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1
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Klimácek B, Åkerström T, Annebäck M, Hellman P, Norlén O, Stålberg P. Evaluation of hand-assisted laparoscopic surgery of small intestinal neuroendocrine tumours as an alternative surgical treatment to open surgery. Langenbecks Arch Surg 2025; 410:90. [PMID: 40047926 PMCID: PMC11885331 DOI: 10.1007/s00423-025-03658-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2024] [Accepted: 02/23/2025] [Indexed: 03/09/2025]
Abstract
PURPOSE Small intestinal neuroendocrine tumours (SI-NETs) are the most common malignancy of the small bowel. Curative treatment is surgical, with exploratory laparotomy considered the standard approach. This study aimed to assess the outcomes of minimally invasive surgery compared to open approach for SI-NETs at the Endocrine surgical unit at Uppsala University Hospital. METHODS This retrospective cohort study included patients who underwent surgery for SI-NET between 2013 and 2023 at Uppsala University Hospital. Variables such as operative time, length of hospital stay, use of analgesia and radicality were compared between groups of patients operated on before and after 2019, when hand-port assisted laparoscopic surgery (HALS) for SI-NETs was introduced at our unit. Outcomes were further compared between open and hand-port assisted laparoscopic approaches. The primary outcome was the rate of radicality achieved for stage II-III patients. Secondary outcomes included operative time, the length of hospital stay and the use of epidural and patient-controlled analgesia. RESULTS Of 97 patients, 58 (59.8%) underwent open surgery and 39 (40.2%) underwent hand-port assisted laparoscopic surgery. There was no significant difference in operative time (121 min [91.3-150.3] vs 108 min [83-141]), length of hospital stay, 6 days [4-7] vs 5 days [4-8]), and surgical radicality in patients with stage II-III, 85.2% vs 100%, (p = 0.079). 86.2% of patients with explorative laparotomy required epidural analgesia compared to only 23.1% with HALS (p < 0.001). CONCLUSION Hand-port assisted laparoscopic surgery of SI-NETs is a feasible approach that preserves radical resection while enhancing postoperative recovery, with a lower requirement of epidural analgesia.
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Affiliation(s)
- Branislav Klimácek
- Department of Surgical Sciences, Uppsala University Hospital, 751 85, Uppsala, Sweden.
| | - Tobias Åkerström
- Department of Surgical Sciences, Uppsala University Hospital, 751 85, Uppsala, Sweden
| | - Matilda Annebäck
- Department of Surgical Sciences, Uppsala University Hospital, 751 85, Uppsala, Sweden
| | - Per Hellman
- Department of Surgical Sciences, Uppsala University Hospital, 751 85, Uppsala, Sweden
| | - Olov Norlén
- Department of Surgical Sciences, Uppsala University Hospital, 751 85, Uppsala, Sweden
| | - Peter Stålberg
- Department of Surgical Sciences, Uppsala University Hospital, 751 85, Uppsala, Sweden
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2
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Webster AP, Thirlwell C. The Molecular Biology of Midgut Neuroendocrine Neoplasms. Endocr Rev 2024; 45:343-350. [PMID: 38123518 PMCID: PMC11074790 DOI: 10.1210/endrev/bnad034] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Revised: 10/12/2023] [Accepted: 11/28/2023] [Indexed: 12/23/2023]
Abstract
Midgut neuroendocrine neoplasms (NENs) are one of the most common subtypes of NEN, and their incidence is rising globally. Despite being the most frequently diagnosed malignancy of the small intestine, little is known about their underlying molecular biology. Their unusually low mutational burden compared to other solid tumors and the unexplained occurrence of multifocal tumors makes the molecular biology of midgut NENs a particularly fascinating field of research. This review provides an overview of recent advances in the understanding of the interplay of the genetic, epigenetic, and transcriptomic landscape in the development of midgut NENs, a topic that is critical to understanding their biology and improving treatment options and outcomes for patients.
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Affiliation(s)
- Amy P Webster
- Department of Clinical and Biomedical Science, University of Exeter College of Medicine and Health, Exeter, EX2 5DW, UK
| | - Chrissie Thirlwell
- Department of Clinical and Biomedical Science, University of Exeter College of Medicine and Health, Exeter, EX2 5DW, UK
- University of Bristol Medical School, University of Bristol, Bristol, BS8 1UD, UK
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3
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Arya S, Ventin M, Nebbia M, Fernandez-Del Castillo C, Lionetto G, Qadan M, Lillemoe KD, Deshpande V, Catalano OA, Thiele EA, Ferrone CR. Long-Term Outcomes of Tuberous Sclerosis Complex-Associated Non-functional Pancreatic Neuroendocrine Tumors: Should We Be More Conservative? Ann Surg Oncol 2023; 30:7748-7755. [PMID: 37648887 PMCID: PMC10562497 DOI: 10.1245/s10434-023-14157-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2023] [Accepted: 07/30/2023] [Indexed: 09/01/2023]
Abstract
BACKGROUND Hereditary syndromes such as tuberous sclerosis complex (TSC) account for 10% of pancreatic neuroendocrine tumors (PNETs). Surgical intervention is the current standard of care for sporadic PNETs (spPNETs) that are >2 cm in size. We compared the long-term outcomes of resected TSC-PNETs with patients with spPNETs. METHODS We conducted a retrospective review of perioperative data and outcomes of TSC-PNETs compared with spPNETs. Inclusion criteria involved selecting patients whose tumors were no larger than 5.1 cm, the maximum size observed in the TSC-PNET group. RESULTS Of the 347 patients resected for PNETs, 14 were TSC-PNETs and 241 were non-functional spPNETs. The median age for the whole cohort was 56 years (interquartile range [IQR] 21.0) and 47% were female. The median follow-up was 103.8 months (95% confidence interval [CI] 89.2-118.6). Specifically, 14 patients with TSC-PNETs and 194 patients with spPNETs were included. Compared with spPNETs, patients with TSC-PNETs were operated on at a younger age (24.0 vs. 57.5 years; p < 0.001), were more frequently multifocal (28.5% vs. 0.0%; p < 0.001), were more likely to undergo minimally invasive operations (78.6% vs. 24.3%; p < 0.001), and had more R1 resections (28.6% vs. 5.7%; p = 0.006). Local and distant tumor recurrence was only observed in the spPNET group. The 5-year mortality rates for the spPNET and TSC-PNET groups were 6.2% and 0.0%, respectively. No PNET-related deaths were observed among TSC-PNETs. CONCLUSION None of the TSC-PNET patients recurred after a median follow-up of 78.0 months. The risk-benefit of aggressive pancreatic operations in TSC-PNET patients is still unclear and our findings suggest a conservative approach should be considered.
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Affiliation(s)
- Shahrzad Arya
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Marco Ventin
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Martina Nebbia
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | | | - Gabriella Lionetto
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Motaz Qadan
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Keith D Lillemoe
- Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Vikram Deshpande
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Onofrio A Catalano
- Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Elizabeth A Thiele
- Herscot Center for Tuberous Sclerosis Complex, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Cristina R Ferrone
- Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
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4
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Kupietzky A, Dover R, Mazeh H. Surgical aspects of small intestinal neuroendocrine tumors. World J Gastrointest Surg 2023; 15:566-577. [PMID: 37206065 PMCID: PMC10190731 DOI: 10.4240/wjgs.v15.i4.566] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Revised: 02/25/2023] [Accepted: 03/27/2023] [Indexed: 04/22/2023] Open
Abstract
Small intestinal neuroendocrine tumors (NETs) are a heterogeneous group of epithelial tumors with a predominant neuroendocrine differentiation. Although NETs are usually considered rare neoplasms, small intestinal NETs are the most common primary malignancy of the small bowel, with an increasing prevalence worldwide during the course of the past few decades. The indolent nature of these tumors often leads to a delayed diagnosis, resulting in over one-third of patients presenting with synchronous metastases. Primary tumor resection remains the only curative option for this type of tumor. In this review article, the various surgical aspects for the excision of small intestinal NETs are discussed.
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Affiliation(s)
- Amram Kupietzky
- Department of Surgery, Hadassah Medical Organization and Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 91240, Israel
| | - Roi Dover
- Department of Surgery, Hadassah Medical Organization and Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 91240, Israel
| | - Haggi Mazeh
- Department of Surgery, Hadassah Medical Organization and Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem 91240, Israel
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5
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Independent somatic evolution underlies clustered neuroendocrine tumors in the human small intestine. Nat Commun 2021; 12:6367. [PMID: 34737276 PMCID: PMC8568927 DOI: 10.1038/s41467-021-26581-5] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Accepted: 10/12/2021] [Indexed: 12/13/2022] Open
Abstract
Small intestine neuroendocrine tumor (SI-NET), the most common cancer of the small bowel, often displays a curious multifocal phenotype with several tumors clustered together in a limited intestinal segment. SI-NET also shows an unusual absence of driver mutations explaining tumor initiation and metastatic spread. The evolutionary trajectories that underlie multifocal SI-NET lesions could provide insight into the underlying tumor biology, but this question remains unresolved. Here, we determine the complete genome sequences of 61 tumors and metastases from 11 patients with multifocal SI-NET, allowing for elucidation of phylogenetic relationships between tumors within single patients. Intra-individual comparisons revealed a lack of shared somatic single-nucleotide variants among the sampled intestinal lesions, supporting an independent clonal origin. Furthermore, in three of the patients, two independent tumors had metastasized. We conclude that primary multifocal SI-NETs generally arise from clonally independent cells, suggesting a contribution from a cancer-priming local factor.
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6
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Carpizo DR, Harris CR. Genetic Drivers of Ileal Neuroendocrine Tumors. Cancers (Basel) 2021; 13:cancers13205070. [PMID: 34680217 PMCID: PMC8533727 DOI: 10.3390/cancers13205070] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 10/07/2021] [Accepted: 10/08/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary Although ileal neuroendocrine tumors are the most common tumors of the small intestine, they are not well-defined at the genetic level. Unlike most cancers, they have an unusually low number of mutations, and also lack recurrently mutated genes. Moreover ileal NETs have been difficult to study in the laboratory because there were no animal models and because cell lines were generally unavailable. But recent advances, including the first ileal NET mouse model as well as methods for culturing patient tumor samples, have been described and have already helped to identify IGF2 and CDK4 as two of the genetic drivers for this tumor type. These advances may help in the development of new treatments for patients. Abstract The genetic causes of ileal neuroendocrine tumors (ileal NETs, or I-NETs) have been a mystery. For most types of tumors, key genes were revealed by large scale genomic sequencing that demonstrated recurrent mutations of specific oncogenes or tumor suppressors. In contrast, genomic sequencing of ileal NETs demonstrated a distinct lack of recurrently mutated genes, suggesting that the mechanisms that drive the formation of I-NETs may be quite different than the cell-intrinsic mutations that drive the formation of other tumor types. However, recent mouse studies have identified the IGF2 and RB1 pathways in the formation of ileal NETs, which is supported by the subsequent analysis of patient samples. Thus, ileal NETs no longer appear to be a cancer without genetic causes.
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7
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Gudmundsdottir H, Graham RP, Sonbol MB, Smoot RL, Truty MJ, Kendrick ML, Nagorney DM, Habermann EB, Halfdanarson TR, Cleary SP. Multifocality is not associated with worse survival in sporadic pancreatic neuroendocrine tumors. J Surg Oncol 2021; 124:1077-1084. [PMID: 34310723 DOI: 10.1002/jso.26618] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2021] [Revised: 06/19/2021] [Accepted: 07/11/2021] [Indexed: 12/25/2022]
Abstract
BACKGROUND AND OBJECTIVES Pancreatic neuroendocrine tumors (pNETs) in patients with hereditary cancer syndromes are typically multifocal. In contrast, sporadic pNETs are usually unifocal and the incidence of multifocal sporadic pNETs is unknown. The primary aim of this study was to investigate the incidence of multifocality in sporadic pNETs and any associated effect on recurrence risk and survival. METHODS Patients who underwent resection of pNETs at Mayo Clinic from 2000 to 2019 were identified and clinical data were obtained from medical records. Syndromic disease was defined as pNETs arising in the setting of a hereditary cancer syndrome. Statistical comparisons were made using χ2 , Fisher's exact, and Kruskal-Wallis tests and survival was assessed using the Kaplan-Meier method. RESULTS Six hundred and sixty-one patients with sporadic pNETs and fifty-nine with syndromic pNETs were identified. Multifocal disease was present in 4.8% of sporadic patients and 84.7% of syndromic patients (p < .001). Within patients with sporadic pNETs, clinicopathologic features and recurrence-free and overall survival were similar between patients with unifocal and multifocal disease. CONCLUSIONS Multifocal sporadic pNETs are rare and multifocality is not associated with worse survival or increased recurrence risk. Patients with multifocal sporadic pNETs can likely be safely managed with a combination of resection and observation as indicated for each tumor.
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Affiliation(s)
| | - Rondell P Graham
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
| | - Mohamad B Sonbol
- Department of Medical Oncology, Mayo Clinic, Phoenix, Arizona, USA
| | - Rory L Smoot
- Department of Surgery, Mayo Clinic, Rochester, Minnesota, USA
| | - Mark J Truty
- Department of Surgery, Mayo Clinic, Rochester, Minnesota, USA
| | | | | | - Elizabeth B Habermann
- Mayo Clinic Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, Rochester, Minnesota, USA
| | | | - Sean P Cleary
- Department of Surgery, Mayo Clinic, Rochester, Minnesota, USA
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8
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Multifocal Small Bowel Neuroendocrine Tumours. World J Surg 2021; 45:208-212. [PMID: 32613346 DOI: 10.1007/s00268-020-05663-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
In contemporary surgical series, the incidence of multifocal tumours (MFT) in small bowel neuroendrocrine tumours (SBNET) is as high as 50%. Familial forms of SBNET appear to have an even higher rate of MFTs in the range of 80%. Multifocal disease poses several challenges and questions for the operating surgeon, including the cause of the disease whether it is local metastases or a genetic field defect, the extent of the resection, and the prognosis. The etiology of these multiple tumours appears to be multifactorial and may represent localized metastases in some, a genetic mutation resulting in the rare familial form of this disease in others, or the integration of genetic and epigenetic events within the bowel. Contrary to historical series, recent data suggest that MFT are not associated with a poorer prognosis. The challenge remains on the long-term surveillance of these unique tumours.
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9
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Cheng L, Mann SA, Lopez-Beltran A, Chovanec M, Santoni M, Wang M, Albany C, Adra N, Davidson DD, Cimadamore A, Montironi R, Zhang S. Molecular Characterization of Testicular Germ Cell Tumors Using Tissue Microdissection. Methods Mol Biol 2021; 2195:31-47. [PMID: 32852755 DOI: 10.1007/978-1-0716-0860-9_3] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/10/2023]
Abstract
Testicular germ cell tumors are among the most common malignancies seen in children and young adults. Genomic studies have identified characteristic molecular profiles in testicular cancer, which are associated with histologic subtypes and may predict clinical behavior including treatment responses. Emerging molecular technologies analyzing tumor genomics, transcriptomics, and proteomics may now guide precision management of testicular tumors. Laser-assisted microdissection methods such as laser capture microdissection efficiently isolate selected tumor cells from routine pathology specimens, avoiding contamination from nontarget cell populations. Laser capture microdissection in combination with next generation sequencing makes precise high throughput genetic evaluation effective and efficient. The use of laser capture microdissection (LCM) for molecular testing may translate into great benefits for the clinical management of patients with testicular cancers. This review discusses application protocols for laser-assisted microdissection to investigate testicular germ cell tumors.
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Affiliation(s)
- Liang Cheng
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA. .,Department of Urology, Indiana University School of Medicine, Indianapolis, IN, USA.
| | - Steven A Mann
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Antonio Lopez-Beltran
- Department of Pathology and Surgery, Faculty of Medicine, University of Cordoba, Cordoba, Spain.,Pathology Service, Champalimaud Clinical Center, Lisbon, Portugal
| | - Michal Chovanec
- 2nd Department of Oncology, Faculty of Medicine, Comenius University and National Cancer Institute, Bratislava, Slovakia.,Division of Hematology and Oncology, Indiana University Simon Cancer Center, Indianapolis, IN, USA
| | | | - Mingsheng Wang
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Costantine Albany
- Department of Medicine, Division of Hematology and Oncology, Indiana University Simon Cancer Center, Indianapolis, IN, USA
| | - Nabil Adra
- Department of Medicine, Division of Hematology and Oncology, Indiana University Simon Cancer Center, Indianapolis, IN, USA
| | - Darrell D Davidson
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Alessia Cimadamore
- Section of Pathological Anatomy, Polytechnic University of the Marche Region, School of Medicine, United Hospitals, Ancona, Italy
| | - Rodolfo Montironi
- Section of Pathological Anatomy, Polytechnic University of the Marche Region, School of Medicine, United Hospitals, Ancona, Italy
| | - Shaobo Zhang
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
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10
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Kalifi M, Walter T, Milot L, Hervieu V, Millot I, Gibert B, Roche C, Forestier J, Lombard-Bohas C, Pasquer A, Poncet G. Unifocal versus Multiple Ileal Neuroendocrine Tumors Location: An Embryological Origin. Neuroendocrinology 2021; 111:786-793. [PMID: 32998140 DOI: 10.1159/000511849] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Accepted: 09/24/2020] [Indexed: 11/19/2022]
Abstract
INTRODUCTION Small-intestinal neuroendocrine tumors (SI-NET) are situated preferentially within the ileum. The aim was to describe a potential difference in location between unifocal and multiple ileal-NET. PATIENTS AND METHODS Between December 2010 and December 2019, all consecutive patients who underwent resection in our European Neuroendocrine Tumor Society Center of Excellence, of at least 1 non-duodenal SI-NET, were retrospectively included. The main objective was to prove that multiple ileal-NET were mostly located on the left side of the superior mesenteric artery (SMA) axis (defined as 40 cm from the ileocecal valve), and unifocal ones on the right side. RESULTS Ninety-four patients were included, 6 with unifocal jejunal-NET located 35 cm (range, 10-60) from the duodenojejunal angle (DJA), 44 (47%) with unifocal ileal-NET and 44 (47%) with multiple ileal-NET. The median number of tumors in multiple ileal-NET was 7 (range, 2-95), within a median small bowel segment of 105 cm (10-240). The median length between the proximal tumor and the DJA was 428 cm (300-635) and 540 cm (350-725) for the distal one; 40 (91%) of them were located on the left side of the SMA axis. In contrast, unifocal ileal-NET were located at a median distance of 577 cm (305-820) from the DJA (p < 0.001, compared to multiple ileal-NET); 30 (68%) of them were on the right side of the SMA axis (p < 0.001). CONCLUSION Multiple ileal-NET are mostly located on the left side of the SMA axis. Further studies are warranted to explore the embryological origin of unifocal versus multiple ileal-NET.
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Affiliation(s)
- Maroin Kalifi
- Hospices Civils de Lyon, Hôpital Edouard Herriot, Chirurgie Digestive, Lyon, France
| | - Thomas Walter
- Hospices Civils de Lyon, Hôpital Edouard Herriot, Service de Gastroentérologie et d'Oncologie Digestive, Lyon, France,
- INSERM, UMR 1052-UMR5286, UMR 1032 Lyon Cancer Research Center, Faculté Laennec, Lyon, France,
- Université de Lyon, Université Claude Bernard Lyon 1, Villeurbanne, France,
| | - Laurent Milot
- INSERM, UMR 1052-UMR5286, UMR 1032 Lyon Cancer Research Center, Faculté Laennec, Lyon, France
- Université de Lyon, Université Claude Bernard Lyon 1, Villeurbanne, France
- Hospices Civils de Lyon, Hôpital Edouard Herriot, Radiologie, Lyon, France
| | - Valérie Hervieu
- INSERM, UMR 1052-UMR5286, UMR 1032 Lyon Cancer Research Center, Faculté Laennec, Lyon, France
- Université de Lyon, Université Claude Bernard Lyon 1, Villeurbanne, France
- Hospices Civils de Lyon, Hôpital Edouard Herriot, Service Central d'Anatomie et Cytologie Pathologiques, Lyon, France
| | - Ingrid Millot
- Hospices Civils de Lyon, Hôpital Édouard Herriot, Service d'anesthésie-réanimation, Lyon, France
| | - Benjamin Gibert
- INSERM, UMR 1052-UMR5286, UMR 1032 Lyon Cancer Research Center, Faculté Laennec, Lyon, France
- CNRS Rhône Auvergne, Villeurbanne, France
| | - Colette Roche
- INSERM, UMR 1052-UMR5286, UMR 1032 Lyon Cancer Research Center, Faculté Laennec, Lyon, France
| | - Julien Forestier
- Hospices Civils de Lyon, Hôpital Edouard Herriot, Service de Gastroentérologie et d'Oncologie Digestive, Lyon, France
| | - Catherine Lombard-Bohas
- Hospices Civils de Lyon, Hôpital Edouard Herriot, Service de Gastroentérologie et d'Oncologie Digestive, Lyon, France
| | - Arnaud Pasquer
- Hospices Civils de Lyon, Hôpital Edouard Herriot, Chirurgie Digestive, Lyon, France
| | - Gilles Poncet
- Hospices Civils de Lyon, Hôpital Edouard Herriot, Chirurgie Digestive, Lyon, France
- INSERM, UMR 1052-UMR5286, UMR 1032 Lyon Cancer Research Center, Faculté Laennec, Lyon, France
- Université de Lyon, Université Claude Bernard Lyon 1, Villeurbanne, France
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11
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Zhang Z, Mäkinen N, Kasai Y, Kim GE, Diosdado B, Nakakura E, Meyerson M. Patterns of chromosome 18 loss of heterozygosity in multifocal ileal neuroendocrine tumors. Genes Chromosomes Cancer 2020; 59:535-539. [PMID: 32291827 PMCID: PMC7384092 DOI: 10.1002/gcc.22850] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2020] [Accepted: 03/08/2020] [Indexed: 12/21/2022] Open
Abstract
Ileal neuroendocrine tumors (NETs) represent the most common neoplasm of the small intestine. Although up to 50% of patients with ileal NETs are diagnosed with multifocal disease, the mechanisms by which multifocal ileal NETs arise are not yet understood. In this study, we analyzed genome-wide sequencing data to examine patterns of copy number variation in 40 synchronous primary ileal NETs derived from three patients. Chromosome (chr) 18 loss of heterozygosity (LOH) was the most frequent copy number alteration identified; however, not all primary tumors from the same patient had evidence of this LOH. Our data revealed three distinct patterns of chr18 allelic loss, indicating that primary tumors from the same patient can present different LOH patterns including retention of either parental allele. In conclusion, our results are consistent with the model that multifocal ileal NETs originate independently. In addition, they suggest that there is no specific germline allele on chr18 that is the target of somatic LOH.
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Affiliation(s)
- Zhouwei Zhang
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.,Cancer Program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA
| | - Netta Mäkinen
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.,Cancer Program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA
| | - Yosuke Kasai
- Department of Surgery, University of California San Francisco, San Francisco, California, USA
| | - Grace E Kim
- Department of Pathology, University of California San Francisco, San Francisco, California, USA
| | - Begoña Diosdado
- Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Eric Nakakura
- Department of Surgery, University of California San Francisco, San Francisco, California, USA
| | - Matthew Meyerson
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.,Cancer Program, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.,Departments of Genetics and Medicine, Harvard Medical School, Boston, Massachusetts, USA
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12
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Gangi A, Siegel E, Barmparas G, Lo S, Jamil LH, Hendifar A, Nissen NN, Wolin EM, Amersi F. Multifocality in Small Bowel Neuroendocrine Tumors. J Gastrointest Surg 2018; 22:303-309. [PMID: 29119527 DOI: 10.1007/s11605-017-3586-8] [Citation(s) in RCA: 56] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2017] [Accepted: 09/12/2017] [Indexed: 01/31/2023]
Abstract
BACKGROUND Neuroendocrine tumors (NETs) account for 30% of small bowel (SB) neoplasms. The objectives of this study were to evaluate the incidence of multifocality in primary small bowel neuroendocrine tumors (SBNETs) and to examine the associated outcomes. METHODS Patients with multifocal SBNET were compared to those with a solitary lesion. Only patients who underwent diagnostic workup and surgical intervention at our institution were included in this study. The primary aim of our study was surgical outcomes and mortality and recurrence. The second aim of our study was to evaluate the utility of double-balloon enteroscopy (DBE) and capsule endoscopy. RESULTS Of 178 patients with SBNETs during the study period, 85 met inclusion criteria. The mean age was 61.0 ± 12.6 years and 44.7% were male. The ileum was the primary tumor site for 66 patients (77.7%). Of DBE patients, 28 (62.2%) had additional lesions identified, of which 23 (82.1%) had NET confirmed on pathology. Average tumor size was 1.8 cm and most were well differentiated (89.9%), with Ki-67 of ≥ 2% (65.8%); 74.4% had nodal metastases and 51% of patients had stage IV disease. Forty-six patients (54.1%) had multifocal disease, of whom 37 (80.5%) had an ileal primary. No differences in survival or recurrence were seen for multifocal versus solitary disease. CONCLUSIONS SBNETs have a high incidence of multifocality. DBE can be used in the preoperative assessment to detect multifocal NET. Multifocality has no impact on survival or recurrence outcomes.
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Affiliation(s)
- Alexandra Gangi
- Department of Surgery, Division of Surgical Oncology and Hepatobiliary Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Emily Siegel
- Department of Surgery, Division of Surgical Oncology and Hepatobiliary Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Galinos Barmparas
- Department of Surgery, Division of Surgical Oncology and Hepatobiliary Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Simon Lo
- Center for Digestive Diseases and Gastroenterology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Laith H Jamil
- Center for Digestive Diseases and Gastroenterology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Andrew Hendifar
- Department of Internal Medicine, Division of Hematology and Oncology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Nicholas N Nissen
- Department of Surgery, Division of Surgical Oncology and Hepatobiliary Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Edward M Wolin
- Montefiore Einstein Center for Cancer Care, Bronx, NY, USA
| | - Farin Amersi
- Department of Surgery, Division of Surgical Oncology and Hepatobiliary Surgery, Cedars-Sinai Medical Center, Los Angeles, CA, USA. .,Samuel Oschin Comprehensive Cancer Institute, 8700 Beverly Blvd, #AC-1046A, Los Angeles, CA, 90048, USA.
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13
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Abstract
OBJECTIVES Many patients with small bowel neuroendocrine tumors (SBNETs) have multifocal tumors (MFTs), but the frequency of MFTs has varied widely across SBNET studies. It is also unclear whether patients with MFTs have more advanced disease or worse clinical course than do those with unifocal SBNETs. We set out to determine the frequency of multifocal and unifocal SBNETs and compare clinicopathologic factors, somatostatin receptor 2 expression, and survival. METHODS Clinicopathologic variables from 179 patients with surgically managed SBNETs were collected. Statistical comparisons were made using Welch t-test, Wilcoxon test, and Fisher's exact test. Survival was assessed using the Kaplan-Meier method. Somatostatin receptor 2 expression was analyzed by quantitative polymerase chain reaction, and Ki-67 expression by immunohistochemistry. RESULTS Multifocal tumors were found in 45% of patients with SBNETs. Clinicopathologic factors such as grade, TNM stage, presence of distant metastases, mean somatostatin receptor 2 expression, success of imaging modalities, and preoperative and postoperative hormone levels were not significantly different between multifocal and unifocal groups. Progression-free survival and overall survival were also not significantly affected by multifocality. CONCLUSIONS Clinicopathologic features and survival of patients with MFTs and unifocal tumors are remarkably similar. Although the etiology of MFTs is unclear, patients with MFTs do not have a more aggressive clinical course than patients with unifocal SBNETs.
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Crona J, Skogseid B. GEP- NETS UPDATE: Genetics of neuroendocrine tumors. Eur J Endocrinol 2016; 174:R275-90. [PMID: 27165966 DOI: 10.1530/eje-15-0972] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2015] [Accepted: 12/21/2015] [Indexed: 12/12/2022]
Abstract
Neuroendocrine tumors (NETs) are a heterogeneous group of neoplasms, arising from neuroendocrine cells that are dispersed throughout the body. Around 20% of NETs occur in the context of a genetic syndrome. Today there are at least ten recognized NET syndromes. This includes the classical syndromes: multiple endocrine neoplasias types 1 and 2, and von Hippel-Lindau and neurofibromatosis type 1. Additional susceptibility genes associated with a smaller fraction of NETs have also been identified. Recognizing genetic susceptibility has proved essential both to provide genetic counseling and to give the best preventive care. In this review we will also discuss the knowledge of somatic genetic alterations in NETs. At least 24 genes have been implicated as drivers of neuroendocrine tumorigenesis, and the overall rates of genomic instability are relatively low. Genetic intra-tumoral, as well as inter-tumoral heterogeneity in the same patient, have also been identified. Together these data point towards the common pathways in NET evolution, separating early from late disease drivers. Although knowledge of specific mutations in NETs has limited impact on actual patient management, we predict that in the near future genomic profiling of tumors will be included in the clinical arsenal for diagnostics, prognostics and therapeutic decisions.
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Affiliation(s)
- Joakim Crona
- Department of Medical SciencesUppsala University, Rudbecklaboratoriet, Dag hammarskjölds väg 20, 75185 Uppsala, Sweden
| | - Britt Skogseid
- Department of Medical SciencesUppsala University, Rudbecklaboratoriet, Dag hammarskjölds väg 20, 75185 Uppsala, Sweden
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15
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Clift AK, Faiz O, Al-Nahhas A, Bockisch A, Liedke MO, Schloericke E, Wasan H, Martin J, Ziprin P, Moorthy K, Frilling A. Role of Staging in Patients with Small Intestinal Neuroendocrine Tumours. J Gastrointest Surg 2016; 20:180-8; discussion 188. [PMID: 26394880 DOI: 10.1007/s11605-015-2953-6] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/15/2015] [Accepted: 09/14/2015] [Indexed: 01/31/2023]
Abstract
Small bowel neuroendocrine tumours are the commonest malignancy arising in the small intestine and have substantially increased in incidence in recent decades. Patients with small bowel neuroendocrine tumours commonly develop lymph node and/or distant metastases. Here, we examine the role of staging in 84 surgically treated patients with small bowel neuroendocrine tumours, comparing diagnostic information yielded from morphological, functional and endoscopic modalities. Furthermore, we correlate pre-operative staging with intra-operative findings in a sub-cohort of 20 patients. The vast majority of patients had been histologically confirmed to have low-grade (Ki-67 <2%) disease; however, lymph node and distant metastases were observed in 74 (88.1%) and 51 (60.7%) of patients at presentation, respectively. Liver metastases were evident in 48 (57.1%) patients, with solely peritoneal and bone metastases observed in 2 (2.4%) and 1 (1.2%) patients, respectively. Forty patients (47.6%) received multimodal treatment. In our sub-cohort analysis, pre-operative imaging understaged disease in 14/20 (70%) when compared with intra-operative findings. In patients with multifocal primary tumours and miliary liver metastases, no imaging modality was able to detect entire disease spread. Overall, presently available imaging modalities heavily underestimate disease stage, with meticulous intra-operative abdominal examination being superior to any imaging technology. Multimodal treatment has an important role in prolonging survival.
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Affiliation(s)
- Ashley Kieran Clift
- Department of Surgery and Cancer, Imperial College London, Hammersmith Campus, Du Cane Road, London, W12 0HS, UK
| | - Omar Faiz
- Department of Surgery, St. Mark's Hospital, London, UK
| | - Adil Al-Nahhas
- Department of Nuclear Medicine, Imperial College London, London, UK
| | - Andreas Bockisch
- Department of Nuclear Medicine, University Hospital Essen, Essen, Germany
| | - Marc Olaf Liedke
- Department of Surgery, Westkuesten Klinikum Heide, Heide, Germany
| | - Erik Schloericke
- Department of Surgery, Westkuesten Klinikum Heide, Heide, Germany
| | - Harpreet Wasan
- Department of Surgery and Cancer, Imperial College London, Hammersmith Campus, Du Cane Road, London, W12 0HS, UK
| | - John Martin
- Department of Gastroenterology, Imperial College London, London, UK
| | - Paul Ziprin
- Department of Surgery and Cancer, Imperial College London, Hammersmith Campus, Du Cane Road, London, W12 0HS, UK
| | - Krishna Moorthy
- Department of Surgery and Cancer, Imperial College London, Hammersmith Campus, Du Cane Road, London, W12 0HS, UK
| | - Andrea Frilling
- Department of Surgery and Cancer, Imperial College London, Hammersmith Campus, Du Cane Road, London, W12 0HS, UK.
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16
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Datta S, Malhotra L, Dickerson R, Chaffee S, Sen CK, Roy S. Laser capture microdissection: Big data from small samples. Histol Histopathol 2015; 30:1255-69. [PMID: 25892148 PMCID: PMC4665617 DOI: 10.14670/hh-11-622] [Citation(s) in RCA: 95] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Any tissue is made up of a heterogeneous mix of spatially distributed cell types. In response to any (patho) physiological cue, responses of each cell type in any given tissue may be unique and cannot be homogenized across cell-types and spatial co-ordinates. For example, in response to myocardial infarction, on one hand myocytes and fibroblasts of the heart tissue respond differently. On the other hand, myocytes in the infarct core respond differently compared to those in the peri-infarct zone. Therefore, isolation of pure targeted cells is an important and essential step for the molecular analysis of cells involved in the progression of disease. Laser capture microdissection (LCM) is powerful to obtain a pure targeted cell subgroup, or even a single cell, quickly and precisely under the microscope, successfully tackling the problem of tissue heterogeneity in molecular analysis. This review presents an overview of LCM technology, the principles, advantages and limitations and its down-stream applications in the fields of proteomics, genomics and transcriptomics. With powerful technologies and appropriate applications, this technique provides unprecedented insights into cell biology from cells grown in their natural tissue habitat as opposed to those cultured in artificial petri dish conditions.
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Affiliation(s)
- Soma Datta
- Department of Surgery, Center for Regenerative Medicine and Cell Based Therapies and Comprehensive Wound Center, Laser Capture Molecular Core, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - Lavina Malhotra
- Department of Surgery, Center for Regenerative Medicine and Cell Based Therapies and Comprehensive Wound Center, Laser Capture Molecular Core, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - Ryan Dickerson
- Department of Surgery, Center for Regenerative Medicine and Cell Based Therapies and Comprehensive Wound Center, Laser Capture Molecular Core, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - Scott Chaffee
- Department of Surgery, Center for Regenerative Medicine and Cell Based Therapies and Comprehensive Wound Center, Laser Capture Molecular Core, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - Chandan K Sen
- Department of Surgery, Center for Regenerative Medicine and Cell Based Therapies and Comprehensive Wound Center, Laser Capture Molecular Core, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - Sashwati Roy
- Department of Surgery, Center for Regenerative Medicine and Cell Based Therapies and Comprehensive Wound Center, Laser Capture Molecular Core, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA.
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17
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Abstract
The pathologic classification of neuroendocrine neoplasms has evolved over the past decades, as new understanding of the biological behavior, histologic characteristics, and genetic features have emerged. Nonetheless, many aspects of the classification systems remain confusing or controversial. Despite these difficulties, much progress has been made in determining the features predicting behavior. Genetic findings have helped establish relationships among different types of neuroendocrine neoplasms and revealed potential therapeutic targets. This review summarizes the current approach to the diagnosis, classification, grading, and therapeutic stratification of neuroendocrine neoplasms, with a focus on those arising in the lung and thymus, pancreas, and intestines.
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Affiliation(s)
- David S Klimstra
- Weill Cornell Medical College, 1305 York Avenue, New York, NY 10021, USA; Department of Pathology, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
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18
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Searching for primaries in patients with neuroendocrine tumors (NET) of unknown primary and clinically suspected NET: Evaluation of Ga-68 DOTATOC PET/CT and In-111 DTPA octreotide SPECT/CT. Radiol Oncol 2014; 48:339-47. [PMID: 25435846 PMCID: PMC4230553 DOI: 10.2478/raon-2014-0018] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2013] [Accepted: 02/23/2014] [Indexed: 12/21/2022] Open
Abstract
Background To evaluate the clinical efficacy of In-111 DTPA octreotide SPECT/CT and Ga-68 DOTATOC PET/CT for detection of primary tumors in patients with either neuroendocrine tumor of unknown primary (NETUP) or clinically suspected primary NET (SNET). Patients and methods. A total of 123 patients were included from 2006 to 2009, 52 received Ga-68 DOTATOC PET/CT (NETUP, 33; SNET, 19) and 71 underwent In-111 DTPA octreotide SPECT/CT (50; 21). The standard of reference included histopathology or clinical verification based on follow-up examinations. Results In the NETUP group Ga-68 DOTATOC detected primaries in 15 patients (45.5%) and In-111 DTPA octreotide in 4 patients (8%) (p < 0.001); in the SNET group, only 2 primaries could be detected, all by Ga-68 DOTATOC. In patients with NETUP, primary tumors could be found significantly more often than in patients with SNET (p = 0.01). Out of these 21 patients 14 patients were operated. Conclusion Ga-68 DOTATOC PET/CT is preferable to In-111 DTPA octreotide SPECT/CT when searching for primary NETs in patients with NETUP but should be used with caution in patients with SNET.
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19
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Kidd M, Modlin IM, Drozdov I. Gene network-based analysis identifies two potential subtypes of small intestinal neuroendocrine tumors. BMC Genomics 2014; 15:595. [PMID: 25023465 PMCID: PMC4124138 DOI: 10.1186/1471-2164-15-595] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2014] [Accepted: 07/07/2014] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Tumor transcriptomes contain information of critical value to understanding the different capacities of a cell at both a physiological and pathological level. In terms of clinical relevance, they provide information regarding the cellular "toolbox" e.g., pathways associated with malignancy and metastasis or drug dependency. Exploration of this resource can therefore be leveraged as a translational tool to better manage and assess neoplastic behavior. The availability of public genome-wide expression datasets, provide an opportunity to reassess neuroendocrine tumors at a more fundamental level. We hypothesized that stringent analysis of expression profiles as well as regulatory networks of the neoplastic cell would provide novel information that facilitates further delineation of the genomic basis of small intestinal neuroendocrine tumors. RESULTS We re-analyzed two publically available small intestinal tumor transcriptomes using stringent quality control parameters and network-based approaches and validated expression of core secretory regulatory elements e.g., CPE, PCSK1, secretogranins, including genes involved in depolarization e.g., SCN3A, as well as transcription factors associated with neurodevelopment (NKX2-2, NeuroD1, INSM1) and glucose homeostasis (APLP1). The candidate metastasis-associated transcription factor, ST18, was highly expressed (>14-fold, p < 0.004). Genes previously associated with neoplasia, CEBPA and SDHD, were decreased in expression (-1.5 - -2, p < 0.02). Genomic interrogation indicated that intestinal tumors may consist of two different subtypes, serotonin-producing neoplasms and serotonin/substance P/tachykinin lesions. QPCR validation in an independent dataset (n = 13 neuroendocrine tumors), confirmed up-regulated expression of 87% of genes (13/15). CONCLUSIONS An integrated cellular transcriptomic analysis of small intestinal neuroendocrine tumors identified that they are regulated at a developmental level, have key activation of hypoxic pathways (a known regulator of malignant stem cell phenotypes) as well as activation of genes involved in apoptosis and proliferation. Further refinement of these analyses by RNAseq studies of large-scale databases will enable definition of individual master regulators and facilitate the development of novel tissue and blood-based tools to better understand diagnose and treat tumors.
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Affiliation(s)
- Mark Kidd
- Yale University School of Medicine, New Haven, CT 06510, USA.
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20
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Laser-assisted microdissection in translational research: theory, technical considerations, and future applications. Appl Immunohistochem Mol Morphol 2013; 21:31-47. [PMID: 22495368 DOI: 10.1097/pai.0b013e31824d0519] [Citation(s) in RCA: 59] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Molecular profiling already exerts a profound influence on biomedical research and disease management. Microdissection technologies contribute to the molecular profiling of diseases, enabling investigators to probe genetic characteristics and dissect functional physiology within specific cell populations. Laser-capture microdissection (LCM), in particular, permits collation of genetic, epigenetic, and gene expression differences between normal, premalignant, and malignant cell populations. Its selectivity for specific cell populations promises to greatly improve the diagnosis and management of many human diseases. LCM has been extensively used in cancer research, contributing to the understanding of tumor biology by mutation detection, clonality analysis, epigenetic alteration assessment, gene expression profiling, proteomics, and metabolomics. In this review, we focus on LCM applications for DNA, RNA, and protein analysis in specific cell types and on commercially available LCM platforms. These analyses could clinically be used as aids to cancer diagnosis, clinical management, genomic profile studies, and targeted therapy. In this review, we also discuss the technical details of tissue preparation, analytical yields, tissue selection, and selected applications using LCM.
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21
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Abstract
UNLABELLED Identification of common molecular mechanisms is needed to facilitate the development of new treatment options for patients with ileal carcinoids. PURPOSE OF REVIEW Recent profiling studies on ileal carcinoids were examined to obtain a comprehensive view of risk factors, genetic aberrations, and transcriptional alterations. Special attention was paid to mechanisms that could provide novel targets for therapy. RESULTS Genome-wide association studies have shown that single nucleotide polymorphisms (SNPs) at IL12A and DAD1 are associated with an increased risk of ileal carcinoids. Genomic profiling revealed distinct patterns of copy-number alterations in ileal carcinoids. Two groups of carcinoids could be identified by hierarchical clustering. A major group of tumors was characterized by loss on chromosome 18 followed by additional losses on chromosomes 3p, 11q, and 13. Three minimal common regions of deletions were identified at 18q21.1-q21.31, 18q22.1-q22.2, and 18q22.3-q23. A minor group of tumors was characterized by clustered gains on chromosomes 4, 5, 7, 14, and 20. Expression profiling identified three groups of ileal carcinoids by principal component analysis. Tumor progression was associated with changes in gene expression including downregulation of MIR133A. Candidate genes for targeted therapy included ERBB2/HER2, DAD1, PRKCA, RYBP, CASP1, CASP4, CASP5, VMAT1, RET, APLP1, OR51E1, GPR112, SPOCK1, RUNX1, and MIR133A. CONCLUSION Profiling of ileal carcinoids has revealed recurrent genetic alterations and distinct patterns of gene expression. Frequent alterations in cellular pathways and genes were identified, suggesting novel targets for therapy. Translational studies are needed to validate suggested molecular targets.
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Affiliation(s)
- Ola Nilsson
- Sahlgrenska Cancer Center, Institute of Biomedicine, Sahlgrenska Academy at the University of Gothenburg, Göteborg, Sweden.
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22
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Walsh KM, Choi M, Oberg K, Kulke MH, Yao JC, Wu C, Jurkiewicz M, Hsu LI, Hooshmand SM, Hassan M, Janson ET, Cunningham JL, Vosburgh E, Sackler RS, Lifton RP, Dewan AT, Hoh J. A pilot genome-wide association study shows genomic variants enriched in the non-tumor cells of patients with well-differentiated neuroendocrine tumors of the ileum. Endocr Relat Cancer 2011; 18:171-80. [PMID: 21139019 PMCID: PMC3221459 DOI: 10.1677/erc-10-0248] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
Genetic studies of midgut carcinoid cancer have exclusively focused on genomic changes of the tumor cells. We investigated the role of constitutional genetic polymorphisms in predisposing individuals to ileal carcinoids. In all, 239 cases and 110 controls were collected from three institutions: the Uppsala University Hospital; the Dana-Farber Cancer Institute; and the MD Anderson Cancer Center, and were genotyped using microarrays assaying >300 000 single nucleotide polymorphisms. Association with rs2208059 in KIF16B approached statistical significance (Mantel-Haenszel odds ratio=2.42, P=4.16×10(-7)) at a Bonferroni-corrected level (<1.62×10(-7)). Using two computational algorithms, four copy-number variants (CNVs) were identified in multiple cases that were absent in study controls and markedly less frequent in ∼1500 population-based controls. Of these four constitutional CNVs identified in blood-derived DNA, a 40 kb heterozygous deletion in Chr18q22.1 corresponded with a region frequently showing loss of heterozygosity (LOH) in ileal carcinoid tumor cells based on our meta-analysis of previously published cytogenetic studies (69.7% LOH, 95% confidence interval=60.0-77.9%). We analyzed the constitutional 40 kb deletion on chr18 in our study samples with a real-time quantitative PCR assay; 14/226 cases (6.19%) and 2/97 controls (2.06%) carried the CNV, although the exact boundaries of each deletion have not been determined. Given the small sample size, our findings warrant an independent cohort for a replication study. Owing to the rarity of this disease, we believe these results will provide a valuable resource for future work on this serious condition by allowing others to make efficient use of their samples in targeted studies.
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Affiliation(s)
- Kyle M Walsh
- Department of Epidemiology and Public Health, Yale University, 60 College Street, New Haven, Connecticut 06520, USA
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23
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Hodges KB, Cummings OW, Saxena R, Wang M, Zhang S, Lopez-Beltran A, Montironi R, Nour H, Cheng L. Clonal origin of multifocal hepatocellular carcinoma. Cancer 2010; 116:4078-85. [PMID: 20564142 DOI: 10.1002/cncr.25258] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
BACKGROUND Hepatocellular carcinoma is the most common primary tumor of the liver. Patients frequently have multiple histologically similar, but anatomically separate tumors. The clonal origin of multiple hepatocellular carcinomas is uncertain. METHODS The authors analyzed 31 tumors from 12 different patients (11 women, 1 man), who had multiple hepatocellular carcinomas involving 1 or both lobes. Genomic DNA was extracted from formalin-fixed, paraffin-embedded tissue using laser capture microdissection. DNA was analyzed for loss of heterozygosity (LOH), X chromosome inactivation status, and TP53 gene mutations. RESULTS Ten (83%) of the 12 patients showed LOH in at least 1 of the analyzed microsatellite markers. Concordant LOH patterns between separate hepatocellular carcinomas in individual patients were seen in 8 (80%) of 10 cases, whereas discordant patterns were seen in 2 (20%) of 10 cases. Five (50%) of 10 informative female patients showed identical nonrandom X chromosome inactivation patterns in multiple tumors; 1 case showed discordant nonrandom X chromosome inactivation pattern. TP53 mutations were identified in 8 (67%) of 12 patients. Tumors in 7 (88%) of these 8 patients showed different point mutations. Three patients (Cases 4, 5, and 10) had tumors with additional TP53 point mutations, indicating additional genetic abnormalities in these tumors. CONCLUSIONS The data suggested that the significant proportion of patients with multifocal hepatocellular carcinomas have tumors of common clonal origin.
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Affiliation(s)
- Kurt B Hodges
- Departments of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana
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24
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Abstract
Gastrointestinal (GI) neuroendocrine tumors (NETs) are a heterogeneous group of relatively slow-growing neoplasms with marked site-specific differences in hormonal secretion and clinical behavior. Most are sporadic neoplasms, with only 5% to 10% arising in patients with hereditary disorders, most commonly in multiple endocrine neoplasia type 1. Although a uniform terminology is not universally accepted, use of the 4-category WHO classification of these tumors is becoming more widespread, and recommendations for tumor grading and staging have been recently formulated. Most GI NETs are easily recognized on routine histologic examination; rarely, a limited panel of immunohistochemical markers may be useful in establishing the diagnosis. This article describes general and site-specific features of these tumors and outlines potential pitfalls in diagnosis.
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Affiliation(s)
- Roger K Moreira
- Department of Pathology, Columbia University Medical Center, 630 West 168th Street, New York, NY 20032, USA
| | - Kay Washington
- Department of Pathology, Vanderbilt University Medical Center, 1161 21st Avenue South, Nashville, TN 32732, USA.
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25
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Wang X, Wang M, MacLennan GT, Abdul-Karim FW, Eble JN, Jones TD, Olobatuyi F, Eisenberg R, Cummings OW, Zhang S, Lopez-Beltran A, Montironi R, Zheng S, Lin H, Davidson DD, Cheng L. Evidence for common clonal origin of multifocal lung cancers. J Natl Cancer Inst 2009; 101:560-70. [PMID: 19351924 DOI: 10.1093/jnci/djp054] [Citation(s) in RCA: 120] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Lung cancer is the most common cause of cancer death in the United States. Multiple anatomically separate but histologically similar lung tumors are often found in the same patient. The clonal origin of multiple lung tumors is uncertain. METHODS We analyzed 70 lung tumors from 30 patients (23 females and seven males) who underwent surgical resection for lung epithelial tumors, of whom 26 had non-small cell carcinomas and four had carcinoid/atypical carcinoid tumors. All patients had multiple tumors (two to five) involving one or both lungs. Genomic DNA was extracted from paraffin-embedded tissue sections using laser capture microdissection and analyzed for loss of heterozygosity, TP53 mutations, and X-chromosome inactivation status. The percentage (95% confidence interval [CI]) of patients in whom there were concordant patterns of genetic alteration was calculated. RESULTS All 30 case subjects showed loss of heterozygosity (LOH) in at least one and at most four of the six polymorphic microsatellite markers. Completely concordant LOH patterns between synchronous and metachronous cancers in individual patients were seen in 26 (87%) of 30 informative patients (95% CI = 75% to 99%). Identical point mutations were present in eight of 10 patients who exhibited TP53 mutation by sequencing. Tumors in 18 (78%) of 23 female patients (95% CI = 67% to 98%) showed identical X-chromosome inactivation patterns. Combining the results of LOH studies, TP53 mutation screening analyses, and X-chromosome inactivation data, we demonstrated that the multiple separate tumors in 23 (77%) of 30 patients (95% CI = 62% to 92%) had identical genetic changes, consistent with monoclonal origin of the separate tumors. CONCLUSIONS Our data indicate that the great majority of multifocal lung cancers have a common clonal origin and that multifocality in lung cancer represents local and regional intrapulmonary metastasis.
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Affiliation(s)
- Xiaoyan Wang
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, 350 West 11th Street, Clarian Pathology Laboratory, Indianapolis, IN 46202, USA
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Yu Q, Niu Y, Yu Y, Ding X, Shi Y. Analysis of the progression of intraductal proliferative lesions in the breast by PCR-based clonal assay. Breast Cancer Res Treat 2008; 114:433-40. [DOI: 10.1007/s10549-008-0029-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2008] [Accepted: 04/11/2008] [Indexed: 11/30/2022]
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Abstract
PURPOSE OF REVIEW Neuroendocrine tumors (previously referred to as carcinoids) are ill-understood, enigmatic malignancies that, although slow-growing compared with adenocarcinomas, can behave aggressively. In 2004, they comprised 1.25% of all malignancies; their incidence is increasing by approximately 6% per year. The present review provides an overview on neuroendocrine tumors and focuses on general features and current diagnostic and therapeutic options. RECENT FINDINGS Neuroendocrine tumors may present a considerable diagnostic and therapeutic challenge as their clinical presentation is nonspecific and usually late, when metastases are already evident. Topographic localization is by computed tomography, magnetic resonance imaging, somatostatin receptor scintigraphy, whole-body positron emission tomography or endoscopy/ultrasound. Bronchoscopy is useful to verify the diagnosis when lesions are located centrally in the bronchi. No curative treatment except for radical surgery (almost never feasible) exists. Palliative and symptomatic treatment is based on surgical debulking, tumor embolization, and biotherapy with somatostatin analogues. Chemotherapy and radiotherapy are usually ineffective, but novel drugs such as tyrosine kinase receptor inhibitors show promising results in phase II clinical studies. SUMMARY Tumors of the diffuse neuroendocrine system represent a significant and increasing clinical problem, and there is a need to develop both early diagnostic tests as well as to establish targeted therapeutic strategies.
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O'Malley DP, Orazi A, Dunphy CH, Coleman BR, Marks RA, Wang M, Cheng L. Loss of heterozygosity identifies genetic changes in chronic myeloid disorders, including myeloproliferative disorders, myelodysplastic syndromes and chronic myelomonocytic leukemia. Mod Pathol 2007; 20:1166-71. [PMID: 17704756 DOI: 10.1038/modpathol.3800951] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
This study evaluates changes in genetic loci of chronic myeloid disorders using loss of heterozygosity (LOH) techniques. We present the combined results of three experiments. First, examination of a panel of genetic loci in groups of myeloproliferative disorders was evaluated. The second experiment involved microdissection of megakaryocytes from myeloproliferative disorders and comparison of their genetic changes to surrounding neoplastic marrow elements. Finally, we compared results of LOH studies of myeloproliferative disorders to those of myelodysplastic syndromes and chronic myelomonocytic leukemia. A total of 41 bone marrow biopsies were evaluated. Twenty-seven were myeloproliferative disorders (11 chronic idiopathic myelofibrosis, 11 essential thrombocythemia, 5 polycythemia vera). The remaining cases consisted of myelodysplastic syndromes (total=5; RAEB-1=2; RAEB-2=2; MDS, not otherwise specified=1) and chronic myelomonocytic leukemia (n=8). The abnormalities in myeloproliferative disorders were distributed as follows: D7S2554-4/14 (5/14); D8S263-4/15 (5/15); D9S157-5/15 (5/15); D9S161-7/17 (6/17); D13S319-5/14 (4/14); TP53-5/16 (5/16); D20S108-4/15 (4/15). In 75% cases diagnosed as essential thrombocythemia (6/8), both cases of polycythemia vera (2/2), and 29% cases of chronic idiopathic myelofibrosis (2/7), there were genetic differences between the megakaryocytes and the surrounding marrow. These results suggest that in some cases, megakaryocytes have different clonal abnormalities than surrounding hematopoietic tissue. The genetic profiles of myeloproliferative disorders had several differences from those of myelodysplastic syndromes. Although different from both, chronic myelomonocytic leukemia appeared more similar to myeloproliferative disorders using these techniques.
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Machens A, Schaaf L, Karges W, Frank-Raue K, Bartsch DK, Rothmund M, Schneyer U, Goretzki P, Raue F, Dralle H. Age-related penetrance of endocrine tumours in multiple endocrine neoplasia type 1 (MEN1): a multicentre study of 258 gene carriers. Clin Endocrinol (Oxf) 2007; 67:613-622. [PMID: 17590169 DOI: 10.1111/j.1365-2265.2007.02934.x] [Citation(s) in RCA: 64] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
OBJECTIVE In multiple endocrine neoplasia type 1 (MEN1), age-related tumour penetrance according to the type of MEN1 germline mutation has not been investigated in-depth. This study was conducted to examine whether carriers of out-of-frame/truncating and in-frame MEN1 mutations differ in age-related tumour penetrance. DESIGN A multicentre study with biochemical, hormonal and radiological screening for MEN1-associated tumours. PATIENTS A total of 258 MEN1 carriers from six major German tertiary referral centres averaging 43 years of age at last follow-up. MEASUREMENTS Main outcome measure was time to first diagnosis of MEN1-associated tumours. RESULTS Independent of the year of birth and observation period, time to first tumour diagnosis did not vary much by the type of MEN1 germline mutation or endocrine organ system, and perhaps not even by the type of endocrine tumour when the amount of time was considered by which the diagnosis probably has been advanced through the manifestation of hormonal symptoms. Parathyroid hyperplasia and adenomas developed almost twice as often as enteropancreatic and pituitary tumours (77%vs. 49-32%), and more than five to sevenfold as often as adrenal cortical tumours and carcinoids (77%vs. 15-10%), reaching penetrance rates of up to 90%, 60%, 40%, 26% and 17%, respectively. The heterogeneity of tumour penetrance was marked, ranging from 9 years to 25 years for the earliest, and from 68 years to 77 years for the latest tumour manifestation. CONCLUSIONS Because of our inability of predicting tumour penetrance and malignant transformation individually, life-long follow-up of MEN1 carriers is warranted to prevent tumour morbidity.
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Affiliation(s)
- Andreas Machens
- Department of General, Visceral and Vascular Surgery, Martin-Luther-University, Halle (Saale), Germany.
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Katona TM, O'Malley DP, Cheng L, Hiatt KM, Wang M, Anagnostou JJ, Billings SD, Smoller BR. Loss of Heterozygosity Analysis Identifies Genetic Abnormalities in Mycosis Fungoides and Specific Loci Associated With Disease Progression. Am J Surg Pathol 2007; 31:1552-6. [PMID: 17895757 DOI: 10.1097/pas.0b013e3180408d76] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
Mycosis fungoides (MF) exhibits a variety of underlying molecular defects. Loss of heterozygosity (LOH) is a technique used to detect chromosomal imbalances in neoplastic disorders using archival tissue. We analyzed skin biopsies of MF in different stages for the presence of LOH at specific loci to evaluate underlying genetic aberrations involved in MF and its progression. Twenty-five skin biopsies (15 plaque stage and 10 tumor stage) from 19 patients were evaluated. LOH was examined at 1p22 (D1S2766), 9p21 [IFNA, p15 (D9S1748), p16 (D9S171)], 10q23 [PTEN (D10S185, D10S541, D10S2491)], and 17p13 [p53 (TP53)]. Abnormal lymphocytes were microdissected from formalin-fixed, paraffin-embedded tissue sections. Sixteen of the 25 (64%) specimens evaluated had at least one abnormal LOH locus and LOH was identified in 7 of 15 (47%) plaque and in 9 of 10 (90%) tumor stage lesions, respectively. All 3 patients with sequential biopsies (plaque followed by tumor lesions) had additional LOH abnormalities in tumor specimens compared with plaque stage lesions. LOH most frequently involved chromosome 10, including 7 of 10 (70%) tumor stage lesions. Loss of multiple alleles was only identified in tumor stage cases, with 3 tumors undergoing allelic losses at 3 separate loci. Our results suggest that LOH studies are a robust method for evaluating genetic abnormalities in MF. Tumor stage lesions manifest increasing allelic losses compared with plaque stage. Further, in this series, several loci associated with the tumor suppressor gene PTEN on chromosome 10 appear to be associated with progression from plaque to tumor stage.
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Affiliation(s)
- Terrence M Katona
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
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Katona TM, Jones TD, Wang M, Eble JN, Billings SD, Cheng L. Genetically heterogeneous and clonally unrelated metastases may arise in patients with cutaneous melanoma. Am J Surg Pathol 2007; 31:1029-37. [PMID: 17592269 DOI: 10.1097/pas.0b013e31802b3488] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
Melanoma of the skin frequently metastasizes to multiple regional lymph nodes and to distant sites. It is uncertain whether all metastases originate from the same tumor clone or whether the genetic heterogeneity of the primary tumor is reflected in the multiple metastases. A total of 73 archival, formalin-fixed, paraffin-embedded, melanoma lesions, including 13 primary tumors and 60 metastases, were studied from 13 patients each having 2 or more metastatic tumors. Genomic DNA samples were prepared from tissue sections using laser-assisted microdissection. We find that the majority of melanoma metastases share a common clonal origin with the matched primary tumor. However, significant genetic divergence occurs frequently during the clonal evolution of metastatic melanoma. In addition, using X-chromosome inactivation analysis, we find that, in some cases, multiple coexisting metastases seem to be derived from different, genetically unrelated tumor clones, implying that some primary tumors may arise from more than a single transformed melanocyte.
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Affiliation(s)
- Terrence M Katona
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA
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Abstract
This review provides an update on the pathogenesis and histopathological diagnosis of endocrine tumours of the gastrointestinal tract, concentrating on three different varieties whose careful assessment by pathologists is of particular clinical significance. These are the four types of enterochromaffin-like cell tumour of the gastric corpus, the periampullary somatostatin-containing D-cell tumour of the duodenum, and the frequently chromogranin A-negative L-cell tumour of the appendix and large intestine. In addition, the value of pathological factors in predicting the behaviour of gastrointestinal endocrine tumours and selecting therapy is discussed, and the crucial role of the pathologist in the multidisciplinary team management of these neoplasms is emphasized.
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Affiliation(s)
- G T Williams
- Department of Pathology, Wales College of Medicine, Cardiff University, Cardiff, UK.
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Sung MT, Wang M, MacLennan GT, Eble JN, Tan PH, Lopez-Beltran A, Montironi R, Harris JJ, Kuhar M, Cheng L. Histogenesis of sarcomatoid urothelial carcinoma of the urinary bladder: evidence for a common clonal origin with divergent differentiation. J Pathol 2007; 211:420-30. [PMID: 17236170 DOI: 10.1002/path.2129] [Citation(s) in RCA: 98] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
The histogenesis of sarcomatoid urothelial carcinoma, a rare neoplasm with bidirectional epithelial and mesenchymal differentiation, has been a matter of controversy. To clarify its origin, we analysed the status of X-chromosome inactivation in sarcomatoid urothelial carcinomas from 10 female patients and examined losses of heterozygosity (LOH) in these specimens and in additional 20 tumours from male patients. Six polymorphic microsatellite markers where genetic alterations occur frequently in early or advanced stages of urothelial carcinomas, including D3S3050, D8S261, IFNA, D9S177, D11S569 and TP53, were investigated in the current study. The identical pattern of non-random X-chromosome inactivation in both carcinomatous and sarcomatous components was identified in five of eight informative female patients, and the remaining three informative cases showed a random, but concordant, pattern of X-chromosome inactivation. The concordant X-chromosome inactivation results in all eight informative cases support the concept of a monoclonal origin of both components of this biphasic neoplasm. Among the tumours demonstrating loss of heterozygosity, high incidences of an identical pattern of allelic loss between carcinomatous and sarcomatous components were identified in genetic alterations associated with early carcinogenesis: 86% at D8S261, 78% at D11S569, 75% at D9S177 and 57% at IFNA. In contrast, concordant LOH patterns were less frequently observed for microsatellites related to advanced carcinogenesis: only 40% at D3S3050 and 40% at TP53. The significant overlap of loss of heterozygosity supports a monoclonal cell origin and suggests that clonal divergence may occur during tumour progression and differentiation. Divergent patterns of discordant allelic loss of microsatellite markers imply that heterogeneous pathogenetic pathways may exist in the evolution of this enigmatic neoplasm.
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Affiliation(s)
- M-T Sung
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA, and Chang Gung Memorial Hospital-Kaohsiung Medical Center, Taiwan
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Abstract
In the 100 years since the term Karzinoid was first coined by Siegfried Oberndorfer to describe gastrointestinal tumors that resembled carcinomas but pursued a relatively indolent course, these tumors have captured the attention, not only of internists, surgeons, endocrinologists, and pathologists but of biochemists, physiologists, geneticists, and molecular biologists as well. Initially thought to be limited to the gut, these tumors were soon found to arise in a variety of other organs as well. With the gradual evolution of the concept of a dispersed neuroendocrine cell system and the recognition that it was made up of a galaxy of at least 20 or so functionally distinct cell types (each of which could potentially give rise to a specific type of tumor, each of which could in turn be endocrinologically functional or silent), came the realization that carcinoids should perhaps be considered as a family of neoplasms that, despite sharing certain commonalities, can however, show significant heterogeneity among themselves in some of their other features. While it may seem that our knowledge of this fascinating group of tumors has improved significantly, a closer look reveals that we may have just begun to scratch the surface.
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Affiliation(s)
- Yogeshwar Dayal
- GI Pathology, Northeast Region, Caris Diagnostics, Inc., 320 Needham Street, Suite #200, Newton, MA, USA.
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Sung MT, Eble JN, Wang M, Tan PH, Lopez-Beltran A, Cheng L. Inverted papilloma of the urinary bladder: a molecular genetic appraisal. Mod Pathol 2006; 19:1289-94. [PMID: 16862073 DOI: 10.1038/modpathol.3800667] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Inverted papilloma of urinary bladder is an uncommon urothelial neoplasm. Its relationship to urothelial carcinoma is controversial. Little is known of the genetic abnormalities of inverted papilloma. To better understand its genetics, we analyzed 39 inverted papillomas, including 36 from men and three from women, for loss of heterozygosity (LOH). We examined four polymorphic microsatellite markers located on chromosome 9q32-33(D9S177), chromosome 9p22 (IFNA), chromosome 3p14.2 (D3S1300) and chromosome 17p13.1 (TP53), where genetic alterations occur frequently in urothelial carcinomas. Additionally, the status of inactivation of X-chromosome was examined in three female patients. The frequency of LOH in informative cases was 8% (3 of 37) for D9S177, 10% (4 of 38) for TP53, 8% (3 of 37) for IFNA and 8% (3 of 36) for D3S1300. In the analysis of X-chromosome inactivation, all three cases yielded informative results and one had nonrandom inactivation of X-chromosomes. The monoclonal origin demonstrated in the study of X-chromosome inactivation indicates the clonal process of inverted papilloma; however, the low incidence of LOH supports the view that inverted papilloma in urinary bladder is a benign neoplasm with molecular genetic abnormalities different from those of urothelial carcinoma.
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Affiliation(s)
- Ming-Tse Sung
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA
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Jones TD, Wang M, Sung MT, Zhang S, Ulbright TM, Eble JN, Beck SD, Foster RS, Anagnostou JJ, Conner C, Cheng L. Clonal Origin of Metastatic Testicular Teratomas. Clin Cancer Res 2006; 12:5377-83. [PMID: 16982812 DOI: 10.1158/1078-0432.ccr-06-0444] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE Testicular teratomas in adult patients are histologically diverse tumors that frequently coexist with other germ cell tumor (GCT) components. These mixed GCTs often metastasize to retroperitoneal lymph nodes where multiple GCT elements are frequently present in the same metastatic lesion. Neither the genetic relationships among the different components in metastatic lesions nor the relationships between primary and metastatic GCT components have been elucidated. EXPERIMENTAL DESIGN We examined metastases from 31 patients who underwent primary retroperitoneal lymph node dissection for metastatic testicular GCT. All patients had metastatic mature teratoma with one or more other GCT components. This study included a total of 72 metastatic GCT components and 16 primary GCT components from 31 patients. Genomic DNA samples from each component were prepared from formalin-fixed, paraffin-embedded tissue sections using laser-assisted microdissection. Loss of heterozygosity (LOH) assays for seven microsatellite polymorphic markers on chromosomes 1p36 (D1S1646), 9p21 (D9S171 and IFNA), 9q21 (D9S303), 13q22-q31 (D13S317), 18q22 (D18S543), and 18q21 (D18S60) were done to assess clonality. RESULTS Twenty-nine of 31 (94%) cases showed allelic loss in one or more components of the metastatic GCTs. Twenty-nine of 31 mature teratomas showed allelic loss in at least one of seven microsatellite polymorphic markers analyzed. The frequency of allelic loss in informative cases of metastatic mature teratoma was 27% (8 of 30) with D1S1646, 34% (10 of 29) with D9S171, 37% (10 of 27) with IFNA, 27% (8 of 30) with D9S303, 46% (13 of 28) with D13S317, 26% (7 of 27) with D18S543, and 36% (10 of 28) with D18S60. Completely concordant allelic loss patterns between the mature teratoma and all of the other metastatic GCT components were seen in 26 of 29 cases in which the mature teratoma component showed LOH. Nearly identical allelic loss patterns were seen in the three remaining cases. In six cases analyzed, LOH patterns of each metastatic component were compared with each GCT component of the primary testicular tumor. In all six cases, each primary and metastatic component showed an identical pattern of allelic loss. CONCLUSION Our data support the common clonal origin of metastatic mature teratomas with other components of metastatic testicular GCTs and with each component of the primary tumor.
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Affiliation(s)
- Timothy D Jones
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana 46202, USA, and Department of Pathology, Chang Gung Memorial Hospital-Kaohsiung Medical Center, Kaohsiung, Taiwan
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