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Prela O, Caveney B, Strawderman M, Linehan D, Galka E, Schoeniger L, Hezel A, Badri N, Carpizo DR. A Reassessment of the Clinical Utility of 68Ga-DOTATATE PET/CT in Patients With Gastroenteropancreatic Neuroendocrine Tumors. J Surg Oncol 2025. [PMID: 39757730 DOI: 10.1002/jso.28061] [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: 11/27/2024] [Accepted: 12/03/2024] [Indexed: 01/07/2025]
Abstract
BACKGROUND Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are a rare and biologically diverse group of tumors that are challenging to image. 68Ga-DOTATATE PET/CT is the most sensitive imaging tool for these tumors, and while its use has increased over time, its clinical impact remains unclear, particularly for clinical scenarios involving surveillance after treatment. We sought to reassess its clinical utility across all stages. METHODS Retrospective study of pathologically confirmed GEP-NET patients between 1/1/2020 and 9/1/2022 at a tertiary care center. Demographic, clinical, and radiographic data were analyzed. The primary objective was to determine if PET/CT use was associated with a change in clinical management. The secondary objective was to determine if PET/CT was superior in identifying primary or metastatic lesions compared to traditional imaging. RESULTS One hundred twenty-four patients with GEP-NETs underwent 207 PET/CT scans. The majority of scans were obtained for disease surveillance (70.2%) or staging (37.9%), and the remaining (3.2%) were used to aid in diagnosis or before PRRT initiation (3.2%). Following PET/CT scan, 51 patients (41.1%) had a change in clinical management, with change being higher among those with metastatic disease (44.9% vs. 14.5%). Of the 124, 72 patients had traditional imaging available for comparison. In this subgroup, 34 patients (47.2%) had new lesions identified on PET/CT that were not identified using traditional imaging resulting in a change in management in 79.4% favoring patients with M1 versus M0 disease (26.9% M0 vs. 58.7% M1, p = 0.010). CONCLUSION 68Ga-DOTATATE PET/CT imaging is clinically most useful for initial staging and in surveillance and monitoring response to therapy in the metastatic setting. It is least useful for surveillance in the early-stage setting and does not support its use following curative intent surgery. It remains superior to unlabeled imaging in sensitivity and the additional disease burden detected is highly likely to change management.
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Affiliation(s)
- Orjola Prela
- Department of Surgery, Division of General Surgery, University of Rochester, Rochester, New York, USA
| | - Brennen Caveney
- University of Rochester School of Medicine and Dentistry, Rochester, New York, USA
| | - Myla Strawderman
- Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York, USA
- Department of Biostatistics and Computational Biology, University of Rochester, Rochester, New York, USA
| | - David Linehan
- University of Rochester School of Medicine and Dentistry, Rochester, New York, USA
| | - Eva Galka
- Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York, USA
- Department of Surgery, Division of Surgical Oncology, University of Rochester, Rochester, New York, USA
| | - Luke Schoeniger
- Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York, USA
- Department of Surgery, Division of Surgical Oncology, University of Rochester, Rochester, New York, USA
| | - Aram Hezel
- Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York, USA
- Department of Medicine, Division of Hematology/Oncology, University of Rochester, Rochester, New York, USA
| | - Nabeel Badri
- Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York, USA
- Department of Medicine, Division of Hematology/Oncology, University of Rochester, Rochester, New York, USA
| | - Darren R Carpizo
- Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, New York, USA
- Department of Surgery, Division of Surgical Oncology, University of Rochester, Rochester, New York, USA
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Gonzáles-Yovera JG, Roseboom PJ, Concepción-Zavaleta M, Gutiérrez-Córdova I, Plasencia-Dueñas E, Quispe-Flores M, Ramos-Yataco A, Alcalde-Loyola C, Massucco-Revoredo F, Paz-Ibarra J, Concepción-Urteaga L. Diagnosis and management of small bowel neuroendocrine tumors: A state-of-the-art. World J Methodol 2022; 12:381-391. [PMID: 36186753 PMCID: PMC9516545 DOI: 10.5662/wjm.v12.i5.381] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2022] [Revised: 04/22/2022] [Accepted: 08/05/2022] [Indexed: 02/08/2023] Open
Abstract
This review provides an update on the epidemiology, pathophysiology, symptoms, diagnosis and treatment of neuroendocrine neoplasms (NENs) of the small bowel (SB). These NENs are defined as a group of neoplasms deriving from neuroendocrine cells. NENs are currently the most common primary tumors of the SB, mainly involving the ileum, making the SB the most frequently affected part of the gastrointestinal tract. SB NENs by definition are located between the ligament of Treitz and the ileocecal valve. They are characterized by small size and induce an extensive fibrotic reaction in the small intestine including the mesentery, resulting in narrowing or twisting of the intestine. Clinical manifestations of bowel functionality are related to the precise location of the primary tumor. The majority of them are non-functional NENs and generally asymptomatic; in an advanced stage, NENs present symptoms of mass effect by non-specific abdominal pain or carcinoid syndrome which appears in patients with liver metastasis (around 10%). The main manifestations of the carcinoid syndrome are facial flushing (94%), diarrhea (78%), abdominal cramps (50%), heart valve disease (50%), telangiectasia (25%), wheezing (15%) and edema (19%). Diagnosis is made by imaging or biochemical tests, and the order of request will depend on the initial diagnostic hypothesis, while confirmation will always be histological. All patients with a localized SB NEN with or without near metastasis in the mesentery are recommended for curative resection. Locoregional and distant spread may be susceptible to several therapeutic strategies, such as chemotherapy, somatostatin analogs and palliative resection.
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Affiliation(s)
| | - Pela J Roseboom
- Division of Emergency Medicine, Regional Academic Hospital of Trujillo, Trujillo 13011, Peru
| | | | | | | | - María Quispe-Flores
- Division of Endocrinology, Guillermo Almenara Irigoyen National Hospital, Lima 12590, Peru
| | - Anthony Ramos-Yataco
- Division of Internal Medicine, Ricardo Cruzado Rivarola Hospital, Ica 110301, Peru
| | | | | | - José Paz-Ibarra
- Department of Medicine, School of Medicine, National University of San Marcos, Lima 15001, Peru
| | - Luis Concepción-Urteaga
- Division of Internal Medicine, School of Medicine, National University of Trujillo, Trujillo 13011, Peru
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Maxwell JE, Naraev B, Halperin DM, Choti MA, Halfdanarson TR. Shifting Paradigms in the Pathophysiology and Treatment of Carcinoid Crisis. Ann Surg Oncol 2022; 29:3072-3084. [PMID: 35165817 DOI: 10.1245/s10434-022-11371-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Accepted: 01/16/2022] [Indexed: 11/18/2022]
Abstract
Carcinoid crisis is a potentially fatal condition characterized by various symptoms, including hemodynamic instability, flushing, and diarrhea. The incidence of carcinoid crisis is unknown, in part due to inconsistency in definitions across studies. Triggers of carcinoid crisis include general anesthesia and surgical procedures, but drug-induced and spontaneous cases have also been reported. Patients with neuroendocrine tumors (NETs) and carcinoid syndrome are at risk for carcinoid crisis. The pathophysiology of carcinoid crisis has been attributed to secretion of bioactive substances, such as serotonin, histamine, bradykinin, and kallikrein by NETs. The somatostatin analog octreotide has been considered the standard of care for carcinoid crisis due to its inhibitory effect on hormone release and relatively fast resolution of carcinoid crisis symptoms in several case studies. However, octreotide's efficacy in the treatment of carcinoid crisis has been questioned. This is due to a lack of a common definition for carcinoid crisis, the heterogeneity in clinical presentation, the paucity of prospective studies assessing octreotide efficacy in carcinoid crisis, and the lack of understanding of the pathophysiology of carcinoid crisis. These issues challenge the classical physiologic model of carcinoid crisis and its common etiology with carcinoid syndrome and raise questions regarding the utility of somatostatin analogs in its treatment. As surgical procedures and invasive liver-directed therapies remain important treatment modalities in patients with NETs, the pathophysiology of carcinoid crisis, potential benefits of octreotide, and efficacy of alternative treatment modalities must be studied prospectively to develop an effective evidence-based treatment strategy for carcinoid crisis.
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Affiliation(s)
- Jessica E Maxwell
- Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Boris Naraev
- Banner MD Anderson Cancer Center, Phoenix, AZ, USA
| | - Daniel M Halperin
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | | | - Thorvardur R Halfdanarson
- Division of Medical Oncology, Mayo Clinic, Rochester, MN, USA. .,Mayo Clinic Cancer Center, Rochester, MN, USA.
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4
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Abstract
Small bowel neuroendocrine tumors (SBNETS) are slow-growing neoplasms with a noted propensity toward metastasis and comparatively favorable prognosis. The presentation of SBNETs is varied, although abdominal pain and obstructive symptoms are the most common presenting symptoms. In patients with metastases, hypersecretion of serotonin and other bioactive amines results in diarrhea, flushing, valvular heart disease, and bronchospasm, termed carcinoid syndrome. The treatment of SBNETs is multimodal and includes surgery, liver-directed therapy, somatostatin analogues, targeted therapy, and peptide receptor radionuclide therapy.
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5
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Tran CG, Sherman SK, Howe JR. Small Bowel Neuroendocrine Tumors. Curr Probl Surg 2020; 57:100823. [PMID: 33234227 DOI: 10.1016/j.cpsurg.2020.100823] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Accepted: 04/24/2020] [Indexed: 12/11/2022]
Affiliation(s)
| | - Scott K Sherman
- Division of Surgical Oncology and Endocrine Surgery, University of lowa Carver College of Medicine, lowa City, lowa
| | - James R Howe
- Division of Surgical Oncology and Endocrine Surgery, University of lowa Carver College of Medicine, lowa City, lowa.
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Abstract
Neuroendocrine tumors of the gastrointestinal tract or pancreas are rare. Their presentation overlaps with other intra-abdominal neoplasms, but can have unique features. The workup involves recognition of unusual clinical features associated with the tumors, imaging, analysis of blood or urine concentrations, and biopsy. Functional imaging takes advantage of the neuroendocrine tumor-specific expression of somatostatin receptors. There are characteristic features supporting the diagnosis on contrast-enhanced cross-sectional imaging. The use of tumor markers for biochemical diagnosis requires an understanding of the confounding variables affecting these assays. There are unique and specific immunohistochemical staining and grading requirements for appropriate diagnosis of these tumors.
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Affiliation(s)
- Joseph S Dillon
- Division of Endocrinology, University of Iowa, 200 Hawkins Drive, Iowa City, IA 52242, USA.
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7
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Numbere N, Huber AR, Shi C, Cates JMM, Gonzalez RS. Should Ki67 immunohistochemistry be performed on all lesions in multifocal small intestinal neuroendocrine tumours? Histopathology 2018; 74:424-429. [PMID: 30326145 DOI: 10.1111/his.13771] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2018] [Accepted: 10/12/2018] [Indexed: 02/06/2023]
Abstract
AIMS Well-differentiated small intestinal neuroendocrine tumours (SI-NETs) are often multifocal, and this has been suggested to impart worse disease-free survival. Practice guidelines have not been established for World Health Organisation (WHO) grading of multiple primary lesions. METHODS AND RESULTS We identified 68 patients with ileal/jejunal SI-NET for a combined total of 207 primary lesions. Each case was evaluated for patient age and sex; size of all tumours; presence of lymph node metastases, mesenteric tumour deposits or distant metastases; and disease-specific outcome. Ki67 staining was performed on all 207 primary lesions. The relationship between multifocality and clinicopathological factors was compared using Fisher's exact test. Outcome was tested using Cox proportional hazard regression. Forty-two patients had unifocal disease, and 26 had multifocal disease (median five lesions, range = 2-32). Most tumours were WHO grade 1 (201 of 207, 97%). Of the five patients with grades 2/3 tumours, three patients had unifocal disease, one patient had two subcentimetre grade 2 lesions (including the largest) and eight subcentimetre grade 1 lesions, and one patient had one 1.6-cm grade 3 lesion and one subcentimetre grade 1 lesion. There was a positive correlation between tumour size and Ki67 index (coefficient 0.28; 95% confidence interval 0.05-0.52, P = 0.017). There was no significant association between multifocality and nodal metastases, mesenteric tumour deposits, distant metastases or disease-specific survival. CONCLUSIONS In patients with multifocal SI-NET, unless a particular lesion has a high mitotic rate, only staining the largest lesion for Ki67 should serve to grade almost all cases accurately. Multifocality does not appear to significantly impact patient survival.
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Affiliation(s)
- Numbereye Numbere
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA
| | - Aaron R Huber
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA
| | - Chanjuan Shi
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Justin M M Cates
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Raul S Gonzalez
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA
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8
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Mirakhur B, Pavel ME, Pommier RF, Fisher GA, Phan AT, Massien C, Liyanage N, Lowenthal SP, Vinik AI. BIOCHEMICAL RESPONSES IN SYMPTOMATIC AND ASYMPTOMATIC PATIENTS WITH NEUROENDOCRINE TUMORS: POOLED ANALYSIS OF 2 PHASE 3 TRIALS. Endocr Pract 2018; 24:S1530-891X(20)35469-0. [PMID: 30084687 DOI: 10.4158/ep-2018-0296] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/28/2024]
Abstract
OBJECTIVE Neuroendocrine tumors (NETs) are associated with elevated 5-hydroxyindoleacetic acid (5-HIAA) and chromogranin A (CgA) levels. This study aimed to analyze relationships between urinary 5-HIAA and plasma CgA levels and clinical outcomes. METHODS Centrally assessed biomarker levels and correlations with progression-free survival (PFS) and carcinoid syndrome (CS) symptom control were evaluated in a pooled analysis of CLARINET (96-week randomized, double-blind, placebo-controlled) and ELECT (16-week randomized, double-blind, placebo-controlled, 32-week initial open label and ≥2 year long-term extension open label) studies of adults with NETs, with (ELECT) or without (CLARINET) CS at 97 institutions. Patients were treated with subcutaneous lanreotide depot 120 mg monthly. RESULTS Of 319 pooled patients, 86% and 95% had baseline 5-HIAA and CgA data, respectively, with 47% and 74% having levels greater than the upper limit of normal (ULN). PFS was longer among patients who experienced a decrease in biomarker levels at week 12, with statistical significance reached in the CgA cohort (not reached vs. 14.4 months; P<.0001). A large proportion (87%) of patients without symptoms of CS in the CLARINET study had detectable levels of 5-HIAA (48% >ULN). In ELECT, patients with CS who received lanreotide and experienced a biochemical response (≥50% decrease from baseline) achieved greater symptom control. CONCLUSION This pooled analysis of two randomized, placebo-controlled trials demonstrated that 5-HIAA and CgA are secreted as biochemical biomarkers in many patients with NETs, regardless of clinical syndromes. Significant biochemical response was associated with improved clinical outcomes, as measured by improved PFS or improved CS symptom control. ABBREVIATIONS 5-HIAA = 5-hydroxyindoleacetic acid; CgA = chromogranin A; CI = confidence interval; CLARINET = Controlled Study of Lanreotide Antiproliferative Response in Neuroendocrine Tumors; CS = carcinoid syndrome; ELECT = Evaluation of Lanreotide Depot/Autogel Efficacy and Safety as a Carcinoid Syndrome Treatment; HR = hazard ratio; ITT = intention-to-treat; NET = neuroendocrine tumor; PanNET = pancreatic NET; PFS = progression-free survival; PPI = proton pump inhibitor; SSA = somatostatin analogue; ULN = upper limit of normal.
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Abstract
Small bowel neuroendocrine tumors (NETs) are increasing in incidence and are now the most common primary malignancies of the small intestine. Despite this increase, the vague presentation and slow growth of these tumors lead to long delays in diagnosis, and many patients present with metastases. Patients with metastatic small bowel NETs have a favorable disease prognosis, particularly when contrasted with other GI malignancies, and benefit from aggressive, multimodal therapy. During the past decade, the options for the diagnosis and treatment of small bowel NETs have increased considerably. This review provides a practical framework for the physician who seek to understand the epidemiology, presentation, diagnosis, and management of small bowel NETs.
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Affiliation(s)
- Aaron T. Scott
- University of Iowa Carver College of Medicine, Iowa City, IA
| | - James R. Howe
- University of Iowa Carver College of Medicine, Iowa City, IA
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10
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Howe JR, Cardona K, Fraker DL, Kebebew E, Untch BR, Wang YZ, Law CH, Liu EH, Kim MK, Menda Y, Morse BG, Bergsland EK, Strosberg JR, Nakakura EK, Pommier RF. The Surgical Management of Small Bowel Neuroendocrine Tumors: Consensus Guidelines of the North American Neuroendocrine Tumor Society. Pancreas 2017; 46:715-731. [PMID: 28609357 PMCID: PMC5502737 DOI: 10.1097/mpa.0000000000000846] [Citation(s) in RCA: 266] [Impact Index Per Article: 33.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Small bowel neuroendocrine tumors (SBNETs) have been increasing in frequency over the past decades, and are now the most common type of small bowel tumor. Consequently, general surgeons and surgical oncologists are seeing more patients with SBNETs in their practices than ever before. The management of these patients is often complex, owing to their secretion of hormones, frequent presentation with advanced disease, and difficulties with making the diagnosis of SBNETs. Despite these issues, even patients with advanced disease can have long-term survival. There are a number of scenarios which commonly arise in SBNET patients where it is difficult to determine the optimal management from the published data. To address these challenges for clinicians, a consensus conference was held assembling experts in the field to review and discuss the available literature and patterns of practice pertaining to specific management issues. This paper summarizes the important elements from these studies and the recommendations of the group for these questions regarding the management of SBNET patients.
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Affiliation(s)
- James R Howe
- From the *Department of Surgery, University of Iowa Carver College of Medicine, Iowa City, IA; †Department of Surgery, Winship Cancer Institute of Emory University, Atlanta, GA; ‡Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, PA; §Endocrine Oncology Branch, National Cancer Institute, Bethesda, MD; ∥Gastric and Mixed Tumor Service, Memorial Sloan Kettering Cancer Center, New York, NY; ¶Department of Surgery, LSU Health Sciences Center, New Orleans, LA; #Department of Surgery, University of Toronto, Sunnybrook Health Sciences Center, Toronto, Canada; **Rocky Mountain Cancer Center, Denver, CO; ††Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY; ‡‡Department of Radiology, University of Iowa Carver College of Medicine, Iowa City, IA; §§Department of Radiology, H. Lee Moffitt Cancer Center, University of South Florida, Tampa, FL; ∥∥Department of Medicine, University of California San Francisco, San Francisco, CA; ¶¶Department of Medicine, H. Lee Moffitt Cancer Center, University of South Florida, Tampa, FL; ##Department of Surgery, University of California San Francisco, San Francisco, CA; and ***Department of Surgery, Oregon Health & Science University, Portland, OR
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Jilesen APJ, van Eijck CHJ, in't Hof KH, van Dieren S, Gouma DJ, van Dijkum EJMN. Postoperative Complications, In-Hospital Mortality and 5-Year Survival After Surgical Resection for Patients with a Pancreatic Neuroendocrine Tumor: A Systematic Review. World J Surg 2016; 40:729-48. [PMID: 26661846 PMCID: PMC4746219 DOI: 10.1007/s00268-015-3328-6] [Citation(s) in RCA: 91] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Studies on postoperative complications and survival in patients with pancreatic neuroendocrine tumors (pNET) are sparse and randomized controlled trials are not available. We reviewed all studies on postoperative complications and survival after resection of pNET. A systematic search was performed in the Cochrane Central Register of Controlled Trials, MEDLINE and EMBASE from 2000-2013. Inclusion criteria were studies of resected pNET, which described postoperative complications separately for each surgical procedure and/or 5-year survival after resection. Prospective and retrospective studies were pooled separately and overall pooled if heterogeneity was below 75%. The random-effect model was used. Overall, 2643 studies were identified and after full-text analysis 62 studies were included. Pancreatic fistula (PF) rate of the prospective studies after tumor enucleation was 45%; PF-rates after distal pancreatectomy, pancreatoduodenectomy, or central pancreatectomy were, respectively, 14-14-58%. Delayed gastric emptying rates were, respectively, 5-5-18-16%. Postoperative hemorrhage rates were, respectively, 6-1-7-4%. In-hospital mortality rates were, respectively, 3-4-6-4%. The 5-year overall survival (OS) and disease-specific survival (DSS) of resected pNET without synchronous resected liver metastases were, respectively, 85-93%. Heterogeneity between included studies on 5-year OS in patients with synchronous resected liver metastases was too high to pool all studies. The 5-year DSS in patients with liver metastases was 80%. Morbidity after pancreatic resection for pNET was mainly caused by PF. Liver resection in patients with liver metastases seems to have a positive effect on DSS. To reduce heterogeneity, ISGPS criteria and uniform patient groups should be used in the analysis of postoperative outcome and survival.
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Affiliation(s)
- Anneke P J Jilesen
- Department of Surgery, Academic Medical Center, Meibergdreef 9, P. O. Box 22660, 1105 AZ, Amsterdam, The Netherlands.
| | | | - K H in't Hof
- Department of Surgery, Academic Medical Center, Meibergdreef 9, P. O. Box 22660, 1105 AZ, Amsterdam, The Netherlands
| | - S van Dieren
- Department of Methodology and Statistics Clinical Research Unit, Academic Medical Center, Amsterdam, The Netherlands
| | - Dirk J Gouma
- Department of Surgery, Academic Medical Center, Meibergdreef 9, P. O. Box 22660, 1105 AZ, Amsterdam, The Netherlands
| | - Els J M Nieveen van Dijkum
- Department of Surgery, Academic Medical Center, Meibergdreef 9, P. O. Box 22660, 1105 AZ, Amsterdam, The Netherlands
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Halfdanarson TR, Howe JR, Haraldsdottir S, O'Dorisio TM. Circulating tumor markers in patients with neuroendocrine tumors – a clinical perspective. INTERNATIONAL JOURNAL OF ENDOCRINE ONCOLOGY 2015. [DOI: 10.2217/ije.14.38] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Abstract: Neuroendocrine tumors (NETs) are uncommon malignancies with a very diverse presentation and prognosis. Patients with NETs frequently have circulating tumor biomarkers that may aid in the diagnosis and help with prognostication. The most commonly used and best studied marker is chromogranin A, which appears to reflect the tumor burden and is useful at the time of diagnosis, and to monitor for recurrence after resection as well as to assess response to systemic therapy. Despite being the best studied marker, chromogranin A has significant limitations. Multiple other biomarkers are in use, but most have not been studied well and need further validation before being recommended for clinical practice. We review both established and novel circulating biomarkers, and highlight some of the limitations of tumor marker use in patients with NETs.
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Affiliation(s)
- Thorvardur R Halfdanarson
- Division of Hematology and Medical Oncology, Mayo Clinic Cancer Center and Mayo Clinic Arizona, 13400 E. Shea Boulevard, Scottsdale, Arizona 85259, USA
| | - James R Howe
- Department of Surgery, University of Iowa Hospitals and Clinics, Iowa City, Iowa, USA
| | | | - Thomas M O'Dorisio
- Department of Internal Medicine, Division of Endocrinology, University of Iowa Hospitals and Clinics, Iowa City, Iowa, USA
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13
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Hagen J, Muniz VP, Falls KC, Reed SM, Taghiyev AF, Quelle FW, Gourronc FA, Klingelhutz AJ, Major HJ, Askeland RW, Sherman SK, O'Dorisio TM, Bellizzi AM, Howe JR, Darbro BW, Quelle DE. RABL6A promotes G1-S phase progression and pancreatic neuroendocrine tumor cell proliferation in an Rb1-dependent manner. Cancer Res 2014; 74:6661-70. [PMID: 25273089 DOI: 10.1158/0008-5472.can-13-3742] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Mechanisms of neuroendocrine tumor (NET) proliferation are poorly understood, and therapies that effectively control NET progression and metastatic disease are limited. We found amplification of a putative oncogene, RABL6A, in primary human pancreatic NETs (PNET) that correlated with high-level RABL6A protein expression. Consistent with those results, stable silencing of RABL6A in cultured BON-1 PNET cells revealed that it is essential for their proliferation and survival. Cells lacking RABL6A predominantly arrested in G1 phase with a moderate mitotic block. Pathway analysis of microarray data suggested activation of the p53 and retinoblastoma (Rb1) tumor-suppressor pathways in the arrested cells. Loss of p53 had no effect on the RABL6A knockdown phenotype, indicating that RABL6A functions independent of p53 in this setting. By comparison, Rb1 inactivation partially restored G1 to S phase progression in RABL6A-knockdown cells, although it was insufficient to override the mitotic arrest and cell death caused by RABL6A loss. Thus, RABL6A promotes G1 progression in PNET cells by inactivating Rb1, an established suppressor of PNET proliferation and development. This work identifies RABL6A as a novel negative regulator of Rb1 that is essential for PNET proliferation and survival. We suggest RABL6A is a new potential biomarker and target for anticancer therapy in PNET patients.
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Affiliation(s)
- Jussara Hagen
- Department of Pharmacology, University of Iowa, Iowa City, Iowa
| | - Viviane P Muniz
- Department of Pharmacology, University of Iowa, Iowa City, Iowa. Molecular and Cellular Biology Graduate Program, University of Iowa, Iowa City, Iowa
| | - Kelly C Falls
- Medical Scientist Training Program, University of Iowa, Iowa City, Iowa
| | - Sara M Reed
- Department of Pharmacology, University of Iowa, Iowa City, Iowa. Medical Scientist Training Program, University of Iowa, Iowa City, Iowa
| | - Agshin F Taghiyev
- Department of Pediatrics, College of Medicine, University of Iowa, Iowa City, Iowa
| | - Frederick W Quelle
- Department of Pharmacology, University of Iowa, Iowa City, Iowa. The Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa
| | - Francoise A Gourronc
- Department of Microbiology, College of Medicine, University of Iowa, Iowa City, Iowa
| | - Aloysius J Klingelhutz
- Molecular and Cellular Biology Graduate Program, University of Iowa, Iowa City, Iowa. The Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa. Department of Microbiology, College of Medicine, University of Iowa, Iowa City, Iowa
| | - Heather J Major
- Department of Pediatrics, College of Medicine, University of Iowa, Iowa City, Iowa
| | - Ryan W Askeland
- Department of Pathology, College of Medicine, University of Iowa, Iowa City, Iowa
| | - Scott K Sherman
- Department of Surgery, College of Medicine, University of Iowa, Iowa City, Iowa
| | - Thomas M O'Dorisio
- The Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa. Department of Internal Medicine, College of Medicine, University of Iowa, Iowa City, Iowa
| | - Andrew M Bellizzi
- The Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa. Department of Pathology, College of Medicine, University of Iowa, Iowa City, Iowa
| | - James R Howe
- The Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa. Department of Surgery, College of Medicine, University of Iowa, Iowa City, Iowa
| | - Benjamin W Darbro
- Department of Pediatrics, College of Medicine, University of Iowa, Iowa City, Iowa. The Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa
| | - Dawn E Quelle
- Department of Pharmacology, University of Iowa, Iowa City, Iowa. Molecular and Cellular Biology Graduate Program, University of Iowa, Iowa City, Iowa. Medical Scientist Training Program, University of Iowa, Iowa City, Iowa. The Holden Comprehensive Cancer Center, University of Iowa, Iowa City, Iowa. Department of Pathology, College of Medicine, University of Iowa, Iowa City, Iowa.
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Gene expression accurately distinguishes liver metastases of small bowel and pancreas neuroendocrine tumors. Clin Exp Metastasis 2014; 31:935-44. [PMID: 25241033 DOI: 10.1007/s10585-014-9681-2] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2014] [Accepted: 09/12/2014] [Indexed: 12/31/2022]
Abstract
Small bowel (SBNETs) and pancreatic neuroendocrine tumors (PNETs) often present with liver metastases. Although liver biopsy establishes a neuroendocrine diagnosis, the primary tumor site is frequently unknown without exploratory surgery. Gene expression differences in metastases may distinguish primary SBNETs and PNETs. This study sought to determine expression differences of four genes in neuroendocrine metastases and to create a gene expression algorithm to distinguish the primary site. Nodal and liver metastases from SBNETs and PNETs (n = 136) were collected at surgery under an Institutional Review Board-approved protocol. Quantitative PCR measured expression of bombesin-like receptor-3, opioid receptor kappa-1, oxytocin receptor, and secretin receptor in metastases. Logistic regression models defined an algorithm predicting the primary tumor site. Models were developed on a training set of 21 nodal metastases and performance was validated on an independent set of nodal and liver metastases. Expression of all four genes was significantly different in SBNET compared to PNET metastases. The optimal model employed expression of bombesin-like receptor-3 and opioid receptor kappa-1. When these genes did not amplify, the algorithm used oxytocin receptor and secretin receptor expression, which allowed classification of all 136 metastases with 94.1 % accuracy. In the independent liver metastasis validation set, 52/56 (92.9 %) were correctly classified. Positive predictive values were 92.5 % for SBNETs and 93.8 % for PNETs. This validated algorithm accurately distinguishes SBNET and PNET metastases based on their expression of four genes. High accuracy in liver metastases demonstrates applicability to the clinical setting. Studies assessing this algorithm's utility in prospective clinical decision-making are warranted.
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Sherman SK, Maxwell JE, O'Dorisio MS, O'Dorisio TM, Howe JR. Pancreastatin predicts survival in neuroendocrine tumors. Ann Surg Oncol 2014; 21:2971-80. [PMID: 24752611 DOI: 10.1245/s10434-014-3728-0] [Citation(s) in RCA: 53] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2014] [Indexed: 12/22/2022]
Abstract
BACKGROUND Serum neurokinin A, chromogranin A, serotonin, and pancreastatin reflect tumor burden in neuroendocrine tumors. We sought to determine whether their levels correlate with survival in surgically managed small bowel (SBNETs) and pancreatic neuroendocrine tumors (PNETs). METHODS Clinical data were collected with Institutional Review Board approval for patients undergoing surgery at one center. Progression-free (PFS) and overall (OS) survival were from the time of surgery. Event times were estimated by the Kaplan-Meier method. Preoperative and postoperative laboratory values were tested for correlation with outcomes. A multivariate Cox model adjusted for confounders. RESULTS Included were 98 SBNETs and 78 PNETs. Median follow-up was 3.8 years; 62 % had metastatic disease. SBNETs had lower median PFS than PNETs (2.0 vs. 5.6 years; p < 0.01). Median OS was 10.5 years for PNETs and was not reached for SBNETs. Preoperative neurokinin A did not correlate with PFS or OS. Preoperative serotonin correlated with PFS but not OS. Higher levels of preoperative chromogranin A and pancreastatin showed significant correlation with worse PFS and OS (p < 0.05). After multivariate adjustment for confounders, preoperative and postoperative pancreastatin remained independently predictive of worse PFS and OS (p < 0.05). Whether pancreastatin normalized postoperatively further discriminated outcomes. Median PFS was 1.7 years in patients with elevated preoperative pancreastatin versus 6.5 years in patients with normal levels (p < 0.001). CONCLUSIONS Higher pancreastatin levels are significantly associated with worse PFS and OS in SBNETs and PNETs. This effect is independent of age, primary tumor site, and presence of nodal or metastatic disease. Pancreastatin provides valuable prognostic information and identifies surgical patients at high risk of recurrence who could benefit most from novel therapies.
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Affiliation(s)
- Scott K Sherman
- Department of Surgery, University of Iowa Carver College of Medicine, Iowa City, IA, USA
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Sherman SK, Maxwell JE, Carr JC, Wang D, O'Dorisio MS, O'Dorisio TM, Howe JR. GIPR expression in gastric and duodenal neuroendocrine tumors. J Surg Res 2014; 190:587-93. [PMID: 24565507 DOI: 10.1016/j.jss.2014.01.044] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2013] [Revised: 01/16/2014] [Accepted: 01/24/2014] [Indexed: 01/14/2023]
Abstract
BACKGROUND Compounds targeting somatostatin-receptor-type-2 (SSTR2) are useful for small bowel neuroendocrine tumor (SBNET) and pancreatic neuroendocrine tumor (PNET) imaging and treatment. We recently characterized expression of 13 cell surface receptor genes in SBNETs and PNETs, identifying three drug targets (GIPR, OXTR, and OPRK1). This study set out to characterize expression of this gene panel in the less common neuroendocrine tumors of the stomach and duodenum (gastric and duodenal neuroendocrine tumors [GDNETs]). METHODS Primary tumors and adjacent normal tissue were collected at surgery, RNA was extracted, and expression of 13 target genes was determined by quantitative polymerase chain reaction. Expression was normalized to GAPDH and POLR2A internal control genes. Expression relative to normal tissue (ddCT) and absolute expression (dCT) were calculated. Wilcoxon tests compared median expression with false discovery rate correction for multiple comparisons. RESULTS Gene expression was similar in two gastric and seven duodenal tumors, and these were analyzed together. Like SBNETs (n = 63) and PNETs (n = 51), GDNETs showed significant overexpression compared with normal tissue of BRS3, GIPR, GRM1, GPR113, OPRK1, and SSTR2 (P < 0.05 for all). Of these, SSTR2 had the highest absolute expression in GDNETs (median dCT 4.0). Absolute expression of BRS3, GRM1, GPR113, and OPRK1 was significantly lower than SSTR2 in GDNETs (P < 0.05 for all), whereas expression of GIPR was similar to SSTR2 (median 4.3, P = 0.4). CONCLUSIONS As in SBNETs and PNETs, GIPR shows absolute expression close to SSTR2 but has greater overexpression relative to normal tissue (21.1 versus 3.5-fold overexpression). We conclude that GIPR could provide an improved signal-to-noise ratio for imaging versus SSTR2 and represents a promising novel therapeutic target in GDNETs.
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Affiliation(s)
- Scott K Sherman
- Department of Surgery, University of Iowa Carver College of Medicine, Iowa City, Iowa
| | - Jessica E Maxwell
- Department of Surgery, University of Iowa Carver College of Medicine, Iowa City, Iowa
| | - Jennifer C Carr
- Department of Surgery, University of Iowa Carver College of Medicine, Iowa City, Iowa
| | - Donghong Wang
- Department of Surgery, University of Iowa Carver College of Medicine, Iowa City, Iowa
| | - M Sue O'Dorisio
- Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, Iowa
| | - Thomas M O'Dorisio
- Department of Internal Medicine, University of Iowa Carver College of Medicine, Iowa City, Iowa
| | - James R Howe
- Department of Surgery, University of Iowa Carver College of Medicine, Iowa City, Iowa.
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Sherman SK, Carr JC, Wang D, O'Dorisio MS, O'Dorisio TM, Howe JR. Gastric inhibitory polypeptide receptor (GIPR) is a promising target for imaging and therapy in neuroendocrine tumors. Surgery 2014; 154:1206-13; discussion 1214. [PMID: 24238043 DOI: 10.1016/j.surg.2013.04.052] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2013] [Accepted: 04/25/2013] [Indexed: 01/18/2023]
Abstract
BACKGROUND Ligands binding the somatostatin receptor type 2 (SSTR2) are useful for imaging and treatment of neuroendocrine tumors (NETs), but not all tumors express high levels of these receptors. The aim of this study was to evaluate gene expression of new therapeutic targets in NETs relative to SSTR2. METHODS RNA was extracted from 103 primary small bowel and pancreatic NETs, matched normal tissue, and 123 metastases. Expression of 12 candidate genes was measured by quantitative polymerase chain reaction normalized to internal controls; candidate gene expression was compared with SSTR2. RESULTS Relative to normal tissue, primary NET expression of SSTR2, GPR98, BRS3, GIPR, GRM1, and OPRK1 were increased by 3, 8, 13, 13, 17, and 20-fold, respectively. Similar changes were found in metastases. Although most candidate genes showed lesser absolute expressions than SSTR2, absolute GIPR expression was closest to SSTR2 (mean dCT 3.6 vs. 2.7, P = .01). Absolute OPRK1 and OXTR expression varied greatly by primary tumor type and was close to SSTR2 in small bowel NETs but not pancreatic NETs. CONCLUSION Compared with the current treatment standard SSTR2, GIPR has only somewhat lesser absolute gene expression in tumor tissue but much lesser expression in normal tissue, making it a promising new target for NET imaging and therapy.
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Affiliation(s)
- Scott K Sherman
- Department of Surgery, University of Iowa Carver College of Medicine, Iowa City, IA
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Lorenzen AW, O’Dorisio TM, Howe JR. Neuroendocrine tumors arising in Meckel's diverticula: frequency of advanced disease warrants aggressive management. J Gastrointest Surg 2013; 17:1084-91. [PMID: 23558715 PMCID: PMC4438262 DOI: 10.1007/s11605-013-2191-8] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2013] [Accepted: 03/18/2013] [Indexed: 01/31/2023]
Abstract
BACKGROUND Meckel's diverticulum is a common anomaly of the GI tract, which occasionally gives rise to cancer. The most frequent tumors affecting these diverticula are neuroendocrine tumors (NETs), and whether these should be treated in similar fashion as small bowel NETs or appendiceal NETs is unclear. METHODS A retrospective chart review was conducted at a single academic medical center between 1998 and 2012. Demographic, radiologic, biochemical, and clinicopathologic data were collected as well as status at last follow-up. RESULTS Seven patients were identified with NETs involving Meckel's diverticula, including one with limited information other than management of her late metastases. Of the six other patients, all had involvement of regional nodes, including three patients with tumors <2 cm in size, and four had liver metastases at presentation. CONCLUSIONS NETs in Meckel's diverticula are rare tumors, but when they develop, are often associated with nodal metastases and liver metastases, even when the tumors are small. Therefore, optimal management of these NETs is small bowel resection with regional lymphadenectomy and debulking of liver metastases where feasible.
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Affiliation(s)
| | | | - James R. Howe
- Department of Surgery, University of Iowa Carver College of Medicine
- To who correspondences should be addressed: James R. Howe, M.D., 4644 JCP, University of Iowa Hospitals and Clinics, 200 Hawkins Drive, Iowa City, IA 52242, , Tel. (319)356-1727, Fax (319)353-8940
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Carr JC, Boese EA, Spanheimer PM, Dahdaleh FS, Martin M, Calva D, Schafer B, Thole DM, Braun T, O'Dorisio TM, O'Dorisio MS, Howe JR. Differentiation of small bowel and pancreatic neuroendocrine tumors by gene-expression profiling. Surgery 2013; 152:998-1007. [PMID: 23158174 DOI: 10.1016/j.surg.2012.08.040] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2012] [Accepted: 08/20/2012] [Indexed: 12/17/2022]
Abstract
BACKGROUND Between 10% and 20% of patients with neuroendocrine tumors (NETs) present with metastases of unknown primary site. Because knowledge of the primary site has important implications for treatment, we set out to define gene-expression profiles to differentiate between small-bowel NETs (SBNETs) and pancreatic NETs (PNETs). METHODS RNA was extracted from tumor and normal tissues in 11 patients with SBNETs and 15 patients with PNETs, and qPCR was performed for 367 GPCR genes. Differentially expressed genes were identified using the RT2 Profiler. Whole genome expression analysis was performed on 11 SBNETs, 5 PNETS, and corresponding normal tissues. Statistical significance was evaluated by the Student t test and ANOVA. RESULTS Whole-genome analysis revealed 173 significantly differentially expressed genes in SBNETs and normal tissues and in 52 in PNETs. GPCR arrays identified 28 genes in SBNETs and 18 in PNETs, with significant expression differences from normal tissues. In all SBNETs, 2 genes were significantly upregulated by more than fivefold: OXTR and GPR113. No PNETs shared this profile, whereas 73% had a greater than fivefold downregulation of ADORA1 and SCTR. These genes also allowed for determination of the primary site in 8 of 10 liver metastases. CONCLUSION Differential expression patterns using as few as 2 to 4 GPCR genes successfully discriminated primary sites in small bowel and pancreatic NETs.
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Affiliation(s)
- Jennifer C Carr
- Department of Surgery, University of Iowa Carver College of Medicine, Iowa City, IA 52242-1086, USA
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Dahdaleh FS, Lorenzen A, Rajput M, Carr JC, Liao J, Menda Y, O'Dorisio TM, Howe JR. The value of preoperative imaging in small bowel neuroendocrine tumors. Ann Surg Oncol 2013; 20:1912-7. [PMID: 23283442 DOI: 10.1245/s10434-012-2836-y] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2012] [Indexed: 12/30/2022]
Abstract
BACKGROUND Neuroendocrine tumors of the small bowel (SBNETs) are a rare but important subgroup of malignancies. Since 30 % of SBNETs present with metastatic disease, often with an occult primary, preoperative imaging is critical for determining who will benefit most from abdominal exploration. We set out to evaluate the usefulness of the two most commonly performed imaging modalities in predicting the extent of disease found at exploration in patients with SBNETs. METHODS A retrospective chart review was performed on patients with SBNETs resected at 1 institution. Data from preoperative computed tomography (CT) scans were reviewed to determine whether the primary tumor, nodal, or liver metastases were seen, then compared with intraoperative findings. Results of preoperative somatostatin receptor scintigraphy (SRS) were similarly examined. RESULTS A total of 62 patients with SBNETs were included. Of these patients, 42 of 62 (68 %) had distant metastases and 48 of 62 (77 %) had nodal metastases at exploration. A total of 56 patients had preoperative CT scans and 47 had SRS. Using CT, a primary tumor was localized to the small bowel in 27 of 56 (48 %) and nodal metastases seen in 33 of 56 (79 %) of cases. SRS found intra-abdominal uptake in 35 of 47 cases (74 %). CONCLUSIONS CT and SRS are complementary in making the diagnosis of SBNET, with CT giving more precise anatomical detail, while SRS helps to confirm that lesions are NETs and is useful for identifying occult extrahepatic sites of metastatic disease. However, 10-15 % of SBNETs were not identified by either test preoperatively, and therefore surgical exploration still plays an important role in making the diagnosis in these patients.
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Affiliation(s)
- Fadi S Dahdaleh
- Division of Surgical Oncology and Endocrine Surgery, Department of Surgery, University of Iowa Hospitals and Clinics, Iowa City, IA, USA
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