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Mohamed N, Khan M, Hosler G, Tumminello K. Primary vulvar extragastrointestinal stromal tumor in a 77-year-old woman. J Cutan Pathol 2023. [PMID: 37127848 DOI: 10.1111/cup.14432] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Revised: 03/07/2023] [Accepted: 03/23/2023] [Indexed: 05/03/2023]
Abstract
Extragastrointestinal stromal tumors (EGISTs) carry the same morphological, immunohistochemical and molecular features as gastrointestinal stromal tumors (GISTs) and involve extragastrointestinal tract soft tissue. The majority of reported EGIST cases arise from intraabdominal, retroperitoneal, or pelvic soft tissue. A significant subset of such tumors originates from the gastrointestinal muscle layer, grows in an exophytic manner, then loses attachment to the gastrointestinal tract. Consequently, true EGISTs are exceedingly rare. Herein, we are reporting a case of a vulvar EGIST. A 77-year-old woman presented with a painless subcutaneous nodule on the right perineum. An excisional biopsy showed a fairly circumscribed bland spindle cell lesion in the dermis. The tumor cells were positive for CD117 and ANO1/DOG-1 and negative for smooth muscle myosin, smooth muscle actin, STAT6, low- and high-molecular-weight cytokeratins, SOX10, MART-1, CD10, S-100 protein, and estrogen and progesterone receptors. A diagnosis of EGIST was made and complete excision was recommended. Superficial/subcutaneous EGISTs are extremely rare, and it is important for dermatopathologists to be aware of this entity as it can be misdiagnosed as more common spindle cell neoplasms, both benign and malignant, including but not limited to smooth muscle neoplasms (leiomyoma/leiomyosarcoma), spindle cell melanoma, and sarcomatoid squamous cell carcinoma.
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Affiliation(s)
- Nada Mohamed
- Department of Pathology, Texas A&M College of Medicine-Baylor Scott & White Health, Temple, Texas, USA
| | | | - Gregory Hosler
- ProPath, Dallas, Texas, USA
- Department of Dermatology, University of Texas Southwestern, Dallas, Texas, USA
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2
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Alsulaiman AA, AlAli MN, Essa MS, Alamri O, Albdah AM, Ahmad KS. Unusual Acute, Massive Lower Gastrointestinal Bleeding Secondary to a Proximal Jejunal Gastrointestinal Stromal Tumor: A Case Report. Cureus 2023; 15:e35287. [PMID: 36968934 PMCID: PMC10037224 DOI: 10.7759/cureus.35287] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/13/2023] [Indexed: 02/24/2023] Open
Abstract
The most common primary non-epithelial neoplasms of the gastrointestinal (GI) tract are gastrointestinal stromal tumors (GISTs). Ten percent (10%) of GISTs arise from the jejunum. Usually, patients complain of abdominal discomfort, but they may present with complications such as intestinal obstruction or bleeding. This report describes a 35-year-old male who presented with unusually massive, acute lower GI bleeding. After resuscitation and investigations (including a contrast-enhanced computed tomography of the abdomen and lower GI endoscopy), the patient underwent diagnostic laparoscopy and bowel resection of the affected section with anastomosis, and he had an eventful postoperative course. Studies suggest that GI bleeding in GIST occurs due to the ulceration and necrosis of the overlying mucosa caused by the pressure effect of the mass. Small-bowel GISTs are categorized based on their size. Many guidelines have advocated conservative management for small GISTs (<2 cm) that are in the jejunum. This patient has a rare case of a small jejunal GIST with a rare presentation of massive lower GI bleeding. A multidisciplinary approach is useful in managing such cases, and our case showed that laparoscopic intervention is a feasible option in a stable patient with massive lower GI bleeding.
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3
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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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4
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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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5
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Li C, Yang KL, Wang Q, Tian JH, Li Y, Gao ZD, Yang XD, Ye YJ, Jiang KW. Clinical features of multiple gastrointestinal stromal tumors: A pooling analysis combined with evidence and gap map. World J Gastroenterol 2020; 26:7550-7567. [PMID: 33384554 PMCID: PMC7754550 DOI: 10.3748/wjg.v26.i47.7550] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2020] [Revised: 11/09/2020] [Accepted: 11/21/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Multiple gastrointestinal stromal tumors (MGISTs) are a very rare type of gastrointestinal stromal tumor (GIST) and are usually observed in syndrome.
AIM The paper aimed to describe the clinical and oncological features of MGISTs and to offer evidence for the diagnosis and treatment.
METHODS Data of consecutive patients with MGISTs who were diagnosed at Peking University People’s Hospital (PKUPH) from 2008 to 2019 were retrospectively evaluated. Further, a literature search was conducted by retrieving data from PubMed, EMBASE, and the Cochrane library databases from inception up to November 30, 2019.
RESULTS In all, 12 patients were diagnosed with MGISTs at PKUPH, and 43 published records were ultimately included following the literature review. Combined analysis of the whole individual patient data showed that female (59.30%), young (14.45%), and syndromic GIST (63.95%) patients comprised a large proportion of the total patient population. Tumors were mainly located in the small intestine (58.92%), and both CD117 and CD34 were generally positive. After a mean 78.32-mo follow-up, the estimated median overall survival duration (11.5 years) was similar to single GISTs, but recurrence-free survival was relatively poorer.
CONCLUSION The clinical and oncological features are potentially different between MGISTs and single GIST. Further studies are needed to explore appropriate surgical approach and adjuvant therapy.
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Affiliation(s)
- Chen Li
- Department of Gastroenterological Surgery, Peking University People's Hospital, Beijing 100044, China
| | - Ke-Lu Yang
- Evidence-Based Nursing Center, School of Nursing, Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Quan Wang
- Department of Gastroenterological Surgery, Peking University People's Hospital, Beijing 100044, China
| | - Jin-Hui Tian
- Evidence Based Medicine Center, School of Basic Medical Science of Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Yang Li
- Department of Gastroenterological Surgery, Peking University People's Hospital, Beijing 100044, China
| | - Zhi-Dong Gao
- Department of Gastroenterological Surgery, Peking University People's Hospital, Beijing 100044, China
| | - Xiao-Dong Yang
- Department of Gastroenterological Surgery, Peking University People's Hospital, Beijing 100044, China
| | - Ying-Jiang Ye
- Department of Gastroenterological Surgery, Peking University People's Hospital, Beijing 100044, China
| | - Ke-Wei Jiang
- Department of Gastroenterological Surgery, Peking University People's Hospital, Beijing 100044, China
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6
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Wang Y, Call J. Mutational Testing in Gastrointestinal Stromal Tumor. Curr Cancer Drug Targets 2020; 19:688-697. [PMID: 30914028 DOI: 10.2174/1568009619666190326123945] [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: 11/27/2018] [Revised: 02/05/2019] [Accepted: 03/13/2019] [Indexed: 12/14/2022]
Abstract
Targeted treatment has become a major modality in cancer management. Such cancer drugs are generally designed to treat tumors with certain genetic/genomic makeups. Mutational testing prior to prescribing targeted therapy is crucial in identifying who can receive clinical benefit from specific cancer drugs. Over the last two decades, gastrointestinal stromal tumors (GISTs) have evolved from histogenetically obscure to being identified as distinct gastrointestinal mesenchymal tumors with well-defined clinical and molecular characteristics, for which multiple lines of targeted therapies are available. Although the National Comprehensive Cancer Network (NCCN) strongly recommends mutational testing for optimal management of GIST, many GIST patients still have neither a mutation test performed or any mutation-guided cancer management. Here, we review the mutation-guided landscape of GIST, mutational testing methods, and the recent development of new therapies targeting GIST with specific mutations.
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Affiliation(s)
- Yu Wang
- The Life Raft Group, 155 US-46 Wayne, NJ 07470, United States
| | - Jerry Call
- The Life Raft Group, 155 US-46 Wayne, NJ 07470, United States
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7
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Vankova B, Behenska K, Bauer M, Sedivcova M, Daumova M, Agaimy A, Michal M, Daum O. Morphological features useful in the differential diagnosis between undifferentiated carcinoma and gastrointestinal stromal tumor. Ann Diagn Pathol 2020; 46:151527. [PMID: 32388398 DOI: 10.1016/j.anndiagpath.2020.151527] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Accepted: 04/16/2020] [Indexed: 12/15/2022]
Abstract
Undifferentiated (sarcomatoid) carcinomas may closely mimic gastrointestinal stromal tumors (GISTs) due to possible histological and immunohistochemical overlap between these two entities. To avoid unnecessary employment of a wide spectrum of immunohistochemical stainings and molecular genetics and thus decrease costs, finding simple morphological features to target further investigation of such neoplasms of the gastrointestinal tract would be helpful. Five cases classified as undifferentiated (sarcomatoid) carcinomas with a definite proof of the diagnosis, i. e. the presence of a differentiated carcinomatous component, were retrieved from archives of several institutions. For comparison, 84 cases of GIST mutated in KIT or PDGFRA genes served as the control group. Hematoxylin and eosin stained slides were evaluated for the presence of patterns which might discriminate between sarcomatoid carcinoma and GIST. Lymphatic invasion and entrapment of fat tissue strongly favor the diagnosis of undifferentiated carcinoma, as it was found in all or almost all cases of undifferentiated carcinoma, but in no GIST. Alternation of low- and high- grade areas, formation of angiosarcomatous-like spaces, and the presence of yolk sac-like areas were also detected in all cases of undifferentiated carcinoma, but only in 1.2%, 2.4% and 7.2% of the GISTs, respectively. Furthermore, DOG1 was negative in all cases of undifferentiated carcinoma. According to this study, the presence of the histological findings listed above should prompt extensive tumor sampling in order to find a differentiated carcinomatous component. However, due to the small number of cases of undifferentiated carcinoma available for the study, a larger multi-institutional study is warranted.
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Affiliation(s)
- Bohuslava Vankova
- Sikl's Institute of Pathology, Faculty of Medicine and Teaching Hospital in Plzen, Charles University, Plzen, Czech Republic; Bioptical Laboratory, Ltd., Plzen, Czech Republic
| | - Kristyna Behenska
- Sikl's Institute of Pathology, Faculty of Medicine and Teaching Hospital in Plzen, Charles University, Plzen, Czech Republic
| | - Meret Bauer
- Sikl's Institute of Pathology, Faculty of Medicine and Teaching Hospital in Plzen, Charles University, Plzen, Czech Republic
| | | | - Magdalena Daumova
- Sikl's Institute of Pathology, Faculty of Medicine and Teaching Hospital in Plzen, Charles University, Plzen, Czech Republic; Bioptical Laboratory, Ltd., Plzen, Czech Republic
| | - Abbas Agaimy
- Institute of Pathology, University Hospital, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany
| | - Michal Michal
- Sikl's Institute of Pathology, Faculty of Medicine and Teaching Hospital in Plzen, Charles University, Plzen, Czech Republic
| | - Ondrej Daum
- Sikl's Institute of Pathology, Faculty of Medicine and Teaching Hospital in Plzen, Charles University, Plzen, Czech Republic; Bioptical Laboratory, Ltd., Plzen, Czech Republic.
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Liu P, Tan F, Liu H, Li B, Lei T, Zhao X. The Use of Molecular Subtypes for Precision Therapy of Recurrent and Metastatic Gastrointestinal Stromal Tumor. Onco Targets Ther 2020; 13:2433-2447. [PMID: 32273716 PMCID: PMC7102917 DOI: 10.2147/ott.s241331] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Accepted: 03/10/2020] [Indexed: 12/19/2022] Open
Abstract
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumor in the digestive tract. Tyrosine kinase inhibitors (TKIs), represented by imatinib, sunitinib, and regorafenib, have become the main treatment for recurrent and metastatic GISTs. With the wide application of mutation analysis and the precision medicine, molecular characteristics have been determined that not only predict the prognosis of patients with recurrent and metastatic GISTs, but also are closely related to the efficacy of first-, second- and third-line TKIs for GISTs, as well as other TKIs. Despite the significant effects of TKIs, the emergence of primary and secondary resistance ultimately leads to treatment failure and tumor progression. Currently, due to the signal transmission of KIT/PDGFRA during onset and tumor progression, strategies to counteract drug resistance include the replacement of TKIs and the development of new drugs that are directed towards carcinogenic mutations. In addition, it is also the embodiment of precision medicine for GISTs to explore new carcinogenic mechanisms and develop new drugs relying on new biotechnology. Surgery can benefit specific patients but its major purpose is to diminish the resistant clones. However, the prognosis of recurrent and metastatic patients is still unsatisfactory. Therefore, it is worth paying attention to how to maximize the benefits for patients.
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Affiliation(s)
- Peng Liu
- Department of Gastrointestinal Surgery, Xiangya Hospital, Central South University, Changsha, Hunan410008, People’s Republic of China
| | - Fengbo Tan
- Department of Gastrointestinal Surgery, Xiangya Hospital, Central South University, Changsha, Hunan410008, People’s Republic of China
| | - Heli Liu
- Department of Gastrointestinal Surgery, Xiangya Hospital, Central South University, Changsha, Hunan410008, People’s Republic of China
| | - Bin Li
- Department of Oncology, Xiangya Hospital, Central South University, Changsha410008, Hunan, People’s Republic of China
| | - Tianxiang Lei
- Department of Gastrointestinal Surgery, Xiangya Hospital, Central South University, Changsha, Hunan410008, People’s Republic of China
| | - Xianhui Zhao
- Department of Gastrointestinal Surgery, Xiangya Hospital, Central South University, Changsha, Hunan410008, People’s Republic of China
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IJzerman NS, Drabbe C, den Hollander D, Mohammadi M, van Boven H, Desar IME, Gelderblom H, Grünhagen DJ, Reyners AKL, van Noesel MM, Mathijssen RHJ, Steeghs N, van der Graaf WTA. Gastrointestinal Stromal Tumours (GIST) in Young Adult (18-40 Years) Patients: A Report from the Dutch GIST Registry. Cancers (Basel) 2020; 12:cancers12030730. [PMID: 32244864 PMCID: PMC7140070 DOI: 10.3390/cancers12030730] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Revised: 03/17/2020] [Accepted: 03/18/2020] [Indexed: 02/07/2023] Open
Abstract
Gastrointestinal stromal tumour (GIST) is a disease of older adults and is dominated by KIT/PDGFR mutations. In children, GIST is rare, predominantly occurs in girls, has a stomach location and generally lacks KIT/PDGFR mutations. For young adults (YA), aged 18 to 40 years, the typical phenotypic and genotypic patterns are unknown. We therefore aimed to describe the clinical, pathological and molecular characteristics of GIST in in YA. YA GIST patients registered in the Dutch GIST Registry (DGR) were included, and data were compared to those of older adults (OA). From 1010 patients in the DGR, 52 patients were YA (54% male). Main tumour locations were stomach (46%) and small intestine (46%). GIST genetic profiles were mutations in KIT (69%), PDGFRA (6%), SDH deficient (8%), NF1 associated (4%), ETV6-NTRK3 gene fusion (2%) or wildtype (10%). Statistically significant differences were found between the OA and YA patients (localisation, syndromic and mutational status). YA presented more often than OA in an emergency setting (18% vs. 9%). The overall five-year survival rate was 85%. In conclusion, YA GISTs are not similar to typical adult GISTs and also differ from paediatric GISTs, as described in the literature. In this series, we found a relatively high percentage of small intestine GIST, emergency presentation, 25% non-KIT/PDGFRA mutations and a relatively good survival.
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Affiliation(s)
- Nikki S. IJzerman
- Department of Medical Oncology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands (C.D.); (D.d.H.); (N.S.)
- Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Doctor Molewaterplein 40, 3015 GD Rotterdam, The Netherlands;
| | - Cas Drabbe
- Department of Medical Oncology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands (C.D.); (D.d.H.); (N.S.)
- Department of Medical Oncology, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GA Nijmegen, The Netherlands;
| | - Dide den Hollander
- Department of Medical Oncology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands (C.D.); (D.d.H.); (N.S.)
- Department of Medical Oncology, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GA Nijmegen, The Netherlands;
| | - Mahmoud Mohammadi
- Department of Medical Oncology, Leiden University Medical Center, Albinusdreef 2, 2300 RC Leiden, The Netherlands; (M.M.)
| | - Hester van Boven
- Department of Pathology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands;
| | - Ingrid M. E. Desar
- Department of Medical Oncology, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GA Nijmegen, The Netherlands;
| | - Hans Gelderblom
- Department of Medical Oncology, Leiden University Medical Center, Albinusdreef 2, 2300 RC Leiden, The Netherlands; (M.M.)
| | - Dirk J. Grünhagen
- Department of Surgical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Doctor Molewaterplein 40, 3015 GD Rotterdam, The Netherlands;
| | - An K. L. Reyners
- Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands;
| | - Max M. van Noesel
- Department of Solid Tumors, Princess Maxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS Utrecht, The Netherlands;
| | - Ron H. J. Mathijssen
- Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, Doctor Molewaterplein 40, 3015 GD Rotterdam, The Netherlands;
| | - Neeltje Steeghs
- Department of Medical Oncology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands (C.D.); (D.d.H.); (N.S.)
| | - Winette T. A. van der Graaf
- Department of Medical Oncology, Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands (C.D.); (D.d.H.); (N.S.)
- Department of Medical Oncology, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GA Nijmegen, The Netherlands;
- Correspondence: ; Tel: +31-20-512-6979
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10
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Djerouni M, Dumont SN. [Wild-type gastroinestinal stromal tumors]. Bull Cancer 2020; 107:499-505. [PMID: 32063345 DOI: 10.1016/j.bulcan.2019.12.007] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2019] [Revised: 11/29/2019] [Accepted: 12/05/2019] [Indexed: 02/07/2023]
Abstract
Gastrointestinal stromal tumors (GIST) are the most common non-epithelial tumors of the gastrointestinal tract. Wild-type GISTs (WT-GIST) consist of a rare heterogeneous group characterized by the lack of activating mutations in the tyrosine kinase receptor (Kit) and/or platelet derived growth factor receptor A (PDGFRA). However, WT-GIST is characterized by other genomic alterations, including dehydrogenase succinate (SDH) deficiency or mutations in the Ras pathway. Recent studies have reported many mutations in others genes that may be incriminated in the development of WT-GISTs. Moreover, WT-GIST is frequently associated with hereditary cancer syndromes such as the Carney Triad and Type 1 Neurofibromatosis (NF1). WT-GIST affects usually young and pediatric patients. Most WT-GIST subtypes are insensitive to imatinib; therefore, their therapeutic management is somewhat different from usual GISTs. This review resumes the molecular and therapeutic features of this rare entity.
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Affiliation(s)
- Mohamed Djerouni
- Gustave-Roussy Cancer Campus, département d'oncologie médicale, 114, rue Edouard-Vaillant, 94800 Villejuif, France
| | - Sarah N Dumont
- Gustave-Roussy Cancer Campus, département d'oncologie médicale, 114, rue Edouard-Vaillant, 94800 Villejuif, France.
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11
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Herzberg M, Beer M, Anupindi S, Vollert K, Kröncke T. Imaging pediatric gastrointestinal stromal tumor (GIST). J Pediatr Surg 2018; 53:1862-1870. [PMID: 29685489 DOI: 10.1016/j.jpedsurg.2018.03.022] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2018] [Revised: 03/18/2018] [Accepted: 03/20/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND Gastrointestinal stromal tumors (GIST) are extremely rare in children. Imaging plays a key role in staging and monitoring therapy (surgical and with tyrosine kinase inhibitors). The vast majority of articles addressing imaging of GIST base on adults and are based on CT. The subtype "pediatric GIST" - if at all - is only mentioned in a dependent clause. Although the imaging features in children and adults are similar, histology, clinical course and thus imaging approach are different. METHODS A PubMed search using the search terms "Gastrointestinal stromal tumor, GIST, WT GIST, children, pediatric, carney's triad, imaging, staging, follow-up, MRI, CEUS, ultrasonography, Positron emission tomography" was conducted. Studies that reported on laparoscopy, endoscopy and surgical techniques only were excluded. RESULTS Based on our selective literature review, we present alternative radiological imaging strategies using MRI, contrast enhanced ultrasound (CEUS) and PET-CT to stage and follow-up pediatric GIST patients. As pediatric GIST often is a chronic disease, minimizing exposure to ionizing radiation is mandatory. CONCLUSION MRI, contrast enhanced ultrasound and PET-CT instead of CT are the imaging modalities to evaluate pediatric GIST. TYPE OF STUDY Systematic review LEVEL OF EVIDENCE: III.
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Affiliation(s)
- Moriz Herzberg
- Department of Diagnostic and Interventional Radiology and Neuroradiology, Klinikum Augsburg, Stenglinstraße 2, 86156, Germany.
| | - Meinrad Beer
- Department of Diagnostic and Interventional Radiology and Neuroradiology, University Ulm, Albert-Einstein-Allee 23, 89081, Germany.
| | - Sudha Anupindi
- Department of Radiology at The Children's Hospital of Philadelphia, 3401 Civic Center Blvd, Philadelphia, PA 19104, USA.
| | - Kurt Vollert
- Department of Diagnostic and Interventional Radiology and Neuroradiology, Klinikum Augsburg, Stenglinstraße 2, 86156, Germany.
| | - Thomas Kröncke
- Department of Diagnostic and Interventional Radiology and Neuroradiology, Klinikum Augsburg, Stenglinstraße 2, 86156, Germany.
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12
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Charville GW, Longacre TA. Surgical Pathology of Gastrointestinal Stromal Tumors: Practical Implications of Morphologic and Molecular Heterogeneity for Precision Medicine. Adv Anat Pathol 2017; 24:336-353. [PMID: 28820749 DOI: 10.1097/pap.0000000000000166] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Gastrointestinal stromal tumor (GIST), the most common mesenchymal neoplasm of the gastrointestinal tract, exhibits diverse histologic and clinical manifestations. With its putative origin in the gastrointestinal pacemaker cell of Cajal, GIST can arise in association with any portion of the tubular gastrointestinal tract. Morphologically, GISTs are classified as spindled or epithelioid, though each of these subtypes encompasses a broad spectrum of microscopic appearances, many of which mimic other histologic entities. Despite this morphologic ambiguity, the diagnosis of GIST is aided in many cases by immunohistochemical detection of KIT (CD117) or DOG1 expression. The natural history of GIST ranges from that of a tumor cured by surgical resection to that of a locally advanced or even widely metastatic, and ultimately fatal, disease. This clinicopathologic heterogeneity is paralleled by an underlying molecular diversity: the majority of GISTs are associated with spontaneous activating mutations in KIT, PDGFRA, or BRAF, while additional subsets are driven by genetic lesions-often inherited-of NF1 or components of the succinate dehydrogenase enzymatic complex. Specific gene mutations correlate with particular anatomic or morphologic characteristics and, in turn, with distinct clinical behaviors. Therefore, prognostication and treatment are increasingly dictated not only by morphologic clues, but also by accompanying molecular genetic features. In this review, we provide a comprehensive description of the heterogenous molecular underpinnings of GIST, including implications for the practicing pathologist with regard to morphologic identification, immunohistochemical diagnosis, and clinical management.
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13
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Liu W, Zeng X, Wu X, He J, Gao J, Shuai X, Wang G, Zhang P, Tao K. Clinicopathologic study of succinate-dehydrogenase-deficient gastrointestinal stromal tumors: A single-institutional experience in China. Medicine (Baltimore) 2017; 96:e7668. [PMID: 28796048 PMCID: PMC5556214 DOI: 10.1097/md.0000000000007668] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Gastrointestinal stromal tumors (GISTs) that are not driven by kinase mutations, as are most GISTs, often show loss of function of the succinate dehydrogenase (SDH) complex and are considered SDH-deficient GISTs. SDH-deficient GISTs share many distinct characteristics compared with conventional GISTs. However, data regarding these characteristics, particularly among Asian people, are relatively limited. The objective of this study was to characterize the clinicopathologic characteristics, treatment, and prognosis of these uncommon GISTs.This retrospective observational study enrolled 12 patients with SDH-deficient GISTs, who were selected from 335 patients with GIST diagnosed at our institution between October 31, 2013 and October 31, 2016 by succinate dehydrogenase subunit B staining.There were 8 male and 4 female patients, with a median age of 57 years (range, 21-73 years). Ten patients (83.3%) were diagnosed at or after the age of 40 years and represented 7.2% (10/138) of the entire population of elderly patients with gastric GISTs. The tumor size ranged from 3 to 19 cm (median, 7 cm); the primary tumor was multifocal in 6 cases (50%), and tumors had a multinodular or plexiform architecture in 10 cases (83.3%). Ten cases (83.3%) showed pure epithelioid morphology, with the remaining 2 cases (16.7%) showing mixed histologic subtype. Lymph node metastasis was found at the time of primary resection in 50% (3/6) of patients. Four cases (33.3%) had distant metastasis at presentation. Four patients (33.3%) developed disease progression during imatinib treatment after initial resection, but all of these patients regained disease control when the treatment was altered to sunitinib targeted therapy.SDH-deficient GISTs arise exclusively in the stomach and account for approximately 7.4% (12/162) of gastric GISTs. Moreover, those affecting people older than 40 years are not uncommon and sunitinib may work well for cases showing treatment failure with imatinib.
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Affiliation(s)
| | | | - Xiuli Wu
- Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jun He
- Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jinbo Gao
- Department of Gastrointestinal Surgery
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14
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Neuzillet C, de Mestier L, Rousseau B, Mir O, Hebbar M, Kocher HM, Ruszniewski P, Tournigand C. Unravelling the pharmacologic opportunities and future directions for targeted therapies in gastro-intestinal cancers part 2: Neuroendocrine tumours, hepatocellular carcinoma, and gastro-intestinal stromal tumours. Pharmacol Ther 2017; 181:49-75. [PMID: 28723416 DOI: 10.1016/j.pharmthera.2017.07.006] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Until the 1990s, cytotoxic chemotherapy has been the cornerstone of medical therapy for gastrointestinal (GI) cancers. Better understanding of the cancer cell molecular biology has led to the therapeutic revolution of targeted therapies, i.e. monoclonal antibodies or small molecule inhibitors directed against proteins that are specifically overexpressed or mutated in cancer cells. These agents, being more specific to cancer cells, were expected to be less toxic than conventional cytotoxic agents. However, their effects have sometimes been disappointing, due to intrinsic or acquired resistance mechanisms, or to an activity restricted to some tumour settings, illustrating the importance of patient selection and early identification of predictive biomarkers of response to these therapies. Targeted agents have provided clinical benefit in many GI cancer types. Particularly, some GI tumours are considered chemoresistant and targeted therapies have offered a new therapeutic base for their management. Hence, somatostatin receptor-directed strategies, sorafenib, and imatinib have revolutioned the management of neuroendocrine tumours (NET), hepatocellular carcinoma (HCC), and gastrointestinal stromal tumours (GIST), respectively, and are now used as first-line treatment in many patients affected by these tumours. However, these agents face problems of resistances and identification of predictive biomarkers from imaging and/or biology. We propose a comprehensive two-part review providing a panoramic approach of the successes and failures of targeted agents in GI cancers to unravel the pharmacologic opportunities and future directions for these agents in GI oncology. In this second part, we will focus on NET, HCC, and GIST, whose treatment relies primarily on targeted therapies.
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Affiliation(s)
- Cindy Neuzillet
- INSERM UMR1149, Beaujon University Hospital (Assistance Publique-Hôpitaux de Paris, AP-HP), Paris 7 Diderot University, 100 Boulevard du Général Leclerc, 92110 Clichy, France; Department of Medical Oncology, Henri Mondor University Hospital (AP-HP), Paris Est Créteil University (UPEC), 51 Avenue du Maréchal de Lattre de Tassigny, 94010 Créteil, France; Tumour Biology Laboratory, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, United Kingdom; Barts and The London HPB Centre, The Royal London Hospital, Whitechapel, London E1 1BB, United Kingdom.
| | - Louis de Mestier
- INSERM UMR1149, Beaujon University Hospital (Assistance Publique-Hôpitaux de Paris, AP-HP), Paris 7 Diderot University, 100 Boulevard du Général Leclerc, 92110 Clichy, France; Department of Gastroenterology and Pancreatology, Beaujon University Hospital (AP-HP), Paris 7 Diderot University, 100 Boulevard du Général Leclerc, 92110 Clichy, France
| | - Benoît Rousseau
- Department of Medical Oncology, Henri Mondor University Hospital (AP-HP), Paris Est Créteil University (UPEC), 51 Avenue du Maréchal de Lattre de Tassigny, 94010 Créteil, France; Institut Mondor de Recherche Biomédicale, INSERM UMR955 Team 18, Paris Est Créteil University (UPEC), 51 Avenue du Maréchal de Lattre de Tassigny, 94010 Créteil, France
| | - Olivier Mir
- Department of Cancer Medicine - Sarcoma Group, Department of Early Drug Development (DITEP) - Phase 1 Unit, Gustave Roussy Cancer Campus, University of Paris Sud, 114, Rue Edouard Vaillant, 94800 Villejuif, France
| | - Mohamed Hebbar
- Department of Medical Oncology, Lille University Hospital, 1, Rue Polonovski, 59037 Lille, France
| | - Hemant M Kocher
- Tumour Biology Laboratory, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, United Kingdom; Barts and The London HPB Centre, The Royal London Hospital, Whitechapel, London E1 1BB, United Kingdom
| | - Philippe Ruszniewski
- INSERM UMR1149, Beaujon University Hospital (Assistance Publique-Hôpitaux de Paris, AP-HP), Paris 7 Diderot University, 100 Boulevard du Général Leclerc, 92110 Clichy, France
| | - Christophe Tournigand
- Department of Medical Oncology, Henri Mondor University Hospital (AP-HP), Paris Est Créteil University (UPEC), 51 Avenue du Maréchal de Lattre de Tassigny, 94010 Créteil, France
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15
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Shi SS, Wang X, Xia QY, Rao Q, Shen Q, Ye SB, Li R, Shi QL, Lu ZF, Ma HH, Zhou XJ. P16 overexpression inBRAF-mutated gastrointestinal stromal tumors. Expert Rev Mol Diagn 2016; 17:195-201. [PMID: 28034324 DOI: 10.1080/14737159.2017.1272413] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Affiliation(s)
- Shan-shan Shi
- Department of Pathology, Jinling Hospital, Clinical Medical School of Southern Medical University, Nanjing, P. R. China
| | - Xuan Wang
- Department of Pathology, Jinling Hospital, Clinical Medical School of Southern Medical University, Nanjing, P. R. China
| | - Qiu-yuan Xia
- Department of Pathology, Jinling Hospital, Clinical Medical School of Southern Medical University, Nanjing, P. R. China
| | - Qiu Rao
- Department of Pathology, Jinling Hospital, Clinical Medical School of Southern Medical University, Nanjing, P. R. China
| | - Qin Shen
- Department of Pathology, Jinling Hospital, Clinical Medical School of Southern Medical University, Nanjing, P. R. China
| | - Sheng-bin Ye
- Department of Pathology, Jinling Hospital, Clinical Medical School of Southern Medical University, Nanjing, P. R. China
| | - Rui Li
- Department of Pathology, Jinling Hospital, Clinical Medical School of Southern Medical University, Nanjing, P. R. China
| | - Qun-li Shi
- Department of Pathology, Jinling Hospital, Clinical Medical School of Southern Medical University, Nanjing, P. R. China
| | - Zhen-feng Lu
- Department of Pathology, Jinling Hospital, Clinical Medical School of Southern Medical University, Nanjing, P. R. China
| | - Heng-hui Ma
- Department of Pathology, Jinling Hospital, Clinical Medical School of Southern Medical University, Nanjing, P. R. China
| | - Xiao-jun Zhou
- Department of Pathology, Jinling Hospital, Clinical Medical School of Southern Medical University, Nanjing, P. R. China
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16
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Zhou J, Xu J, Jiang G, Ma Y, Qi J, Li W, Zhang D. Gastrointestinal stromal tumor with a PDGFRA mutation masquerading as gastric plexiform fibromyxoma: A comparative clinicopathological study of two cases. Oncol Lett 2016; 13:887-892. [PMID: 28356974 PMCID: PMC5351284 DOI: 10.3892/ol.2016.5486] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2015] [Accepted: 10/26/2016] [Indexed: 12/13/2022] Open
Abstract
Gastric plexiform fibromyxoma (PF) is a rare mesenchymal tumor with a histologically distinctive multinodular pattern, dissimilar to conventional gastrointestinal stromal tumor (GIST). The current study presents one case of gastric PF, and one case of GIST with a platelet-derived growth factor receptor α (PDGFRA) mutation mimicking PF, and discusses their differential diagnoses. The two patients were a 51-year-old male with PF and a 47-year-old female with GIST, each of whom presented with an occupying lesion in the gastric antrum. Histologically, the two cases shared a rare and approximately unanimous morphological pattern of a prominent multinodular and plexiform figuration in the gastric wall, including mucoid matrix, short spindle cells and small caliber vascular elements, and areas of stromal tumor cells exhibited an epithelioid appearance. Immunohistochemistry revealed that the PF tumor cells were positive for smooth muscle actin (SMA), but negative for mast/stem cell growth factor receptor (KIT), GIST-1 (DOG1), cluster of differentiation (CD) 34, S-100, desmin and cytokeratin AE1/AE3. The case of GIST expressed KIT and DOG1, but was negative for SMA, CD34, S-100, desmin and AE1/AE3. In addition, the GIST case, which was observed to harbor a D842V mutation in exon 18 of PDGFRA, was demonstrated to be genetically distinct from PF. The cases presented in the current study were uncommon in that GIST exhibited a plexiform appearance that mimicked the histology of the rare PF tumor; therefore, GIST must be considered and discounted first when determining a differential diagnosis for a gastrointestinal mesenchymal neoplasm.
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Affiliation(s)
- Jun Zhou
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Jingjing Xu
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Guozhong Jiang
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Yihui Ma
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Jingwen Qi
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Wencai Li
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
| | - Dandan Zhang
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, P.R. China
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17
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Conventional Risk Stratification Fails to Predict Progression of Succinate Dehydrogenase–deficient Gastrointestinal Stromal Tumors. Am J Surg Pathol 2016; 40:1616-1621. [DOI: 10.1097/pas.0000000000000685] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023]
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18
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Kudose S, Kyriakos M, Awad MM. Gastric plexiform schwannoma in association with neurofibromatosis type 2. Clin J Gastroenterol 2016; 9:352-357. [PMID: 27696205 DOI: 10.1007/s12328-016-0687-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2016] [Accepted: 09/22/2016] [Indexed: 12/27/2022]
Abstract
Plexiform schwannoma (PS) is an uncommon variant of schwannoma characterized by a multinodular (plexiform) growth pattern. It comprises up to 5 % of all schwannomas. The association between PS and neurofibromatosis type 1 or type 2 (NF1/NF2) is only rarely reported. Most cases of PS occur in the skin and subcutaneous soft tissue, with only a few reports of digestive tract involvement. We describe an 18-year-old male with NF2 who had bilateral vestibular schwannomas and multiple cutaneous PSs, and a 3-year history of abdominal pain. The patient ultimately underwent a distal gastrectomy for a partially obstructing submucosal antral mass, associated with an overlying ulcer. Histopathologic examination showed the mass to be a PS. The patient is alive and well, without symptoms, 12 months postoperatively. A review of the English language medical literature yielded only ten examples of PS arising in the digestive tract. Our patient is the first to be reported to have a gastric PS, and only the second patient to be reported with a digestive tract PS to have NF2, and the only patient reported to have both digestive tract and cutaneous PSs. Despite its rare occurrence with NF2, the finding of PS at any site should stimulate an examination for other manifestations of this disorder. CLINICAL TRIAL REGISTRATION None.
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Affiliation(s)
- Satoru Kudose
- Division of Surgical Pathology, Washington University School of Medicine, St. Louis, MO, USA. .,Department of Pathology and Immunology, Washington University, 660 S. Euclid Ave., Campus Box 8118, St. Louis, MO, 63110, USA.
| | - Michael Kyriakos
- Division of Surgical Pathology, Washington University School of Medicine, St. Louis, MO, USA
| | - Michael Magdi Awad
- Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA
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19
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Szucs Z, Thway K, Fisher C, Bulusu R, Constantinidou A, Benson C, van der Graaf WT, Jones RL. Molecular subtypes of gastrointestinal stromal tumors and their prognostic and therapeutic implications. Future Oncol 2016; 13:93-107. [PMID: 27600498 DOI: 10.2217/fon-2016-0192] [Citation(s) in RCA: 83] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Gastrointestinal stromal tumors (GISTs) are composed of various molecular subtypes, with differing prognostic and predictive relevance. Previously, tumors lacking mutations in the KIT and PDGFRA genes have been designated as 'wild-type' GISTs; however, they represent a heterogeneous group currently undergoing further subclassification. Primary and secondary resistance to imatinib poses a significant clinical challenge, therefore ongoing research is trying to evaluate mechanisms to overcome resistance. Thorough understanding of the prognostic and predictive relevance of different genetic subtypes of GIST can guide clinical decision-making both in the adjuvant and the metastatic setting. Further work is required to identify tailored therapies for specific subgroups of GISTs wild-type for KIT and PDGFRA mutations and to identify predictive factors of resistance to currently approved systemic therapies.
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Affiliation(s)
- Zoltan Szucs
- The Royal Marsden Hospital NHS Foundation Trust, Fulham Road, London, SW3 6JJ, UK
| | - Khin Thway
- The Royal Marsden Hospital NHS Foundation Trust, Fulham Road, London, SW3 6JJ, UK
| | - Cyril Fisher
- The Royal Marsden Hospital NHS Foundation Trust, Fulham Road, London, SW3 6JJ, UK
| | - Ramesh Bulusu
- Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Hills Road, Cambridge, CB2 0QQ, UK
| | | | - Charlotte Benson
- The Royal Marsden Hospital NHS Foundation Trust, Fulham Road, London, SW3 6JJ, UK
| | - Winette Ta van der Graaf
- The Royal Marsden Hospital NHS Foundation Trust, Fulham Road, London, SW3 6JJ, UK.,The Institute of Cancer Research, Cotswold Road, Sutton, SM2 5NG, UK
| | - Robin L Jones
- The Royal Marsden Hospital NHS Foundation Trust, Fulham Road, London, SW3 6JJ, UK
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20
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Refinements in Sarcoma Classification in the Current 2013 World Health Organization Classification of Tumours of Soft Tissue and Bone. Surg Oncol Clin N Am 2016; 25:621-43. [PMID: 27591490 DOI: 10.1016/j.soc.2016.05.001] [Citation(s) in RCA: 109] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
The fourth edition of the World Health Organization (WHO) Classification of Tumours of Soft Tissue and Bone was published in February 2013. The 2013 WHO volume provides an updated classification scheme and reproducible diagnostic criteria, which are based on recent clinicopathologic studies and genetic and molecular data that facilitated refined definition of established tumor types, recognition of novel entities, and the development of novel diagnostic markers. This article reviews updates and changes in the classification of bone and soft tissue tumors from the 2002 volume.
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21
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Bhatt NR, Collins D, Crotty P, Ridgway PF. Prognosis and management of adult wild type gastrointestinal stromal tumours (GISTs): A pooled analysis and review of literature. Surg Oncol 2016; 25:152-7. [PMID: 27566016 DOI: 10.1016/j.suronc.2016.05.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2015] [Revised: 03/28/2016] [Accepted: 05/08/2016] [Indexed: 02/06/2023]
Abstract
A pooled review was performed to determine survival in adult WT GIST (Wild Type GastroIntestinal Stromal Tumours) and compare the same with pediatric WT GISTs. Electronic databases were searched using the terms "Wild type" AND "GIST". Eighty-two adult patients from 14 studies were included in the pooled analysis. Cumulative survival was greater than 50% in both age groups, hence medial survival could not be computed. Mean survival in adults was 15.7 years ± 0.78 and in children was 18.8 years ± 1.3 (p = 0.241). Median disease free survival in adults was 10 years while 5-year overall survival was 88%. There was no statistically significant difference in the survival between the two groups (p = 0.241). Overall survival in adults with WT GISTs is favourable compared to other adult GIST subtypes likely reflects a common molecular pathway similar to pediatric GIST.
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Affiliation(s)
- N R Bhatt
- Department of Surgery, Tallaght Hospital, Dublin, Ireland
| | - D Collins
- Department of Surgery, Tallaght Hospital, Dublin, Ireland
| | - P Crotty
- Department of Pathology, Tallaght Hospital, Dublin, Ireland
| | - P F Ridgway
- Department of Surgery, Tallaght Hospital, Dublin, Ireland.
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22
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Kim SH, Lee MS, Cho BS, Park JS, Han HY, Kang DW. Gastrointestinal Stromal Tumor of the Stomach Presenting as Multilobular with Diffuse Calcifications. J Gastric Cancer 2016; 16:58-62. [PMID: 27104029 PMCID: PMC4834623 DOI: 10.5230/jgc.2016.16.1.58] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2016] [Revised: 02/28/2016] [Accepted: 03/06/2016] [Indexed: 12/13/2022] Open
Abstract
Gastrointestinal stromal tumors (GISTs) are the most common primary mesenchymal neoplasms of the gastrointestinal tract and usually appear as a well-circumscribed mass. However, it may be difficult to confirm the extent of the disease for some GISTs. A 70-year-old asymptomatic female presented for a regular physical exam. An esophagogastroduodenoscopy showed a 2.0 cm protruding mass on the gastric fundus. Endoscopic ultrasound revealed an ill-defined heterogenous hypoechoic lesion (3.0×1.5 cm). A computed tomography (CT) scan demonstrated a 4.5 cm multifocal calcified mass at the gastric body as well as at the gastric fundus. Laparoscopic gastric wedge resection was performed according to the extent of multifocal calcifications that are shown on the CT. Intraoperative specimen mammography and intraoperative biopsy might be helpful to obtain a tumor-free margin. Final pathologic diagnosis was an intermediate risk GIST in multilobular form. In patients with diffuse multifocal calcifications in the stomach, the possibility of GIST should be considered.
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Affiliation(s)
- Sae Hee Kim
- Department of Internal Medicine, Eulji University Hospital, Daejeon, Korea
| | - Moon-Soo Lee
- Department of Surgery, Eulji University Hospital, Daejeon, Korea
| | - Byung Sun Cho
- Department of Surgery, Eulji University Hospital, Daejeon, Korea
| | - Joo-Seung Park
- Department of Surgery, Eulji University Hospital, Daejeon, Korea
| | - Hyun-Young Han
- Department of Radiology, Eulji University Hospital, Daejeon, Korea
| | - Dong-Wook Kang
- Department of Pathology, Eulji University Hospital, Daejeon, Korea
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23
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Patil DT, Ma S, Konishi M, Carver PD, Pukay M, Beadling C, Corless CL, Rubin BP. Utility of BRAF V600E mutation-specific immunohistochemistry in detecting BRAF V600E-mutated gastrointestinal stromal tumors. Am J Clin Pathol 2015; 144:782-9. [PMID: 26486743 DOI: 10.1309/ajcprk3v2eiiupqz] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
OBJECTIVES As patients with BRAF V600E mutation respond to BRAF inhibitors, it is important to identify these mutations to stratify patients for the appropriate therapy. In this study, we evaluated the utility of a BRAF V600E allele-specific antibody in gastrointestinal stromal tumors (GISTs). METHODS BRAF V600E mutation-specific immunohistochemistry (negative, weak, or moderate/strong expression) and BRAF sequencing were performed on 38 consecutive GISTs diagnosed between January 2013 and April 2014. RESULTS GISTs from a cohort of 25 men and 13 women (mean age, 61 years; range, 39-88 years) were localized to the stomach (18), small bowel (10), colon (three), rectum (two), and pelvis/omentum (five). Strong and diffuse cytoplasmic BRAF expression was noted in two (5%) of 38 cases, while eight (21%) of 38 cases showed weak staining, and 28 (74%) of 38 cases were negative. Both of the strongly positive cases arose in the stomach, occurring in a 42-year-old and a 47-year-old woman, respectively. The lesions measured 0.8 and 1 cm, showed spindle cell morphology, and had no risk of progressive disease by Miettinen criteria. Both cases showed heterozygous BRAF V600E, while no BRAF mutations were detected in cases with weak or negative BRAF expression. CONCLUSIONS BRAF V600E mutation-specific immunohistochemistry is a highly sensitive and specific method for detecting BRAF-mutated GISTs.
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24
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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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25
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Subbiah V, Bupathi M, Kato S, Livingston A, Slopis J, Anderson PM, Hong DS. Clinical next-generation sequencing reveals aggressive cancer biology in adolescent and young adult patients. Oncoscience 2015; 2:646-58. [PMID: 26328274 PMCID: PMC4549362 DOI: 10.18632/oncoscience.176] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2015] [Accepted: 07/01/2015] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND The aggressive biology of cancers arising in adolescent and young adult (AYA; ages 15-39 years) patients is thought to contribute to poor survival outcomes. METHODS We used clinical next-generation sequencing (NGS) results to examine the molecular alterations and diverse biology of cancer in AYA patients referred to the Phase 1 program at UT MD Anderson Cancer Center. RESULTS Among the 28 patients analyzed (14 female and 14 male), 12 had pediatric-type cancers, six had adult-type cancers, and ten had orphan cancers. Unique, hitherto unreported aberrations were identified in all types of cancers. Aberrations in TP53, NKX2-1, KRAS, CDKN2A, MDM4, MCL1, MYC, BCL2L2, and RB1 were demonstrated across all tumor types. Five patients harbored TP53 aberrations; three patients harbored MYC, MCL1, and CDKN2A aberrations; and two patients harbored NKX2-1, KRAS, MDM4, BCL2L2, and RB1 alterations. Several patients had multiple aberrations; a patient with wild-type gastrointestinal stromal tumor harbored five alterations (MDM4, MCL1, KIT, AKT3, and PDGRFA). CONCLUSIONS This preliminary report of NGS of cancer in AYA patients reveals diverse and unique aberrations. Further molecular profiling and a deeper understanding of the biology of these unique aberrations are warranted and may lead to targeted therapeutic interventions.
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Affiliation(s)
- Vivek Subbiah
- Department of Phase I Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Manojkumar Bupathi
- Department of Phase I Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Shumei Kato
- Department of Phase I Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Andrew Livingston
- Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - John Slopis
- Department of Neuro-oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
| | - Pete M. Anderson
- Pediatric Hematology Oncology and Blood and Marrow Transplantation, Cleveland Clinic Foundation, Cleveland, OH, USA
| | - David S. Hong
- Department of Phase I Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA
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Joensuu H, Martin-Broto J, Nishida T, Reichardt P, Schöffski P, Maki RG. Follow-up strategies for patients with gastrointestinal stromal tumour treated with or without adjuvant imatinib after surgery. Eur J Cancer 2015; 51:1611-7. [PMID: 26022432 DOI: 10.1016/j.ejca.2015.05.009] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2015] [Accepted: 05/05/2015] [Indexed: 02/07/2023]
Abstract
BACKGROUND Patients with gastrointestinal stromal tumour (GIST) are often followed up after surgery with longitudinally repeated imaging examinations to detect recurrence early. Studies on follow-up of GIST patients are few, the optimal follow-up methods are unknown and the recommendations for follow-up vary in guidelines. METHODS We reviewed the current evidence for follow-up of patients treated with surgery alone and of patients who were treated with adjuvant or neoadjuvant imatinib. RESULTS Imaging of the abdomen and the pelvis with computerised tomography (CT) or magnetic resonance imaging (MRI) usually suffices, since metastases are uncommon at other sites. The frequency of imaging may be adjusted with the risk of recurrence with time. Very low risk GISTs are very frequently cured with surgery and usually require no regular follow-up after complete surgery, and annual CT of the abdomen and the pelvis for 5 years suffices for most patients with a low to intermediate risk for recurrence. Most high-risk patients are treated with imatinib for at least 3 years after surgery. CT or MRI may be carried out 6-monthly during adjuvant imatinib, 3 to 4-monthly during the 2 years that follow discontinuation of imatinib when the risk of recurrence is high, and then at 6-12 month intervals to complete 10 years of follow-up. Recurrence after the first 10 years of follow-up is infrequent. CONCLUSIONS The follow-up schedules are best tailored with the risk of recurrence. The risk of recurrence should be estimated with the prognostic tools that consider the most relevant prognostic factors.
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Affiliation(s)
- H Joensuu
- Comprehensive Cancer Center Helsinki, and University of Helsinki, Helsinki, Finland.
| | - J Martin-Broto
- Virgen del Rocío University Hospital, Instituto de Biomedicina de Sevilla (IBIS), Sevilla, Spain.
| | - T Nishida
- National Cancer Center Hospital East, Chiba, Japan.
| | - P Reichardt
- Cancer Center Berlin-Buch, HELIOS Klinikum, Berlin, Germany.
| | - P Schöffski
- Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium.
| | - R G Maki
- Memorial Sloan-Kettering Cancer Center, New York, USA.
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Pantaleo MA, Lolli C, Nannini M, Astolfi A, Indio V, Saponara M, Urbini M, La Rovere S, Gill A, Goldstein D, Ceccarelli C, Santini D, Rossi G, Fiorentino M, Di Scioscio V, Fusaroli P, Mandrioli A, Gatto L, Catena F, Basso U, Ercolani G, Pinna AD, Biasco G. Good survival outcome of metastatic SDH-deficient gastrointestinal stromal tumors harboring SDHA mutations. Genet Med 2015; 17:391-395. [PMID: 25188872 DOI: 10.1038/gim.2014.115] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2014] [Accepted: 07/23/2014] [Indexed: 01/29/2023] Open
Abstract
PURPOSE A subset of patients with KIT/PDGFRA wild-type gastrointestinal stromal tumors show loss of function of succinate dehydrogenase, mostly due to germ-line mutations of succinate dehydrogenase subunits, with a predominance of succinate dehydrogenase subunit A. The clinical outcome of these patients seems favorable, as reported in small series in which patients were individually described. This work evaluates a retrospective survival analysis of a series of patients with metastatic KIT/PDGFRA wild-type succinate dehydrogenase-deficient gastrointestinal stromal tumors. METHODS Sixty-nine patients with metastatic gastrointestinal stromal tumors were included in the study (11 KIT/PDGFRA wild-type, of whom 6 were succinate dehydrogenase deficient, 5 were non-succinate dehydrogenase deficient, and 58 were KIT/PDGFRA mutant). All six succinate dehydrogenase-deficient patients harbored SDHA mutations. Kaplan-Meier curves and log-rank tests were used to compare the survival of patients with succinate dehydrogenase subunit A-mutant gastrointestinal stromal tumors with that of KIT/PDGFRA wild-type patients without succinate dehydrogenase deficiency and patients with KIT/PDGFRA-mutant gastrointestinal stromal tumors. RESULTS Follow-up ranged from 8.5 to 200.7 months. The difference between succinate dehydrogenase subunit A-mutant gastrointestinal stromal tumors and KIT/PDGFRA-mutant or KIT/PDGFRA wild-type non-succinate dehydrogenase deficient gastrointestinal stromal tumors was significant considering different analyses (P = 0.007 and P = 0.033, respectively, from diagnosis of gastrointestinal stromal tumor for the whole study population; P = 0.005 and P = 0.018, respectively, from diagnosis of metastatic disease for the whole study population; P = 0.007 for only patients who were metastatic at diagnosis). CONCLUSION Patients with metastatic KIT/PDGFRA wild-type succinate dehydrogenase-deficient gastrointestinal stromal tumors harboring succinate dehydrogenase subunit A mutations present an impressively long survival. These patients should be identified in clinical practice to better tailor treatments and follow-up over time.
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Affiliation(s)
- Maria A Pantaleo
- 1] Department of Specialized, Experimental and Diagnostic Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy [2] "Giorgio Prodi" Cancer Research Center, University of Bologna, Bologna, Italy
| | - Cristian Lolli
- Department of Specialized, Experimental and Diagnostic Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
| | - Margherita Nannini
- Department of Specialized, Experimental and Diagnostic Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
| | - Annalisa Astolfi
- 8220;Giorgio Prodi" Cancer Research Center, University of Bologna, Bologna, Italy
| | - Valentina Indio
- 8220;Giorgio Prodi" Cancer Research Center, University of Bologna, Bologna, Italy
| | - Maristella Saponara
- Department of Specialized, Experimental and Diagnostic Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
| | - Milena Urbini
- 8220;Giorgio Prodi" Cancer Research Center, University of Bologna, Bologna, Italy
| | | | - Antony Gill
- Department of Anatomical Pathology, Royal North Shore Hospital, Australia and University of Sydney, Sydney, Australia
| | - David Goldstein
- 1] Prince of Wales Hospital, Sydney, Australia [2] Prince of Wales Clinical School, University of New South Wales, New South Wales, Australia
| | - Claudio Ceccarelli
- Pathology Unit, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
| | - Donatella Santini
- Pathology Unit, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
| | - Giulio Rossi
- Section of Pathologic Anatomy and Division of Oncology, Modena University Hospital Trust, Modena, Italy
| | - Michelangelo Fiorentino
- Laboratory of Oncological and Transplant Molecular Pathology, Pathology Unit, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
| | - Valerio Di Scioscio
- Department of Radiology, Sant'Orsola Malpighi Hospital, Bologna University, Bologna, Italy
| | - Pietro Fusaroli
- GI Unit, Department of Medical and Surgical Sciences, University of Bologna/Hospital of Imola , Bologna, Italy
| | - Anna Mandrioli
- Department of Specialized, Experimental and Diagnostic Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
| | - Lidia Gatto
- Department of Specialized, Experimental and Diagnostic Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
| | - Fausto Catena
- Department of Surgery and Transplantation, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
| | - Umberto Basso
- Medical Oncology 1, Veneto Oncology Institute, IRCCS, Padua, Italy
| | - Giorgio Ercolani
- Department of Surgery and Transplantation, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
| | - Antonio Daniele Pinna
- Department of Surgery and Transplantation, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy
| | - Guido Biasco
- 1] Department of Specialized, Experimental and Diagnostic Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy [2] "Giorgio Prodi" Cancer Research Center, University of Bologna, Bologna, Italy
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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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Wang YM, Gu ML, Ji F. Succinate dehydrogenase-deficient gastrointestinal stromal tumors. World J Gastroenterol 2015; 21:2303-2314. [PMID: 25741136 PMCID: PMC4342905 DOI: 10.3748/wjg.v21.i8.2303] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/24/2014] [Revised: 09/22/2014] [Accepted: 12/16/2014] [Indexed: 02/07/2023] Open
Abstract
Most gastrointestinal stromal tumors (GISTs) are characterized by KIT or platelet-derived growth factor alpha (PDGFRA) activating mutations. However, there are still 10%-15% of GISTs lacking KIT and PDGFRA mutations, called wild-type GISTs (WT GISTs). Among these so-called WT GISTs, a small subset is associated with succinate dehydrogenase (SDH) deficiency, known as SDH-deficient GISTs. In addition, GISTs that occur in Carney triad and Carney-Stratakis syndrome represent specific examples of SDH-deficient GISTs. SDH-deficient GISTs locate exclusively in the stomach, showing predilection for children and young adults with female preponderance. The tumor generally pursues an indolent course and exhibits primary resistance to imatinib therapy in most cases. Loss of succinate dehydrogenase subunit B expression and overexpression of insulin-like growth factor 1 receptor (IGF1R) are common features of SDH-deficient GISTs. In WT GISTs without succinate dehydrogenase activity, upregulation of hypoxia-inducible factor 1α may lead to increased growth signaling through IGF1R and vascular endothelial growth factor receptor (VEGFR). As a result, IGF1R and VEGFR are promising to be the novel therapeutic targets of GISTs. This review will update the current knowledge on characteristics of SDH-deficient GISTs and further discuss the possible mechanisms of tumorigenesis and clinical management of SDH-deficient GISTs.
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30
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Blay JY, Casali PG, Dei Tos AP, Le Cesne A, Reichardt P. Management of Gastrointestinal Stromal Tumour: Current Practices and Visions for the Future. Oncology 2015; 89:1-13. [DOI: 10.1159/000374120] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2014] [Accepted: 12/23/2014] [Indexed: 11/19/2022]
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31
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Quatrième édition de la classification OMS des tumeurs des tissus mous. Ann Pathol 2015; 35:71-85. [DOI: 10.1016/j.annpat.2014.11.003] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2014] [Accepted: 11/13/2014] [Indexed: 12/11/2022]
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32
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[Intra-abdominal soft tissue tumors. What needs to be known to reach the diagnosis with the help of immunohistochemistry, FISH and molecular biology]. Ann Pathol 2014; 35:114-25. [PMID: 25541116 DOI: 10.1016/j.annpat.2014.11.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2014] [Accepted: 11/25/2014] [Indexed: 11/22/2022]
Abstract
Connective tissue tumors located inside the abdomen are a rare heterogeneous group of tumors, except for gastro-intestinal stromal tumors. They may be benign, malignant, or intermediate in terms of biologic potential. Pathologists have to remember the list of all the lesions possibly involved, with their immunohistochemical characteristics, and to know which molecular analyses are needed, with which expected results, and by which team they can be performed. The main tumor types are discussed with diagnostic tools and treatment consequences.
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Yamamoto H, Oda Y. Gastrointestinal stromal tumor: recent advances in pathology and genetics. Pathol Int 2014; 65:9-18. [PMID: 25414046 DOI: 10.1111/pin.12230] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2014] [Accepted: 10/07/2014] [Indexed: 12/21/2022]
Abstract
The discovery of KIT gene mutation in gastrointestinal stromal tumor (GIST) has provided a paradigm shift in the classification, diagnosis and molecular-targeted therapy of gastrointestinal mesenchymal tumors. There is growing evidence of phenotype-genotype (KIT, platelet-derived growth factor receptor-alpha, succinate dehydrogenase or other driver gene mutation) and genotype-therapeutic (sensitivity to imatinib) correlations in GIST. Risk stratification based on mitotic counts, tumor size and rupture is useful for the prognostication and management of patients with GIST. Blood vessel invasion is a strong indicator of liver metastasis in GIST. In addition, novel biomarkers such as cell-cycle regulators, microRNAs and their targets have been discovered by using high throughput molecular analyses. In contrast, leiomyosarcoma of the gastrointestinal tract has become a very rare entity in the 'KIT' era, and its molecular pathogenetic mechanism is unclear. Recent studies have revealed a wide spectrum of cytological atypia, mitotic counts and biological behavior of gastrointestinal smooth muscle tumors, suggesting the necessity of establishing the criteria for malignancy. Collectively, both classical histopathological procedures and modern molecular investigations are indispensable for the evolution of diagnosis and treatment of GIST and mimics.
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Affiliation(s)
- Hidetaka Yamamoto
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University and Division of Pathology, Kyushu University Hospital, Fukuoka, Japan
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34
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Tornillo L. Gastrointestinal stromal tumor - an evolving concept. Front Med (Lausanne) 2014; 1:43. [PMID: 25593916 PMCID: PMC4291900 DOI: 10.3389/fmed.2014.00043] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2014] [Accepted: 10/17/2014] [Indexed: 12/18/2022] Open
Abstract
Gastrointestinal stromal tumors (GISTs) are the most frequent mesenchymal tumors of the gastrointestinal tract. The discovery that these tumors, formerly thought of smooth muscle origin, are indeed better characterized by specific activating mutation in genes coding for the receptor tyrosine kinases (RTKs) CKIT and PDGFRA and that these mutations are strongly predictive for the response to targeted therapy with RTK inhibitors has made GISTs the typical example of the integration of basic molecular knowledge in the daily clinical activity. The information on the mutational status of these tumors is essential to predict (and subsequently to plan) the therapy. As resistant cases are frequently wild type, other possible oncogenic events, defining other "entities," have been discovered (e.g., succinil dehydrogenase mutation/dysregulation, insuline growth factor expression, and mutations in the RAS-RAF-MAPK pathway). The classification of disease must nowadays rely on the integration of the clinico-morphological characteristics with the molecular data.
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Affiliation(s)
- Luigi Tornillo
- Institute of Pathology, University of Basel , Basel , Switzerland
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35
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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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36
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Nannini M, Astolfi A, Urbini M, Indio V, Santini D, Heinrich MC, Corless CL, Ceccarelli C, Saponara M, Mandrioli A, Lolli C, Ercolani G, Brandi G, Biasco G, Pantaleo MA. Integrated genomic study of quadruple-WT GIST (KIT/PDGFRA/SDH/RAS pathway wild-type GIST). BMC Cancer 2014; 14:685. [PMID: 25239601 PMCID: PMC4181714 DOI: 10.1186/1471-2407-14-685] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2014] [Accepted: 09/17/2014] [Indexed: 12/24/2022] Open
Abstract
Background About 10-15% of adult gastrointestinal stromal tumors (GIST) and the vast majority of pediatric GIST do not harbour KIT or platelet-derived growth factor receptor alpha (PDGFRA) mutations (J Clin Oncol 22:3813–3825, 2004; Hematol Oncol Clin North Am 23:15–34, 2009). The molecular biology of these GIST, originally defined as KIT/PDGFRA wild-type (WT), is complex due to the existence of different subgroups with distinct molecular hallmarks, including defects in the succinate dehydrogenase (SDH) complex and mutations of neurofibromatosis type 1 (NF1), BRAF, or KRAS genes (RAS-pathway or RAS-P). In this extremely heterogeneous landscape, the clinical profile and molecular abnormalities of the small subgroup of WT GIST suitably referred to as quadruple wild-type GIST (quadrupleWT or KITWT/PDGFRAWT/SDHWT/RAS-PWT) remains undefined. The aim of this study is to investigate the genomic profile of KITWT/PDGFRAWT/SDHWT/RAS-PWT GIST, by using a massively parallel sequencing and microarray approach, and compare it with the genomic profile of other GIST subtypes. Methods We performed a whole genome analysis using a massively parallel sequencing approach on a total of 16 GIST cases (2 KITWT/PDGFRAWT/SDHWT and SDHBIHC+/SDHAIHC+, 2 KITWT/PDGFRAWT/SDHAmut and SDHBIHC-/SDHAIHC- and 12 cases of KITmut or PDGFRAmut GIST). To confirm and extend the results, whole-genome gene expression analysis by microarray was performed on 9 out 16 patients analyzed by RNAseq and an additional 20 GIST patients (1 KITWT/PDGFRAWTSDHAmut GIST and 19 KITmut or PDGFRAmut GIST). The most impressive data were validated by quantitave PCR and Western Blot analysis. Results We found that both cases of quadrupleWT GIST had a genomic profile profoundly different from both either KIT/PDGFRA mutated or SDHA-mutated GIST. In particular, the quadrupleWT GIST tumors are characterized by the overexpression of molecular markers (CALCRL and COL22A1) and of specific oncogenes including tyrosine and cyclin- dependent kinases (NTRK2 and CDK6) and one member of the ETS-transcription factor family (ERG). Conclusion We report for the first time an integrated genomic picture of KITWT/PDGFRAWT/SDHWT/RAS-PWT GIST, using massively parallel sequencing and gene expression analyses, and found that quadrupleWT GIST have an expression signature that is distinct from SDH-mutant GIST as well as GIST harbouring mutations in KIT or PDGFRA. Our findings suggest that quadrupleWT GIST represent another unique group within the family of gastrointestintal stromal tumors. Electronic supplementary material The online version of this article (doi:10.1186/1471-2407-14-685) contains supplementary material, which is available to authorized users.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | | | | | - Maria A Pantaleo
- Department of Specialized, Experimental and Diagnostic Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Via Massarenti 9, 40138 Bologna, Italy.
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Abstract
The fourth edition of the World Health Organization (WHO) Classification of Tumours of Soft Tissue and Bone was published in February 2013, and serves to provide an updated classification scheme and reproducible diagnostic criteria for pathologists. Given the relative rarity of soft tissue tumours and the rapid rate of immunohistochemical and genetic/molecular developments (not infrequently facilitating recognition of new tumour entities), this updated text edited by a consensus group is important for both practising pathologists and oncologists. The 2013 WHO classification includes several changes in soft tissue tumour classification, including several new entities (e.g., pseudomyogenic haemangioendothelioma, haemosiderotic fibrolipomatous tumour, and acral fibromyxoma), three newly included sections for gastrointestinal stromal tumours, nerve sheath tumours, and undifferentiated/unclassified soft tissue tumours, respectively, various 'reclassified' tumours, and a plethora of new genetic and molecular data for established tumour types that facilitate better definition and are useful as diagnostic tools. This article briefly outlines these updates based on the 2013 WHO classification of soft tissue tumours.
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Tirumani SH, Tirumani H, Jagannathan JP, Shinagare AB, Hornick JL, George S, Wagner AJ, Ramaiya NH. MDCT features of succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumours. Br J Radiol 2014; 87:20140476. [PMID: 25189191 DOI: 10.1259/bjr.20140476] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
Abstract
OBJECTIVE To describe the multidetector CT (MDCT) features and metastatic pattern of succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumours (GISTs). METHODS In this institutional review board-approved, Health Insurance Portability and Accountability Act-compliant study, we retrospectively identified 34 patients (20 females; mean age, 34 years; range, 12-59 years) with histopathology-confirmed SDH-deficient GIST, who were seen at our institution from 1999 through 2012. MDCT of primary tumour in 8 patients and follow-up imaging in all 34 patients over median follow-up of 106 months [interquartile range (IQR), 52-175 months] were reviewed by two radiologists in consensus. Clinical information was extracted from electronic medical records. RESULTS Primary tumour in all 34 patients was located in the stomach. Mean tumour size (n = 8) was 9.6 cm (range, 8-14 cm). Primary tumours were lobulated, variable in growth pattern, hypo- (1/8) to isodense (7/8) and similar in enhancement to the skeletal muscle. Two were multifocal, four of eight had necrosis and one of eight had haemorrhage. Tumour rupture with haemoperitoneum and tumour-bowel fistula was noted in one patient each. During follow-up, 12/34 patients developed tumour in surgical bed, and 28/34 patients developed metastases. Most common sites of metastases were the liver (24/34), peritoneum (20/34) and lymph nodes (18/34). Carney triad and Carney-Stratakis syndrome were noted in 5/34 and 1/34 patients, respectively. At the time of writing, six patients had deceased at a median interval of 109 months (IQR, 54-126 months). CONCLUSION SDH-deficient GISTs occur in young patients, commonly arise in stomach, can be multifocal and may be associated with Carney triad or Carney-Stratakis syndrome. They frequently metastasize to lymph nodes in addition to the liver and peritoneum and are associated with indolent course despite metastatic spread. ADVANCES IN KNOWLEDGE The presence of features unusual for conventional GIST on imaging should alert the radiologist for the possibility of SDH-deficient GIST, especially, because SDH-deficient GISTs are resistant to imatinib. Young age at diagnosis, prolonged survival, association with Carney triad and Carney-Stratakis syndrome and occurrence of concurrent renal cell carcinoma and thyroid malignancies necessitates long-term follow-up of patients with SDH-deficient GISTs.
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Affiliation(s)
- S H Tirumani
- 1 Department of Radiology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
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Doyle LA. Sarcoma classification: an update based on the 2013 World Health Organization Classification of Tumors of Soft Tissue and Bone. Cancer 2014; 120:1763-74. [PMID: 24648013 DOI: 10.1002/cncr.28657] [Citation(s) in RCA: 275] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2014] [Accepted: 02/10/2014] [Indexed: 12/18/2022]
Abstract
The 2013 World Health Organization Classification of Tumors of Soft Tissue and Bone incorporates changes in tumor classification, as well as new genetic insights into the pathogenesis of many different tumor types that have emerged over the 11 years since the publication of the prior volume. This article reviews changes in the classification of soft tissue and bone sarcomas as well as tumors of intermediate biologic potential in the 2013 World Health Organization volume, new molecular insights into these tumors, and associated surgical and clinical implications.
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Affiliation(s)
- Leona A Doyle
- Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
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40
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Novel uses of immunohistochemistry in the diagnosis and classification of soft tissue tumors. Mod Pathol 2014; 27 Suppl 1:S47-63. [PMID: 24384853 DOI: 10.1038/modpathol.2013.177] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2013] [Accepted: 07/30/2013] [Indexed: 12/13/2022]
Abstract
Immunohistochemistry plays a key role in the diagnosis of soft tissue tumors. Until recently, however, the primary purpose of immunohistochemistry in this context was simply to attempt to demonstrate a line of differentiation. Unfortunately, most traditional markers (predominantly directed against cytoplasmic determinants) show relatively limited specificity. Over the last decade or so, much more specific immunohistochemical markers for soft tissue tumors have been developed. This review will provide an update of some of the most useful new diagnostic markers, which are significantly changing clinical practice for surgical pathologists, separated into three general categories: (1) lineage-restricted transcription factors, (2) protein correlates of molecular alterations, and (3) diagnostic markers identified by gene expression profiling.
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41
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Doyle LA, Hornick JL. Gastrointestinal stromal tumours: from KIT to succinate dehydrogenase. Histopathology 2013; 64:53-67. [DOI: 10.1111/his.12302] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Affiliation(s)
- Leona A Doyle
- Department of Pathology; Brigham and Women's Hospital ; Harvard Medical School; Boston MA USA
| | - Jason L Hornick
- Department of Pathology; Brigham and Women's Hospital ; Harvard Medical School; Boston MA USA
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Chan JKC. Newly Available Antibodies With Practical Applications in Surgical Pathology. Int J Surg Pathol 2013; 21:553-72. [PMID: 24225578 DOI: 10.1177/1066896913507601] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Selected antibodies that have become available in recent years and have applications in diagnostic pathology are discussed. They include antibodies that are organ-related, provide information on cellular differentiation or histogenetic type, have predictive value in tumors, and highlight infective agents. PAX8 (paired box gene 8) is a marker expressed in the lower female genital tract, thyroid, and kidney and their tumors. Napsin A is expressed in the lung and kidney and is an alternative marker for pulmonary adenocarcinoma. Arginase A is a sensitive and specific marker for liver tumors. ERG (Ets-related gene) is an excellent marker for endothelium and vascular tumors as well as prostatic cancer (about 50% of cases). SOX10 (SRY-related HMG box) is expressed predominantly in melanocytic and Schwann cells and the corresponding tumors. DOG1 (discovered on GIST 1) is an excellent marker for gastrointestinal stromal tumor (GIST) and acinic cell carcinoma. OCT3/4 is a pan–germ cell tumor marker, except yolk sac tumor. SALL4 is positive in various types of germ cell tumors, including yolk sac tumor. MUC4 (mucin-related antigen 4) is a sensitive and specific marker for low-grade fibromyxoid sarcoma. Langerin is a specific marker for Langerhans cells and their tumors. SOX11 is a sensitive marker for mantle cell lymphoma. New generation antibodies against anaplastic lymphoma kinase (ALK) are required to reliably demonstrate ALK gene translocation in pulmonary carcinomas. Lack of expression of succinate dehydrogenase B is seen in paragangliomas of the hereditary form and in the pediatric type of GIST. Antibodies against Trepenoma pallidum can facilitate the diagnosis of syphilis, whereas those against SV40 (simian virus 40) are helpful for diagnosis of BK virus infection and progressive multifocal leukoencephalopathy.
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Bellizzi AM. Contributions of molecular analysis to the diagnosis and treatment of gastrointestinal neoplasms. Semin Diagn Pathol 2013; 30:329-61. [DOI: 10.1053/j.semdp.2013.11.001] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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Abstract
Gastrointestinal stromal tumours (GISTs) are mesenchymal neoplasms that arise in the gastrointestinal tract, usually in the stomach or the small intestine and rarely elsewhere in the abdomen. They can occur at any age, the median age being 60-65 years, and typically cause bleeding, anaemia, and pain. GISTs have variable malignant potential, ranging from small lesions with a benign behaviour to fatal sarcomas. Most tumours stain positively for the mast/stem cell growth factor receptor KIT and anoctamin 1 and harbour a kinase-activating mutation in either KIT or PDGFRA. Tumours without such mutations could have alterations in genes of the succinate dehydrogenase complex or in BRAF, or rarely RAS family genes. About 60% of patients are cured by surgery. Adjuvant treatment with imatinib is recommended for patients with a substantial risk of recurrence, if the tumour has an imatinib-sensitive mutation. Tyrosine kinase inhibitors substantially improve survival in advanced disease, but secondary drug resistance is common.
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Affiliation(s)
- Heikki Joensuu
- Department of Oncology, Helsinki University Central Hospital, Helsinki, Finland.
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Gastrointestinal stromal tumors (GIST): lesser known facts. Clin Imaging 2013; 37:821-9. [DOI: 10.1016/j.clinimag.2013.04.005] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2013] [Accepted: 04/16/2013] [Indexed: 11/20/2022]
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Gastrointestinal stromal tumors: risk assessment and adjuvant therapy. Hematol Oncol Clin North Am 2013; 27:889-904. [PMID: 24093166 DOI: 10.1016/j.hoc.2013.07.004] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Adjuvant imatinib prolongs recurrence-free survival and probably overall survival of patients who have undergone surgery for gastrointestinal stromal tumor (GIST). Estimation of the risk of recurrence with a prognostication tool and tumor mutation analysis is essential before imatinib initiation, because approximately 60% of patients with GIST with operable tumor are cured by surgery alone and some mutated tyrosine kinases are insensitive to imatinib. Adjuvant imatinib is usually administered for 3 years at the dose of 400 mg once daily. Early detection of tumors that recur despite adjuvant therapy with longitudinal imaging of the abdomen is likely beneficial.
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Abstract
Mesenchymal tumors involve the gastrointestinal (GI) tract more frequently than other visceral organs. Many such tumors are small, and are benign and increasingly being detected incidentally during colonoscopic screening. Some tumors show distinctive features at this site, such as schwannoma and clear cell sarcoma-like tumor of the GI tract. Without knowledge of these features, recognition of these tumor types can be difficult. This reviews addresses recent developments and diagnostic features of mesenchymal tumors of the GI tract other than gastrointestinal stromal tumor (GIST).
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Nannini M, Biasco G, Astolfi A, Pantaleo MA. An overview on molecular biology of KIT/PDGFRA wild type (WT) gastrointestinal stromal tumours (GIST). J Med Genet 2013; 50:653-61. [DOI: 10.1136/jmedgenet-2013-101695] [Citation(s) in RCA: 67] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
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Kang G, Park YS, Jung ES, Joo M, Kang MS, Ahn S, Kang GH, Kim KM. Gastrointestinal stromal tumors in children and young adults: a clinicopathologic and molecular genetic study of 22 Korean cases. APMIS 2013; 121:938-44. [PMID: 23755839 DOI: 10.1111/apm.12085] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2012] [Accepted: 12/19/2012] [Indexed: 12/17/2022]
Abstract
Studies on gastrointestinal stromal tumors (GISTs) in young patients are limited due to their rarity, and none have been conducted in Asian populations. GISTs from patients under the age of 30 were retrospectively reviewed and were analyzed for clinicopathologic features, immunohistochemistry for SDHB (succinate dehydrogenase subunit B), and mutations for exon 9, 11, 13, and 17 of KIT gene and exon 12, 14, and 18 of PDGFRA gene. We found two pediatric (<18 years old) and 20 young adult (18-30 years old) GIST cases. Pediatric GISTs occurred in two girls, both as solitary masses with epithelioid histology in the stomach. Both GISTs were wild type for KIT and PDGFRA genes, were negative for SDHB, and there was no recurrence during follow-up. Of the 20 GISTs in young adults, 12 (60%) were from extra-gastric locations (six duodenum, five jejunum, and one esophagus), and 16 (80%) showed a spindle cell morphology. Mutations of KIT or PDGFRA genes were identified in 14 (78%) of the 18 cases. One patient with multiple gastric GISTs with perigastric lymph node metastases at presentation developed multiple distant metastases and died of the disease 7.3 years after diagnosis. Of the 19 R0-resected young adult patients, one patient with small intestinal GIST harboring KIT exon 11 deletion mutation developed recurrence and showed partial responses for imatinib. In summary, compared with pediatric GIST cases, young adult GISTs are heterogeneous and share the characteristics of both pediatric and adult GISTs. When a mesenchymal tumor is clinically suspected in the small intestine of young adults, a GIST should be included in the differential diagnoses. Further mutation studies and extensive treatments are recommended for these cases.
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Affiliation(s)
- Guhyun Kang
- Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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Nannini M, Astolfi A, Paterini P, Urbini M, Santini D, Catena F, Indio V, Casadio R, Pinna AD, Biasco G, Pantaleo MA. Expression of IGF-1 receptor in KIT/PDGF receptor-α wild-type gastrointestinal stromal tumors with succinate dehydrogenase complex dysfunction. Future Oncol 2013; 9:121-6. [PMID: 23252569 DOI: 10.2217/fon.12.170] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
KIT/PDGF receptor-α (PDGFRA) wild-type (WT) gastrointestinal stromal tumors (GIST) are characterized by an overexpression of IGF-1 receptor (IGF1R) at the mRNA and protein level. More recently, germline and somatic mutations in succinate dehydrogenase (SDH) subunits A, B and C have been identified in KIT/PDGFRA WT sporadic GIST. Until now, the molecular basis of IGF1R overexpression in KIT/PDGFRA WT GIST has not been explained. In this brief report we investigate the status of the SDH complex at the genomic and protein level in relation to IGF1R expression at the mRNA and protein level in seven KIT/PDGFRA WT sporadic GIST patients. We found that IGF1R was upregulated in all patients harboring SDH mutations or displaying a SDH dysfunction, with respect to KIT/PDGFRA WT GIST without SDH mutations. Western blot analysis confirmed that all patients with an upregulation of IGF1R mRNA had detectable IGF1R protein expression. This report would suggest that IGF1R overexpression in KIT/PDGFRA WT GIST could be driven by the loss-of-function of the SDH mitochondrial complex.
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Affiliation(s)
- Margherita Nannini
- Department of Hematology & Oncological Sciences L&A Seràgnoli, S. Orsola-Malpighi Hospital, University of Bologna, Via Massarenti 9, 40138, Bologna, Italy.
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