherent limitations of diagnostic tests. The recognition of sarcomas occurring in cancer predisposition syndromes is critical, with implications not only for the index patient but also potentially for family members, including the need for genetic counseling and sometimes particular types of surveillance. Together, contemporary sarcoma evaluation involves combining the initial morphologic evaluation with diagnostically relevant cytogenetic, molecular, and immunohistochemical testing methods.
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Affiliation(s)
- Inga-Marie Schaefer
- Inga-Marie Schaefer and Jason L. Hornick, Brigham and Women’s Hospital-Harvard Medical School; and Gregory M. Cote, Massachusetts General Hospital Cancer Center-Harvard Medical School, Boston, MA
| | - Gregory M. Cote
- Inga-Marie Schaefer and Jason L. Hornick, Brigham and Women’s Hospital-Harvard Medical School; and Gregory M. Cote, Massachusetts General Hospital Cancer Center-Harvard Medical School, Boston, MA
| | - Jason L. Hornick
- Inga-Marie Schaefer and Jason L. Hornick, Brigham and Women’s Hospital-Harvard Medical School; and Gregory M. Cote, Massachusetts General Hospital Cancer Center-Harvard Medical School, Boston, MA
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27
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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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28
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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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29
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68Ga-DOTA-TATE PET/CT for Molecular Imaging of Somatostatin Receptor Expression in Extra-adrenal Paraganglioma in a Case of Complete Carney Triad. Clin Nucl Med 2017; 42:e527-e528. [DOI: 10.1097/rlu.0000000000001864] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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30
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Collins RRJ, Patel K, Putnam WC, Kapur P, Rakheja D. Oncometabolites: A New Paradigm for Oncology, Metabolism, and the Clinical Laboratory. Clin Chem 2017; 63:1812-1820. [PMID: 29038145 DOI: 10.1373/clinchem.2016.267666] [Citation(s) in RCA: 69] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2017] [Accepted: 09/19/2017] [Indexed: 12/13/2022]
Abstract
BACKGROUND Pediatric clinical laboratories commonly measure tricarboxylic acid cycle intermediates for screening, diagnosis, and monitoring of specific inborn errors of metabolism, such as organic acidurias. In the past decade, the same tricarboxylic acid cycle metabolites have been implicated and studied in cancer. The accumulation of these metabolites in certain cancers not only serves as a biomarker but also directly contributes to cellular transformation, therefore earning them the designation of oncometabolites. CONTENT D-2-hydroxyglutarate, L-2-hydroxyglutarate, succinate, and fumarate are the currently recognized oncometabolites. They are structurally similar and share metabolic proximity in the tricarboxylic acid cycle. As a result, they promote tumorigenesis in cancer cells through similar mechanisms. This review summarizes the currently understood common and distinct biological features of these compounds. In addition, we will review the current laboratory methodologies that can be used to quantify these metabolites and their downstream targets. SUMMARY Oncometabolites play an important role in cancer biology. The metabolic pathways that lead to the production of oncometabolites and the downstream signaling pathways that are activated by oncometabolites represent potential therapeutic targets. Clinical laboratories have a critical role to play in the management of oncometabolite-associated cancers through development and validation of sensitive and specific assays that measure oncometabolites and their downstream effectors. These assays can be used as screening tools and for follow-up to measure response to treatment, as well as to detect minimal residual disease and recurrence.
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Affiliation(s)
- Rebecca R J Collins
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX.,Department of Pathology and Laboratory Medicine, Children's Health, Dallas, TX
| | - Khushbu Patel
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX.,Department of Pathology and Laboratory Medicine, Children's Health, Dallas, TX
| | - William C Putnam
- Office of Clinical and Translational Research, Texas Tech University Health Sciences Center, Dallas, TX
| | - Payal Kapur
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX
| | - Dinesh Rakheja
- Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX; .,Department of Pathology and Laboratory Medicine, Children's Health, Dallas, TX.,Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX
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31
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Schaefer IM, Fletcher CDM. Recent advances in the diagnosis of soft tissue tumours. Pathology 2017; 50:37-48. [PMID: 28950990 DOI: 10.1016/j.pathol.2017.07.007] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2017] [Accepted: 07/21/2017] [Indexed: 12/12/2022]
Abstract
Soft tissue tumours are relatively rare, but are diagnostically challenging as they comprise a large spectrum of diagnostic entities. Substantial advances have been made in recent years in identifying the underlying recurrent chromosomal and genomic alterations in a significant subset of soft tissue tumours, and this continues to enrich our understanding of the biological mechanisms of tumour development and progression. Ongoing validation and integration of these findings into existing pathological-diagnostic algorithms has led to re- or subclassification of diagnostic categories and will continue to shape a more nuanced (and hopefully clinically relevant) tumour classification system in the future. This review provides a selective overview of recent diagnostic or conceptual advances in the categories of peripheral nerve sheath tumours, vascular and adipocytic tumours, round cell and myogenic sarcomas, and gastrointestinal stromal tumours, as well as their underlying molecular mechanisms, some of which have been translated successfully into useful immunohistochemical stains. A thorough and critical validation of newly identified diagnostic markers-acknowledging the fact that some genetic alterations may not necessarily be tumour-specific-and ongoing correlation with clinical and prognostic implications will be necessary in this regard.
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Affiliation(s)
- Inga-Marie Schaefer
- Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States
| | - Christopher D M Fletcher
- Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, United States.
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32
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Abstract
The classification "gastrointestinal stromal tumor" (GIST) became commonplace in the 1990s and since that time various advances have characterized the GIST lineage of origin, tyrosine kinase mutations, and mechanisms of response and resistance to targeted therapies. In addition to tyrosine kinase mutations and their constitutive activation of downstream signaling pathways, GISTs acquire a sequence of chromosomal aberrations. These include deletions of chromosomes 14q, 22q, 1p, and 15q, which harbor putative tumor suppressor genes required for stepwise progression from microscopic, preclinical forms of GIST (microGIST) to clinically relevant tumors with malignant potential. Recent advances extend our understanding of GIST biology beyond that of the oncogenic KIT/PDGFRA tyrosine kinases and beyond mechanisms of KIT/PDGFRA-inhibitor treatment response and resistance. These advances have characterized ETV1 as an essential interstitial cell of Cajal-GIST transcription factor in oncogenic KIT signaling pathways, and have characterized the biologically distinct subgroup of succinate dehydrogenase deficient GIST, which are particularly common in young adults. Also, recent discoveries of MAX and dystrophin genomic inactivation have expanded our understanding of GIST development and progression, showing that MAX inactivation is an early event fostering cell cycle activity, whereas dystrophin inactivation promotes invasion and metastasis.
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Belinsky MG, Cai KQ, Zhou Y, Luo B, Pei J, Rink L, von Mehren M. Succinate dehydrogenase deficiency in a PDGFRA mutated GIST. BMC Cancer 2017; 17:512. [PMID: 28768491 PMCID: PMC5541693 DOI: 10.1186/s12885-017-3499-7] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2017] [Accepted: 07/24/2017] [Indexed: 12/21/2022] Open
Abstract
Background Most gastrointestinal stromal tumors (GISTs) harbor mutually exclusive gain of function mutations in the receptor tyrosine kinase (RTK) KIT (70–80%) or in the related receptor PDGFRA (~10%). These GISTs generally respond well to therapy with the RTK inhibitor imatinib mesylate (IM), although initial response is genotype-dependent. An alternate mechanism leading to GIST oncogenesis is deficiency in the succinate dehydrogenase (SDH) enzyme complex resulting from genetic or epigenetic inactivation of one of the four SDH subunit genes (SDHA, SDHB, SDHC, SDHD, collectively referred to as SDHX). SDH loss of function is generally seen only in GIST lacking RTK mutations, and SDH-deficient GIST respond poorly to imatinib therapy. Methods Tumor and normal DNA from a GIST case carrying the IM-resistant PDGFRA D842V mutation was analyzed by whole exome sequencing (WES) to identify additional potential targets for therapy. The tumors analyzed were separate recurrences following progression on imatinib, sunitinib, and the experimental PDGFRA inhibitor crenolanib. Tumor sections from the GIST case and a panel of ~75 additional GISTs were subjected to immunohistochemistry (IHC) for the SDHB subunit. Results Surprisingly, a somatic, loss of function mutation in exon 4 of the SDHB subunit gene (c.291_292delCT, p.I97Mfs*21) was identified in both tumors. Sanger sequencing confirmed the presence of this inactivating mutation, and IHC for the SDHB subunit demonstrated that these tumors were SDH-deficient. IHC for the SDHB subunit across a panel of ~75 GIST cases failed to detect SDH deficiency in other GISTs with RTK mutations. Conclusions This is the first reported case of a PDGFRA mutant GIST exhibiting SDH-deficiency. A brief discussion of the relevant GIST literature is included. Electronic supplementary material The online version of this article (doi:10.1186/s12885-017-3499-7) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Martin G Belinsky
- Molecular Therapeutics Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111-2497, USA.
| | - Kathy Q Cai
- Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA, USA
| | - Yan Zhou
- Biostatistics and Bioinformatics Facility, Fox Chase Cancer Center, Philadelphia, PA, USA
| | - Biao Luo
- Molecular Diagnostics Laboratory, Fox Chase Cancer Center, Philadelphia, PA, USA
| | - Jianming Pei
- Genomics Services, Fox Chase Cancer Center, Philadelphia, PA, USA
| | - Lori Rink
- Molecular Therapeutics Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111-2497, USA
| | - Margaret von Mehren
- Molecular Therapeutics Program, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111-2497, USA
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Boikos SA, Pappo AS, Killian JK, LaQuaglia MP, Weldon CB, George S, Trent JC, von Mehren M, Wright JA, Schiffman JD, Raygada M, Pacak K, Meltzer PS, Miettinen MM, Stratakis C, Janeway KA, Helman LJ. Molecular Subtypes of KIT/PDGFRA Wild-Type Gastrointestinal Stromal Tumors: A Report From the National Institutes of Health Gastrointestinal Stromal Tumor Clinic. JAMA Oncol 2017; 2:922-8. [PMID: 27011036 DOI: 10.1001/jamaoncol.2016.0256] [Citation(s) in RCA: 265] [Impact Index Per Article: 33.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
IMPORTANCE Wild-type (WT) gastrointestinal stromal tumors (GISTs), which lack KIT and PDGFRA gene mutations, are the primary form of GIST in children and occasionally occur in adults. They respond poorly to standard targeted therapy. Better molecular and clinical characterization could improve management. OBJECTIVE To evaluate the clinical and tumor genomic features of WT GIST. DESIGN, SETTING, AND PARTICIPANTS Patients enrolled in an observational study at the National Institutes of Health starting in 2008 and were evaluated in a GIST clinic held once or twice yearly. Patients provided access to existing medical records and tumor specimens. Self-referred or physician-referred patients younger than 19 years with GIST or 19 years or older with known WT GIST (no mutations in KIT or PDGFRA) were recruited; 116 patients with WT GIST were enrolled, and 95 had adequate tumor specimen available. Tumors were characterized by immunohistochemical analysis (IHC) for succinate dehydrogenase (SDH) subunit B, sequencing of SDH genes, and determination of SDHC promoter methylation. Testing of germline SDH genes was offered to consenting patients and families. MAIN OUTCOMES AND MEASURES For classification, tumors were characterized by SDHA, B, C, or D (SDHX) mutations and other genetic and epigenetic alterations, including presence of mutations in germline. Clinical characteristics were categorized. RESULTS Wild-type GIST specimens from 95 patients (median age, 23 [range, 7-78] years; 70% female) were classified into 3 molecular subtypes: SDH-competent (n = 11), defined by detection of SDHB by IHC; and 2 types of SDH-deficient GIST (n = 84). Of SDH-deficient tumors, 63 (67%) had SDH mutations, and in 31 of 38 (82%), the SDHX mutation was also present in germline. Twenty-one (22%) SDH-deficient tumors had methylation of the SDHC promoter leading to silencing of expression. Mutations in known cancer-associated pathways were identified in 9 of 11 SDH-competent tumors. Among patients with SDH-mutant tumors, 62% were female (39 of 63), median (range) age was 23 (7-58) years, and approximately 30% presented with metastases (liver [12 of 58], peritoneal [6 of 58], lymph node [15 of 23]). SDHC-epimutant tumors mostly affected young females (20 of 21; median [range] age, 15 [8-50] years), and approximately 40% presented with metastases (liver [7 of 19], peritoneal [1 of 19], lymph node [3 of 8]). SDH-deficient tumors occurred only in the stomach and had an indolent course. CONCLUSIONS AND RELEVANCE An observational study of WT GIST permitted the evaluation of a large number of patients with this rare disease. Three molecular subtypes with implications for prognosis and clinical management were identified.
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Affiliation(s)
- Sosipatros A Boikos
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland2now with Sarcoma and Rare Tumors Program, Division of Hematology, Oncology, and Palliative Care, Massey Cancer Center, Virginia Commonwealth University, R
| | - Alberto S Pappo
- Department of Oncology, St Jude Children's Research Hospital, Memphis, Tennessee
| | - J Keith Killian
- Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
| | - Michael P LaQuaglia
- Pediatric Surgical Service, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Chris B Weldon
- Department of Surgery, Boston Children's Hospital, Boston, Massachusetts
| | - Suzanne George
- Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Jonathan C Trent
- Division of Hematology/Oncology, Department of Medicine, Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida
| | - Margaret von Mehren
- Division of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania
| | - Jennifer A Wright
- Pediatric Hematology and Oncology, Huntsman Cancer Institute, Salt Lake City, Utah
| | - Josh D Schiffman
- Pediatric Hematology and Oncology, Huntsman Cancer Institute, Salt Lake City, Utah
| | - Margarita Raygada
- Division of Intramural Research, National Institute of Child Health and Human Development, Bethesda, Maryland
| | - Karel Pacak
- Section of Medical Neuroendocrinology, National Institute of Child Health and Human Development, Bethesda, Maryland
| | - Paul S Meltzer
- Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
| | - Markku M Miettinen
- Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
| | - Constantine Stratakis
- Section of Endocrinology and Genetics, National Institute of Child Health and Human Development, Bethesda, Maryland
| | - Katherine A Janeway
- Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, Massachusetts
| | - Lee J Helman
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
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Scollon S, Anglin AK, Thomas M, Turner JT, Wolfe Schneider K. A Comprehensive Review of Pediatric Tumors and Associated Cancer Predisposition Syndromes. J Genet Couns 2017; 26:387-434. [PMID: 28357779 DOI: 10.1007/s10897-017-0077-8] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2016] [Accepted: 01/30/2017] [Indexed: 12/11/2022]
Abstract
An understanding of the role of inherited cancer predisposition syndromes in pediatric tumor diagnoses continues to develop as more information is learned through the application of genomic technology. Identifying patients and their relatives at an increased risk for developing cancer is an important step in the care of this patient population. The purpose of this review is to highlight various tumor types that arise in the pediatric population and the cancer predisposition syndromes associated with those tumors. The review serves as a guide for recognizing genes and conditions to consider when a pediatric cancer referral presents to the genetics clinic.
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Affiliation(s)
- Sarah Scollon
- Department of Pediatrics, Baylor College of Medicine, Texas Children's Cancer Center, Texas Children's Hospital, 1102 Bates St, FC 1200, Houston, TX, 77030, USA.
| | | | | | - Joyce T Turner
- Department of Genetics and Metabolism, Children's National Medical Center, Washington, DC, USA
| | - Kami Wolfe Schneider
- Department of Pediatrics, University of Colorado, Center for Cancer and Blood Disorders, Children's Hospital Colorado, Aurora, CO, USA
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36
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Ricci R. Syndromic gastrointestinal stromal tumors. Hered Cancer Clin Pract 2016; 14:15. [PMID: 27437068 PMCID: PMC4950812 DOI: 10.1186/s13053-016-0055-4] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2016] [Accepted: 06/09/2016] [Indexed: 12/28/2022] Open
Abstract
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of gastrointestinal tract. They feature heterogeneous triggering mechanisms, implying relevant clinical differences. The vast majority of GISTs are sporadic tumors. Rarely, however, GIST-prone syndromes occur, mostly depending on heritable GIST predisposing molecular defects involving the entire organism. These conditions need to be properly identified in order to plan appropriate diagnostic, prognostic and therapeutic procedures. Clinically, GIST-prone syndromes must be thought of whenever GISTs are multiple and/or associated with accompanying signs peculiar to the background tumorigenic trigger, either in single individuals or in kindreds. Moreover, syndromic GISTs, individually considered, tend to show distinctive features depending on the underlying condition. When applicable, genotyping is usually confirmatory. In GIST-prone conditions, the prognostic features of each GIST, defined according to the criteria routinely applied to sporadic GISTs, combine with the characters proper to the background syndromes, defining peculiar clinical settings which challenge physicians to undertake complex decisions. The latter concern preventive therapy and single tumor therapy, implying possible surgical and molecularly targeted options. In the absence of specific comprehensive guidelines, this review will highlight the traits characteristic of GIST-predisposing syndromes, with particular emphasis on diagnostic, prognostic and therapeutic implications, which can help the clinical management of these rare diseases.
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Affiliation(s)
- Riccardo Ricci
- Department of Pathology, Università Cattolica del S. Cuore, Largo Agostino Gemelli, 8, I-00168 Rome, Italy
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37
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Use of monoclonal antibodies to detect specific mutations in formalin-fixed, paraffin-embedded tissue sections. Hum Pathol 2016; 53:168-77. [DOI: 10.1016/j.humpath.2016.03.013] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2016] [Revised: 03/10/2016] [Accepted: 03/12/2016] [Indexed: 02/08/2023]
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38
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Pillai S, Gopalan V, Smith RA, Lam AKY. Updates on the genetics and the clinical impacts on phaeochromocytoma and paraganglioma in the new era. Crit Rev Oncol Hematol 2016; 100:190-208. [DOI: 10.1016/j.critrevonc.2016.01.022] [Citation(s) in RCA: 83] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2015] [Revised: 11/13/2015] [Accepted: 01/20/2016] [Indexed: 12/18/2022] Open
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Taghavi K, Feltham J, Schroeder D, Dhabuwala A. Paediatric gastrointestinal stromal tumours: a pictorial update. ANZ J Surg 2015; 88:E334-E335. [PMID: 26470997 DOI: 10.1111/ans.13333] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Affiliation(s)
- Kiarash Taghavi
- Department of General Surgery, Hutt Hospital, Lower Hutt, New Zealand
| | - Joe Feltham
- Pacific Radiology, Wellington Hospital, Wellington, New Zealand
| | | | - Atul Dhabuwala
- Department of General Surgery, Hutt Hospital, Lower Hutt, New Zealand.,General Surgical Service, Boulcott Hospital, Lower Hutt, New Zealand
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40
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Combined PET/CT by 18F-FDOPA, 18F-FDA, 18F-FDG, and MRI correlation on a patient with Carney triad. Clin Nucl Med 2015; 40:70-2. [PMID: 25423347 DOI: 10.1097/rlu.0000000000000616] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Carney triad is a rare syndrome involving gastrointestinal stromal tumor, pulmonary chondroma, and extra-adrenal paraganglioma. We present a 21-year-old woman with the complete triad who was evaluated with MRI, F-FDOPA, F-FDA, and F-FDG. F-FDOPA best demonstrated the paraganglioma, whereas hepatic metastases noted by MRI demonstrated increased uptake only by F-FDG.
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41
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Killian JK, Miettinen M, Walker RL, Wang Y, Zhu YJ, Waterfall JJ, Noyes N, Retnakumar P, Yang Z, Smith WI, Killian MS, Lau CC, Pineda M, Walling J, Stevenson H, Smith C, Wang Z, Lasota J, Kim SY, Boikos SA, Helman LJ, Meltzer PS. Recurrent epimutation of SDHC in gastrointestinal stromal tumors. Sci Transl Med 2015; 6:268ra177. [PMID: 25540324 DOI: 10.1126/scitranslmed.3009961] [Citation(s) in RCA: 140] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Succinate dehydrogenase (SDH) is a conserved effector of cellular metabolism and energy production, and loss of SDH function is a driver mechanism in several cancers. SDH-deficient gastrointestinal stromal tumors (dSDH GISTs) collectively manifest similar phenotypes, including hypermethylated epigenomic signatures, tendency to occur in pediatric patients, and lack of KIT/PDGFRA mutations. dSDH GISTs often harbor deleterious mutations in SDH subunit genes (SDHA, SDHB, SDHC, and SDHD, termed SDHx), but some are SDHx wild type (WT). To further elucidate mechanisms of SDH deactivation in SDHx-WT GIST, we performed targeted exome sequencing on 59 dSDH GISTs to identify 43 SDHx-mutant and 16 SDHx-WT cases. Genome-wide DNA methylation and expression profiling exposed SDHC promoter-specific CpG island hypermethylation and gene silencing in SDHx-WT dSDH GISTs [15 of 16 cases (94%)]. Six of 15 SDHC-epimutant GISTs occurred in the setting of the multitumor syndrome Carney triad. We observed neither SDHB promoter hypermethylation nor large deletions on chromosome 1q in any SDHx-WT cases. Deep genome sequencing of a 130-kbp (kilo-base pair) window around SDHC revealed no recognizable sequence anomalies in SDHC-epimutant tumors. More than 2000 benign and tumor reference tissues, including stem cells and malignancies with a hypermethylator epigenotype, exhibit solely a non-epimutant SDHC promoter. Mosaic constitutional SDHC promoter hypermethylation in blood and saliva from patients with SDHC-epimutant GIST implicates a postzygotic mechanism in the establishment and maintenance of SDHC epimutation. The discovery of SDHC epimutation provides a unifying explanation for the pathogenesis of dSDH GIST, whereby loss of SDH function stems from either SDHx mutation or SDHC epimutation.
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Affiliation(s)
- J Keith Killian
- Genetics Branch, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD 20892, USA
| | - Markku Miettinen
- Laboratory of Pathology, Center for Cancer Research, NIH, Bethesda, MD 20892, USA
| | - Robert L Walker
- Genetics Branch, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD 20892, USA
| | - Yonghong Wang
- Genetics Branch, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD 20892, USA
| | - Yuelin Jack Zhu
- Genetics Branch, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD 20892, USA
| | - Joshua J Waterfall
- Genetics Branch, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD 20892, USA
| | - Natalia Noyes
- Genetics Branch, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD 20892, USA
| | - Parvathy Retnakumar
- Genetics Branch, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD 20892, USA
| | - Zhiming Yang
- Laboratory of Pathology, Center for Cancer Research, NIH, Bethesda, MD 20892, USA
| | - William I Smith
- Department of Pathology, Suburban Hospital, Bethesda, MD 20814, USA
| | | | - C Christopher Lau
- Genetics Branch, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD 20892, USA
| | - Marbin Pineda
- Genetics Branch, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD 20892, USA
| | - Jennifer Walling
- Genetics Branch, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD 20892, USA
| | - Holly Stevenson
- Genetics Branch, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD 20892, USA
| | - Carly Smith
- National Heart Lung and Blood Institute, NIH, Bethesda, MD 20892, USA
| | - Zengfeng Wang
- Laboratory of Pathology, Center for Cancer Research, NIH, Bethesda, MD 20892, USA
| | - Jerzy Lasota
- Laboratory of Pathology, Center for Cancer Research, NIH, Bethesda, MD 20892, USA
| | - Su Young Kim
- Pediatric Oncology Branch, Center for Cancer Research, NIH, Bethesda, MD 20892, USA
| | - Sosipatros A Boikos
- Pediatric Oncology Branch, Center for Cancer Research, NIH, Bethesda, MD 20892, USA
| | - Lee J Helman
- Pediatric Oncology Branch, Center for Cancer Research, NIH, Bethesda, MD 20892, USA
| | - Paul S Meltzer
- Genetics Branch, National Cancer Institute, National Institutes of Health (NIH), Bethesda, MD 20892, USA.
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Carney triad can be (rarely) associated with germline succinate dehydrogenase defects. Eur J Hum Genet 2015; 24:569-73. [PMID: 26173966 DOI: 10.1038/ejhg.2015.142] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2015] [Revised: 05/15/2015] [Accepted: 05/27/2015] [Indexed: 12/15/2022] Open
Abstract
Carney triad, the association of paragangliomas/pheochromocytomas, gastrointestinal stromal tumors and pulmonary chondromas, is a sporadic condition that is significantly more frequent in females; its genetic etiology remains unknown. Carney triad is distinct from the dyad of paragangliomas/pheochromocytomas and gastrointestinal stromal tumors, known as Carney-Stratakis syndrome, which is inherited in an autosomal- dominant manner and is almost always caused by succinate dehydrogenase subunit mutations. In the present study, we investigated the largest cohort of Carney triad patients that is available internationally: 63 unrelated patients. Six patients (9.5%) were found to have germline variants in the SDHA, SDHB or SDHC genes. All six patients, except one, had multifocal gastrointestinal stromal tumors, chondromas and/or paragangliomas. A patient with Carney triad and SDHC variant had a ganglioneuroma. One of the patients with Carney triad and SDHB mutation had a nephew with the same sequence defect, who developed a neuroblastoma. Other relatives, carriers of the identified SDHA, SDHB or SDHC mutations, have not developed any of the components of Carney triad or Carney-Stratakis syndrome. None of the other 57 Carney triad patients had any genomic defects of SDHA, SDHB or SDHC genes. We conclude that, in rare occasions, Carney triad can be allelic to Carney-Stratakis syndrome. Although for the vast majority of patients with Carney triad the causative defect(s) remain(s) unknown, testing for SDHA, SDHB or SDHC variations should be offered, as carriers may develop isolated paragangliomas/pheochromocytomas and occasionally other tumors.
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43
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Abstract
Approximately 85-90% of adult gastrointestinal stromal tumors (GISTs) harbor KIT and PDGFRA mutations. The remaining cases, including the majority of pediatric GISTs, lack these mutations, and have been designated as KIT/PDGFRA wild-type (WT) GISTs. Nearly 15% of WT GISTs harbor BRAF mutations, while others arise in patients with type I neurofibromatosis. Recent work has confirmed that 20-40% of KIT/PDGFRA WT GISTs show loss of function of succinate dehydrogenase complex. Less than 5% of GISTs lack known molecular alterations ("quadruple-negative" GISTs). Thus, it is important to consider genotyping these tumors to help better define their clinical behavior and therapy.
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Affiliation(s)
- Deepa T Patil
- Department of Pathology, Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic, 9500 Euclid Avenue, L-25, Cleveland, OH 44195, USA.
| | - Brian P Rubin
- Department of Pathology, Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic, 9500 Euclid Avenue, L-25, Cleveland, OH 44195, USA; Department of Molecular Genetics, Cleveland Clinic and Lerner Research Institute, 9500 Euclid Avenue, L-25, Cleveland, OH 44195, USA
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44
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Szarek E, Ball ER, Imperiale A, Tsokos M, Faucz FR, Giubellino A, Moussallieh FM, Namer IJ, Abu-Asab MS, Pacak K, Taïeb D, Carney JA, Stratakis CA. Carney triad, SDH-deficient tumors, and Sdhb+/- mice share abnormal mitochondria. Endocr Relat Cancer 2015; 22:345-52. [PMID: 25808178 PMCID: PMC4433412 DOI: 10.1530/erc-15-0069] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/25/2015] [Indexed: 12/20/2022]
Abstract
Carney triad (CTr) describes the association of paragangliomas (PGL), pulmonary chondromas, and gastrointestinal (GI) stromal tumors (GISTs) with a variety of other lesions, including pheochromocytomas and adrenocortical tumors. The gene(s) that cause CTr remain(s) unknown. PGL and GISTs may be caused by loss-of-function mutations in succinate dehydrogenase (SDH) (a condition known as Carney-Stratakis syndrome (CSS)). Mitochondrial structure and function are abnormal in tissues that carry SDH defects, but they have not been studied in CTr. For the present study, we examined mitochondrial structure in human tumors and GI tissue (GIT) of mice with SDH deficiency. Tissues from 16 CTr tumors (n=12), those with isolated GIST (n=1), and those with CSS caused by SDHC (n=1) and SDHD (n=2) mutations were studied by electron microscopy (EM). Samples of GIT from mice with a heterozygous deletion in Sdhb (Sdhb(+) (/-), n=4) were also studied by EM. CTr patients presented with mostly epithelioid GISTs that were characterized by plump cells containing a centrally located, round nucleus and prominent nucleoli; these changes were almost identical to those seen in the GISTs of patients with SDH. In tumor cells from patients, regardless of diagnosis or tumor type, cytoplasm contained an increased number of mitochondria with a 'hypoxic' phenotype: mitochondria were devoid of cristae, exhibited structural abnormalities, and were of variable size. Occasionally, mitochondria were small and round; rarely, they were thin and elongated with tubular cristae. Many mitochondria exhibited amorphous fluffy material with membranous whorls or cystic structures. A similar mitochondrial hypoxic phenotype was seen in Sdhb(+) (/-) mice. We concluded that tissues from SDH-deficient tumors, those from mouse GIT, and those from CTr tumors shared identical abnormalities in mitochondrial structure and other features. Thus, the still-elusive CTr defect(s) is(are) likely to affect mitochondrial function, just like germline SDH-deficiency does.
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Affiliation(s)
- Eva Szarek
- Section on Endocrinology and Genetics (SEGEN)Program on Developmental Endocrinology and Genetics (PDEGEN), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Building 10, CRC, Room 1-3330, 10 Center Drive, MSC1103, Bethesda, Maryland 20892, USADepartment of Biophysics and Nuclear MedicineUniversity Hospitals of Strasbourg, Strasbourg, FranceFaculty of MedicineIcube UMR 7357 University of Strasbourg/CNRS and FMTS, Strasbourg, FranceLaboratory of PathologyNational Cancer Institute (NCI), NIH, Bethesda, Maryland 20892, USASection on Medical Neuroendocrinology (SMN)Program on Reproductive and Adult Endocrinology (PRAE), NICHD, NIH, Bethesda, Maryland 20892, USASection of Immunopathology and Laboratory of ImmunologyNational Eye Institute, U.S. National Institutes of Health, Bethesda, Maryland 20892, USADepartment of Nuclear MedicineLa Timone University Hospital, CERIMED, 264, Rue Saint-Pierre, 13385 Marseille Cedex 5, FranceInstitut Paoli-CalmettesInserm UMR1068 Marseille Cancerology Research Center, Marseille, FranceEmeritus Staff CenterMayo Clinic Rochester, 200 First Street Southwest, Rochester, Minnesota 55905, USA
| | - Evan R Ball
- Section on Endocrinology and Genetics (SEGEN)Program on Developmental Endocrinology and Genetics (PDEGEN), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Building 10, CRC, Room 1-3330, 10 Center Drive, MSC1103, Bethesda, Maryland 20892, USADepartment of Biophysics and Nuclear MedicineUniversity Hospitals of Strasbourg, Strasbourg, FranceFaculty of MedicineIcube UMR 7357 University of Strasbourg/CNRS and FMTS, Strasbourg, FranceLaboratory of PathologyNational Cancer Institute (NCI), NIH, Bethesda, Maryland 20892, USASection on Medical Neuroendocrinology (SMN)Program on Reproductive and Adult Endocrinology (PRAE), NICHD, NIH, Bethesda, Maryland 20892, USASection of Immunopathology and Laboratory of ImmunologyNational Eye Institute, U.S. National Institutes of Health, Bethesda, Maryland 20892, USADepartment of Nuclear MedicineLa Timone University Hospital, CERIMED, 264, Rue Saint-Pierre, 13385 Marseille Cedex 5, FranceInstitut Paoli-CalmettesInserm UMR1068 Marseille Cancerology Research Center, Marseille, FranceEmeritus Staff CenterMayo Clinic Rochester, 200 First Street Southwest, Rochester, Minnesota 55905, USA
| | - Alessio Imperiale
- Section on Endocrinology and Genetics (SEGEN)Program on Developmental Endocrinology and Genetics (PDEGEN), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Building 10, CRC, Room 1-3330, 10 Center Drive, MSC1103, Bethesda, Maryland 20892, USADepartment of Biophysics and Nuclear MedicineUniversity Hospitals of Strasbourg, Strasbourg, FranceFaculty of MedicineIcube UMR 7357 University of Strasbourg/CNRS and FMTS, Strasbourg, FranceLaboratory of PathologyNational Cancer Institute (NCI), NIH, Bethesda, Maryland 20892, USASection on Medical Neuroendocrinology (SMN)Program on Reproductive and Adult Endocrinology (PRAE), NICHD, NIH, Bethesda, Maryland 20892, USASection of Immunopathology and Laboratory of ImmunologyNational Eye Institute, U.S. National Institutes of Health, Bethesda, Maryland 20892, USADepartment of Nuclear MedicineLa Timone University Hospital, CERIMED, 264, Rue Saint-Pierre, 13385 Marseille Cedex 5, FranceInstitut Paoli-CalmettesInserm UMR1068 Marseille Cancerology Research Center, Marseille, FranceEmeritus Staff CenterMayo Clinic Rochester, 200 First Street Southwest, Rochester, Minnesota 55905, USA Section on Endocrinology and Genetics (SEGEN)Program on Developmental Endocrinology and Genetics (PDEGEN), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Building 10, CRC, Room 1-3330, 10 Center Drive, MSC1103, Bethesda, Maryland 20892, USADepartment of Biophysics and Nuclear MedicineUniversity Hospitals of Strasbourg, Strasbourg, FranceFaculty of MedicineIcube UMR 7357 University of Strasbourg/CNRS and FMTS, Strasbourg, FranceLaboratory of PathologyNational Cancer Institute (NCI), NIH, Bethesda, Maryland 20892, USASection on Medical Neuroendocrinology (SMN)Program on Reproductive and Adult Endocrinology (PRAE), NICHD, NIH, Bethesda, Maryland 20892, USASection of Immunopathology and Laboratory of Immunolo
| | - Maria Tsokos
- Section on Endocrinology and Genetics (SEGEN)Program on Developmental Endocrinology and Genetics (PDEGEN), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Building 10, CRC, Room 1-3330, 10 Center Drive, MSC1103, Bethesda, Maryland 20892, USADepartment of Biophysics and Nuclear MedicineUniversity Hospitals of Strasbourg, Strasbourg, FranceFaculty of MedicineIcube UMR 7357 University of Strasbourg/CNRS and FMTS, Strasbourg, FranceLaboratory of PathologyNational Cancer Institute (NCI), NIH, Bethesda, Maryland 20892, USASection on Medical Neuroendocrinology (SMN)Program on Reproductive and Adult Endocrinology (PRAE), NICHD, NIH, Bethesda, Maryland 20892, USASection of Immunopathology and Laboratory of ImmunologyNational Eye Institute, U.S. National Institutes of Health, Bethesda, Maryland 20892, USADepartment of Nuclear MedicineLa Timone University Hospital, CERIMED, 264, Rue Saint-Pierre, 13385 Marseille Cedex 5, FranceInstitut Paoli-CalmettesInserm UMR1068 Marseille Cancerology Research Center, Marseille, FranceEmeritus Staff CenterMayo Clinic Rochester, 200 First Street Southwest, Rochester, Minnesota 55905, USA
| | - Fabio R Faucz
- Section on Endocrinology and Genetics (SEGEN)Program on Developmental Endocrinology and Genetics (PDEGEN), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Building 10, CRC, Room 1-3330, 10 Center Drive, MSC1103, Bethesda, Maryland 20892, USADepartment of Biophysics and Nuclear MedicineUniversity Hospitals of Strasbourg, Strasbourg, FranceFaculty of MedicineIcube UMR 7357 University of Strasbourg/CNRS and FMTS, Strasbourg, FranceLaboratory of PathologyNational Cancer Institute (NCI), NIH, Bethesda, Maryland 20892, USASection on Medical Neuroendocrinology (SMN)Program on Reproductive and Adult Endocrinology (PRAE), NICHD, NIH, Bethesda, Maryland 20892, USASection of Immunopathology and Laboratory of ImmunologyNational Eye Institute, U.S. National Institutes of Health, Bethesda, Maryland 20892, USADepartment of Nuclear MedicineLa Timone University Hospital, CERIMED, 264, Rue Saint-Pierre, 13385 Marseille Cedex 5, FranceInstitut Paoli-CalmettesInserm UMR1068 Marseille Cancerology Research Center, Marseille, FranceEmeritus Staff CenterMayo Clinic Rochester, 200 First Street Southwest, Rochester, Minnesota 55905, USA
| | - Alessio Giubellino
- Section on Endocrinology and Genetics (SEGEN)Program on Developmental Endocrinology and Genetics (PDEGEN), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Building 10, CRC, Room 1-3330, 10 Center Drive, MSC1103, Bethesda, Maryland 20892, USADepartment of Biophysics and Nuclear MedicineUniversity Hospitals of Strasbourg, Strasbourg, FranceFaculty of MedicineIcube UMR 7357 University of Strasbourg/CNRS and FMTS, Strasbourg, FranceLaboratory of PathologyNational Cancer Institute (NCI), NIH, Bethesda, Maryland 20892, USASection on Medical Neuroendocrinology (SMN)Program on Reproductive and Adult Endocrinology (PRAE), NICHD, NIH, Bethesda, Maryland 20892, USASection of Immunopathology and Laboratory of ImmunologyNational Eye Institute, U.S. National Institutes of Health, Bethesda, Maryland 20892, USADepartment of Nuclear MedicineLa Timone University Hospital, CERIMED, 264, Rue Saint-Pierre, 13385 Marseille Cedex 5, FranceInstitut Paoli-CalmettesInserm UMR1068 Marseille Cancerology Research Center, Marseille, FranceEmeritus Staff CenterMayo Clinic Rochester, 200 First Street Southwest, Rochester, Minnesota 55905, USA
| | - François-Marie Moussallieh
- Section on Endocrinology and Genetics (SEGEN)Program on Developmental Endocrinology and Genetics (PDEGEN), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Building 10, CRC, Room 1-3330, 10 Center Drive, MSC1103, Bethesda, Maryland 20892, USADepartment of Biophysics and Nuclear MedicineUniversity Hospitals of Strasbourg, Strasbourg, FranceFaculty of MedicineIcube UMR 7357 University of Strasbourg/CNRS and FMTS, Strasbourg, FranceLaboratory of PathologyNational Cancer Institute (NCI), NIH, Bethesda, Maryland 20892, USASection on Medical Neuroendocrinology (SMN)Program on Reproductive and Adult Endocrinology (PRAE), NICHD, NIH, Bethesda, Maryland 20892, USASection of Immunopathology and Laboratory of ImmunologyNational Eye Institute, U.S. National Institutes of Health, Bethesda, Maryland 20892, USADepartment of Nuclear MedicineLa Timone University Hospital, CERIMED, 264, Rue Saint-Pierre, 13385 Marseille Cedex 5, FranceInstitut Paoli-CalmettesInserm UMR1068 Marseille Cancerology Research Center, Marseille, FranceEmeritus Staff CenterMayo Clinic Rochester, 200 First Street Southwest, Rochester, Minnesota 55905, USA Section on Endocrinology and Genetics (SEGEN)Program on Developmental Endocrinology and Genetics (PDEGEN), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Building 10, CRC, Room 1-3330, 10 Center Drive, MSC1103, Bethesda, Maryland 20892, USADepartment of Biophysics and Nuclear MedicineUniversity Hospitals of Strasbourg, Strasbourg, FranceFaculty of MedicineIcube UMR 7357 University of Strasbourg/CNRS and FMTS, Strasbourg, FranceLaboratory of PathologyNational Cancer Institute (NCI), NIH, Bethesda, Maryland 20892, USASection on Medical Neuroendocrinology (SMN)Program on Reproductive and Adult Endocrinology (PRAE), NICHD, NIH, Bethesda, Maryland 20892, USASection of Immunopathology and Laboratory of Immunolo
| | - Izzie-Jacques Namer
- Section on Endocrinology and Genetics (SEGEN)Program on Developmental Endocrinology and Genetics (PDEGEN), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Building 10, CRC, Room 1-3330, 10 Center Drive, MSC1103, Bethesda, Maryland 20892, USADepartment of Biophysics and Nuclear MedicineUniversity Hospitals of Strasbourg, Strasbourg, FranceFaculty of MedicineIcube UMR 7357 University of Strasbourg/CNRS and FMTS, Strasbourg, FranceLaboratory of PathologyNational Cancer Institute (NCI), NIH, Bethesda, Maryland 20892, USASection on Medical Neuroendocrinology (SMN)Program on Reproductive and Adult Endocrinology (PRAE), NICHD, NIH, Bethesda, Maryland 20892, USASection of Immunopathology and Laboratory of ImmunologyNational Eye Institute, U.S. National Institutes of Health, Bethesda, Maryland 20892, USADepartment of Nuclear MedicineLa Timone University Hospital, CERIMED, 264, Rue Saint-Pierre, 13385 Marseille Cedex 5, FranceInstitut Paoli-CalmettesInserm UMR1068 Marseille Cancerology Research Center, Marseille, FranceEmeritus Staff CenterMayo Clinic Rochester, 200 First Street Southwest, Rochester, Minnesota 55905, USA Section on Endocrinology and Genetics (SEGEN)Program on Developmental Endocrinology and Genetics (PDEGEN), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Building 10, CRC, Room 1-3330, 10 Center Drive, MSC1103, Bethesda, Maryland 20892, USADepartment of Biophysics and Nuclear MedicineUniversity Hospitals of Strasbourg, Strasbourg, FranceFaculty of MedicineIcube UMR 7357 University of Strasbourg/CNRS and FMTS, Strasbourg, FranceLaboratory of PathologyNational Cancer Institute (NCI), NIH, Bethesda, Maryland 20892, USASection on Medical Neuroendocrinology (SMN)Program on Reproductive and Adult Endocrinology (PRAE), NICHD, NIH, Bethesda, Maryland 20892, USASection of Immunopathology and Laboratory of Immunolo
| | - Mones S Abu-Asab
- Section on Endocrinology and Genetics (SEGEN)Program on Developmental Endocrinology and Genetics (PDEGEN), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Building 10, CRC, Room 1-3330, 10 Center Drive, MSC1103, Bethesda, Maryland 20892, USADepartment of Biophysics and Nuclear MedicineUniversity Hospitals of Strasbourg, Strasbourg, FranceFaculty of MedicineIcube UMR 7357 University of Strasbourg/CNRS and FMTS, Strasbourg, FranceLaboratory of PathologyNational Cancer Institute (NCI), NIH, Bethesda, Maryland 20892, USASection on Medical Neuroendocrinology (SMN)Program on Reproductive and Adult Endocrinology (PRAE), NICHD, NIH, Bethesda, Maryland 20892, USASection of Immunopathology and Laboratory of ImmunologyNational Eye Institute, U.S. National Institutes of Health, Bethesda, Maryland 20892, USADepartment of Nuclear MedicineLa Timone University Hospital, CERIMED, 264, Rue Saint-Pierre, 13385 Marseille Cedex 5, FranceInstitut Paoli-CalmettesInserm UMR1068 Marseille Cancerology Research Center, Marseille, FranceEmeritus Staff CenterMayo Clinic Rochester, 200 First Street Southwest, Rochester, Minnesota 55905, USA
| | - Karel Pacak
- Section on Endocrinology and Genetics (SEGEN)Program on Developmental Endocrinology and Genetics (PDEGEN), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Building 10, CRC, Room 1-3330, 10 Center Drive, MSC1103, Bethesda, Maryland 20892, USADepartment of Biophysics and Nuclear MedicineUniversity Hospitals of Strasbourg, Strasbourg, FranceFaculty of MedicineIcube UMR 7357 University of Strasbourg/CNRS and FMTS, Strasbourg, FranceLaboratory of PathologyNational Cancer Institute (NCI), NIH, Bethesda, Maryland 20892, USASection on Medical Neuroendocrinology (SMN)Program on Reproductive and Adult Endocrinology (PRAE), NICHD, NIH, Bethesda, Maryland 20892, USASection of Immunopathology and Laboratory of ImmunologyNational Eye Institute, U.S. National Institutes of Health, Bethesda, Maryland 20892, USADepartment of Nuclear MedicineLa Timone University Hospital, CERIMED, 264, Rue Saint-Pierre, 13385 Marseille Cedex 5, FranceInstitut Paoli-CalmettesInserm UMR1068 Marseille Cancerology Research Center, Marseille, FranceEmeritus Staff CenterMayo Clinic Rochester, 200 First Street Southwest, Rochester, Minnesota 55905, USA
| | - David Taïeb
- Section on Endocrinology and Genetics (SEGEN)Program on Developmental Endocrinology and Genetics (PDEGEN), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Building 10, CRC, Room 1-3330, 10 Center Drive, MSC1103, Bethesda, Maryland 20892, USADepartment of Biophysics and Nuclear MedicineUniversity Hospitals of Strasbourg, Strasbourg, FranceFaculty of MedicineIcube UMR 7357 University of Strasbourg/CNRS and FMTS, Strasbourg, FranceLaboratory of PathologyNational Cancer Institute (NCI), NIH, Bethesda, Maryland 20892, USASection on Medical Neuroendocrinology (SMN)Program on Reproductive and Adult Endocrinology (PRAE), NICHD, NIH, Bethesda, Maryland 20892, USASection of Immunopathology and Laboratory of ImmunologyNational Eye Institute, U.S. National Institutes of Health, Bethesda, Maryland 20892, USADepartment of Nuclear MedicineLa Timone University Hospital, CERIMED, 264, Rue Saint-Pierre, 13385 Marseille Cedex 5, FranceInstitut Paoli-CalmettesInserm UMR1068 Marseille Cancerology Research Center, Marseille, FranceEmeritus Staff CenterMayo Clinic Rochester, 200 First Street Southwest, Rochester, Minnesota 55905, USA Section on Endocrinology and Genetics (SEGEN)Program on Developmental Endocrinology and Genetics (PDEGEN), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Building 10, CRC, Room 1-3330, 10 Center Drive, MSC1103, Bethesda, Maryland 20892, USADepartment of Biophysics and Nuclear MedicineUniversity Hospitals of Strasbourg, Strasbourg, FranceFaculty of MedicineIcube UMR 7357 University of Strasbourg/CNRS and FMTS, Strasbourg, FranceLaboratory of PathologyNational Cancer Institute (NCI), NIH, Bethesda, Maryland 20892, USASection on Medical Neuroendocrinology (SMN)Program on Reproductive and Adult Endocrinology (PRAE), NICHD, NIH, Bethesda, Maryland 20892, USASection of Immunopathology and Laboratory of Immunolo
| | - J Aidan Carney
- Section on Endocrinology and Genetics (SEGEN)Program on Developmental Endocrinology and Genetics (PDEGEN), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Building 10, CRC, Room 1-3330, 10 Center Drive, MSC1103, Bethesda, Maryland 20892, USADepartment of Biophysics and Nuclear MedicineUniversity Hospitals of Strasbourg, Strasbourg, FranceFaculty of MedicineIcube UMR 7357 University of Strasbourg/CNRS and FMTS, Strasbourg, FranceLaboratory of PathologyNational Cancer Institute (NCI), NIH, Bethesda, Maryland 20892, USASection on Medical Neuroendocrinology (SMN)Program on Reproductive and Adult Endocrinology (PRAE), NICHD, NIH, Bethesda, Maryland 20892, USASection of Immunopathology and Laboratory of ImmunologyNational Eye Institute, U.S. National Institutes of Health, Bethesda, Maryland 20892, USADepartment of Nuclear MedicineLa Timone University Hospital, CERIMED, 264, Rue Saint-Pierre, 13385 Marseille Cedex 5, FranceInstitut Paoli-CalmettesInserm UMR1068 Marseille Cancerology Research Center, Marseille, FranceEmeritus Staff CenterMayo Clinic Rochester, 200 First Street Southwest, Rochester, Minnesota 55905, USA
| | - Constantine A Stratakis
- Section on Endocrinology and Genetics (SEGEN)Program on Developmental Endocrinology and Genetics (PDEGEN), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Building 10, CRC, Room 1-3330, 10 Center Drive, MSC1103, Bethesda, Maryland 20892, USADepartment of Biophysics and Nuclear MedicineUniversity Hospitals of Strasbourg, Strasbourg, FranceFaculty of MedicineIcube UMR 7357 University of Strasbourg/CNRS and FMTS, Strasbourg, FranceLaboratory of PathologyNational Cancer Institute (NCI), NIH, Bethesda, Maryland 20892, USASection on Medical Neuroendocrinology (SMN)Program on Reproductive and Adult Endocrinology (PRAE), NICHD, NIH, Bethesda, Maryland 20892, USASection of Immunopathology and Laboratory of ImmunologyNational Eye Institute, U.S. National Institutes of Health, Bethesda, Maryland 20892, USADepartment of Nuclear MedicineLa Timone University Hospital, CERIMED, 264, Rue Saint-Pierre, 13385 Marseille Cedex 5, FranceInstitut Paoli-CalmettesInserm UMR1068 Marseille Cancerology Research Center, Marseille, FranceEmeritus Staff CenterMayo Clinic Rochester, 200 First Street Southwest, Rochester, Minnesota 55905, USA
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Lin G, Doyle LA. An update on the application of newly described immunohistochemical markers in soft tissue pathology. Arch Pathol Lab Med 2015; 139:106-21. [PMID: 25549147 DOI: 10.5858/arpa.2014-0488-ra] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
CONTEXT During the last 5 to 10 years, significant progress has been made in the molecular characterization of soft tissue tumors, predominantly with the identification of recurrent translocations or amplification of certain genes in different tumor types. Alongside this, translational efforts have identified many novel and diagnostically useful immunohistochemical markers for many of these tumor types. OBJECTIVE This article reviews a select group of recently described immunohistochemical markers of particular use in the evaluation of mesenchymal neoplasms; the underlying biology of the protein product, practical utility, and limitations of each marker are discussed in detail. DATA SOURCES Literature review, authors' research data, and personal practice experience serve as sources. CONCLUSIONS There are many diagnostically useful immunohistochemical markers to help confirm the diagnosis of many different soft tissue tumor types, some of which have reduced the need for additional, and more costly, studies, such as fluorescence in situ hybridization. However, no one marker is 100% specific for a given tumor, and knowledge of potential pitfalls and overlap in patterns of staining among other tumor types is crucial to ensure the appropriate application of these markers in clinical practice.
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Affiliation(s)
- George Lin
- From the Department of Laboratory Medicine, Geisinger Medical Center, Danville, Pennsylvania (Dr Lin); and the Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts (Dr Doyle)
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Abstract
PURPOSE OF REVIEW Knowledge related to gastrointestinal stromal tumor (GIST) in the setting of nonhereditary and hereditary multiple tumor syndromes continues to expand. This review describes associations between sporadic GIST and second malignancies, as well as new contributions to our knowledge about hereditary GIST multiple tumor syndromes. RECENT FINDINGS Sporadic GIST patients have increased risk of developing synchronous/metachronous cancers, including nonhematologic and hematologic malignancies. Data suggest these associations are nonrandom, more prevalent in men and increase with age. New adrenal tumors have also been associated with nonhereditary Carney's triad. Meanwhile, understanding of the molecular basis of heritable GIST syndromes has improved. Several new familial GIST kindreds have been reported, including those with germline KIT and PDGFRα mutations. Knowledge about succinate dehydrogenase (SDH) deficiency and mutations in hereditary GIST syndromes has expanded. It is now known that neurofibromatosis-1-associated GISTs are SDHB-positive, whereas Carney-Stratakis syndrome-associated GISTs are SDHB-deficient with underlying germline mutations in SDH subunits A-D. SUMMARY Recognition and early diagnosis of GIST syndromes allows for improved comprehensive medical care. With additional understanding of the molecular pathogenesis of GIST multiple tumor syndromes, we can refine our screening programs and management of these patients and their families.
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Boikos SA, Stratakis CA. The genetic landscape of gastrointestinal stromal tumor lacking KIT and PDGFRA mutations. Endocrine 2014; 47:401-8. [PMID: 25027296 PMCID: PMC4729312 DOI: 10.1007/s12020-014-0346-3] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2014] [Accepted: 06/24/2014] [Indexed: 12/17/2022]
Abstract
About 10-15 % of adult gastrointestinal stromal tumors (GISTs) and 85 % of pediatric GISTs do not have mutations in the KIT or PDGFRA genes and are generally classified as KIT/PDGFRA wild type (WT). Recent studies have shown that this group of KIT/PDGFRA WT GISTs is quite heterogeneous in terms of clinical phenotype, genetic etiology, and molecular pathways. Succinate dehydrogenase subunit (SDH)-deficient GISTs, which include tumors that are part of multiple endocrine neoplasia syndromes, are the newest group of KIT/PDGFRA WT GIST to be molecularly elucidated. This review aims to describe the different genetic subgroups of KIT/PDGFRA WT GIST, with a special focus on the SDH-deficient GIST.
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Affiliation(s)
- Sosipatros A Boikos
- The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA,
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Jové M, Mora J, Sanjuan X, Rodriguez E, Robledo M, Farran L, Garcia del Muro X. Simultaneous KIT mutation and succinate dehydrogenase (SDH) deficiency in a patient with a gastrointestinal stromal tumour and Carney-Stratakis syndrome: a case report. Histopathology 2014; 65:712-7. [DOI: 10.1111/his.12506] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Affiliation(s)
- Maria Jové
- Department of Medical Oncology; Institut Català d'Oncologia; L'Hospitalet de Llobregat; Barcelona Spain
| | - Jaume Mora
- Department of Pediatric Oncology; Hospital Sant Joan de Déu (HSJD); Barcelona Spain
| | - Xavier Sanjuan
- Department of Pathology; Hospital Universitari de Bellvitge; L'Hospitalet de Llobregat; Barcelona Spain
| | - Eva Rodriguez
- Department of Pediatric Oncology; Hospital Sant Joan de Déu (HSJD); Barcelona Spain
| | - Mercedes Robledo
- Hereditary Endocrine Cancer, Group Leader, Human Cancer Genetics Programme; Spanish National Cancer Centre (CNIO); Madrid Spain
| | - Leandre Farran
- Department of Surgery; Hospital Universitari de Bellvitge; L'Hospitalet de Llobregat; Barcelona Spain
| | - Xavier Garcia del Muro
- Department of Medical Oncology; Institut Català d'Oncologia; L'Hospitalet de Llobregat; Barcelona Spain
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LeBlanc M, Tabrizi M, Kapsner P, Hanson JA. Synchronous adrenocortical neoplasms, paragangliomas, and pheochromocytomas: syndromic considerations regarding an unusual constellation of endocrine tumors. Hum Pathol 2014; 45:2502-6. [PMID: 25288237 DOI: 10.1016/j.humpath.2014.08.011] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2014] [Revised: 08/09/2014] [Accepted: 08/13/2014] [Indexed: 11/19/2022]
Abstract
The most common clinical syndromes presenting with paragangliomas and/or pheochromocytomas as their endocrine components are multiple endocrine neoplasia type 2, neurofibromatosis, Von Hippel-Lindau syndrome, Carney-Stratakis syndrome, Carney triad, and the recently described hereditary paraganglioma syndrome. Only Carney triad is known to also present with adrenocortical adenomas, currently representing the only described syndrome in which all 3 of the aforementioned tumors are found together. In most cases, prototypical lesions of the triad such as gastrointestinal stromal tumor and pulmonary chondromas are also seen. We present a case of a young woman with synchronous paragangliomas, adrenal/extra-adrenal cortical neoplasms, and pheochromocytoma without genetic mutations for multiple endocrine neoplasia 2, Von Hippel-Lindau syndrome, neurofibromatosis, and succinate dehydrogenase. We speculate that this represents a previously undescribed presentation of Carney triad and, at the very least, indicates the need for monitoring for the development of other tumors of the triad.
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Affiliation(s)
- Melissa LeBlanc
- Department of Pathology, University of New Mexico School of Medicine, Albuquerque, NM 87131
| | - Mohsen Tabrizi
- Department of Endocrinology, Diabetes, and Metabolism, University of New Mexico School of Medicine, Albuquerque, NM 87131
| | - Patricia Kapsner
- Department of Endocrinology, Diabetes, and Metabolism, University of New Mexico School of Medicine, Albuquerque, NM 87131
| | - Joshua Anspach Hanson
- Department of Pathology, University of New Mexico School of Medicine, Albuquerque, NM 87131.
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Abstract
Gastrointestinal stromal tumor (GIST) is the most common sarcoma of the intestinal tract. Nearly all tumors have a mutation in the KIT or, less often, platelet-derived growth factor receptor (PDGFRA) or B-rapidly Accelerated Fibrosarcoma (BRAF) gene. The discovery of constitutive KIT activation as the central mechanism of GIST pathogenesis, suggested that inhibiting or blocking KIT signaling might be the milestone in the targeted therapy of GISTs. Indeed, imatinib mesylate inhibits KIT kinase activity and represents the front line drug for the treatment of unresectable and advanced GISTs, achieving a partial response or stable disease in about 80% of patients with metastatic GIST. KIT mutation status has a significant impact on treatment response. Patients with the most common exon 11 mutation experience higher rates of tumor shrinkage and prolonged survival, as tumors with an exon 9 mutation or wild-type KIT are less likely to respond to imatinib. Although imatinib achieves a partial response or stable disease in the majority of GIST patients, complete and lasting responses are rare. About half of the patients who initially benefit from imatinib treatment eventually develop drug resistance. The most common mechanism of resistance is through polyclonal acquisition of second site mutations in the kinase domain, which highlights the future therapeutic challenges in salvaging these patients after failing kinase inhibitor monotherapies. More recently, sunitinib (Sutent, Pfizer, New York, NY), which inhibits vascular endothelial growth factor receptor (VEGFR) in addition to KIT and PDGFRA, has proven efficacious in patients who are intolerant or refractory to imatinib. This review summarizes the recent knowledge on targeted therapy in GIST, based on the central role of KIT oncogenic activation, as well as discussing mechanisms of resistance.
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