Its EARLYgrab some coffee Carcinoid Tumors Rare or
It’s EARLY…grab some coffee…
Carcinoid Tumors Rare or Rarely Not? An Evidence Based Update 2019 AAPCE Annual Conference San Diego, California 11/2/2019 John R. Fleming, Jr. , M. D. , FAAFP, HMDC Magnolia Family Practice, LLC Sumter, SC jrflemingjr@palmettodoc. com
Santa’s not ready yet…
John R. Fleming, Jr. , M. D. , FAAFP, HMDC • University of Kentucky College of Medicine • Fort Wayne Medical Education Program Family Medicine Residency Program • Private Practice in Sumter, SC – Founding partner of Palmetto Family Practice, LLC • Sold Palmetto Family Practice LLC to PH USC MG 8/1/18 • Didn’t like being employed, left PFP 9/2019 • Founding partner of Magnolia Family Practice LLC, 9/2019
Financial Disclosures • I do take advantage of drug rep lunches, samples, and dinners (especially at nice restaurants). • My wife and I spent a fair amount of money over the last 2 days supporting the local economy of San Diego. • My wife will probably continue to support the local economy while I am in this conference. • I’ve learned that setting up a private practice can be costly, especially if purchasing a building. • I have no other disclosures to report.
Carcinoid Tumors Objectives • Discuss the incidence, etiology, characteristics, pathology, locations, types, and clinical manifestations of carcinoid tumors. • Discuss carcinoid syndrome. • Discuss identification of carcinoid tumors in the colon and stomach. • Discuss treatment including techniques of removal of carcinoid tumors of the colon.
Carcinoid Tumors History
Carcinoid Tumors The Beginnings - Siegfried Oberndorfer Obendorfer S: Karzinoide tumoren des dunndarms. Frankf Z Pathol 1: 425‐ 429, 1907
Siegfried Oberndorfer • The first to adequately characterize the nature of the tumors and refer to them as “benign carcinomas. ” • During his tenure at the Pathological Institute of the University of Munich, Oberndorfer noted in 1907 that the lesions were distinct clinical entities and named them “karzinoide” (“carcinoma‐like”), emphasizing in particular their benign features. • In 1929 he amended his classification to include the possibility that these small bowel tumors could be malignant and also metastasize. Hum Pathol. 2004 Dec; 35(12): 1440‐ 51. Siegfried Oberndorfer: origins and perspectives of carcinoid tumors.
Carcinoid Tumors Description
Carcinoid Tumors • Carcinoid and neuroendocrine tumors arise from the ubiquitous neuroendocrine cells, also referred to as clear cells or amine precursor uptake and decarboxylation (APUD) cells. • Capable of secreting many different cytokines and hormones. • Tend to be slow growing. Clin Colon Rectal Surg 2006; 19: 45– 48. Carcinoid and Neuroendocrine Tumors of the Colon and Rectum
Carcinoid Tumors • Histologically – positive reaction to silver stains as well as markers of neuroendocrine tissue • Neuron specific enolase • Synaptophysin • Chromogranin NEJM 1999‐ 03 vol 340(11) pp 858‐ 68. Carcinoid Tuomors
Carcinoid Tumors • Under the electron microscope – many membrane bound secretory vessicles that contain a variety of hormones and biogenic amines • • Serotonin Corticotropin Histamine Dopamine Substance P Neurotensin Prostaglandins Kallikrein NEJM 1999‐ 03 vol 340(11) pp 858‐ 68. Carcinoid Tuomors
Neurosecretory Granules
Carcinoid Tumors • Serotonin is the best characterized, and probably the most important of these hormones
Carcinoid Tumors • Serotonin is the best characterized, and probably the most important of these hormones • 5‐hydroxytyptophan is converted to serotonin by the enzyme aromatic acid decarboxylase • Serotonin is then metabolized to 5‐hydroxy‐ indoleacetic acid (5‐HIAA) by the enzyme monoamine oxidase • 5‐HIAA excreted in the urine NEJM 1999‐ 03 vol 340(11) pp 858‐ 68. Carcinoid Tuomors
Carcinoid Tumors • Can involve a wide variety of organs • Most commonly involve • Lungs • Bronchi • Gastrointestinal tract NEJM 1999‐ 03 vol 340(11) pp 858‐ 68. Carcinoid Tuomors
Carcinoid Tumors Classification
Carcinoid Tumors - Classification • Originally classified by Williams and Sandler in 1963 according to their embryonic origin • Foregut • Midgut • Hindgut • Embryonic origin is tied to vascular supply • Foregut – Celiac Artery • Midgut – Superior Mesenteric Artery • Hindgut – Inferior Mesenteric Artery Clin Colon Rectal Surg 2006; 19: 45– 48. Carcinoid and Neuroendocrine Tumors of the Colon and Rectum
Carcinoid Tumors - Classification
Carcinoid Tumors – Classification • Foregut • Lungs • Bronchi • Stomach • Midgut • Small intestines • Appendix • Ascending colon‐proximal transverse • Hindgut • Mid transverse colon to the rectum
Carcinoid Tumors - Classification
Carcinoid Tumors - Classification
Carcinoid Tumors - Classification
Carcinoid Tumors - Classification World J Gastrointest Endosc 2011 vol 3(7) pp 133‐ 139 ‐ Management of early gastrointestinal neuroendocrine neoplasms
Carcinoid Tumors Characteristics
Carcinoid Tumors - Characteristics • Appendiceal Carcinoids • Most common tumor of the appendix • Fourth or fifth decade of life • Some speculation that they may regress with age (following the regression of subepithelial endocrine cells) • Most often diagnosed incidentally at time of appendectomy • Less than 10% cause symptoms – 75% located in distal third of appendix • 95% are less than 2 cm – metastasis is rare NEJM 1999‐ 03 vol 340(11) pp 858‐ 68. Carcinoid Tuomors
Carcinoid Tumors - Characteristics • Colonic Carcinoids • Less than 1% of all colon tumors • Symptom presentation usually in seventh decade – pain, anorexia, weight loss • Less than 5% have carcinoid syndrome • Average tumor size 5 cm, two thirds have metastasis • Majority are treated with radical colectomy NEJM 1999‐ 03 vol 340(11) pp 858‐ 68. Carcinoid Tuomors
Carcinoid Tumors - Characteristics • Rectal Carcinoids • 1‐ 2% of all rectal tumors • Most common in sixth decade of life • Contain glucagon and glicentin‐related peptides instead of serotonin • Symptoms usually include rectal pain, bleeding, constipation • Carcinoid syndrome is rare NEJM 1999‐ 03 vol 340(11) pp 858‐ 68. Carcinoid Tuomors
Carcinoid Tumors - Characteristics • Rectal Carcinoids • Metastasis dependent on size, < 1 cm = < 5%, > 2 cm = majority • Metastasis usually to the liver • Treatment: • < 1 cm – local excision • 1‐ 2 cm – controversial, but most can be treated with local excision, muscular involvement or symptoms or ulceration are poor prognostic indicators • > 2 cm – anterior resection • Some studies show advanced procedures don’t extend life beyond that seen with local excision NEJM 1999‐ 03 vol 340(11) pp 858‐ 68. Carcinoid Tuomors
Carcinoid Tumors - Characteristics Am Fam Physician 2006; 74: 429‐ 34. Carcinoid Tuomors
Carcinoid Tumors Incidence
Carcinoid Tuomors - Incidence • Incidence increasing in recent decades • Most likely the result of improved and sophisticated methods of detection • • • Endoscopy Computed Tomogrophy Magnetic Resonance Imaging Ultrasonography Scintigraphy Clin Colon Rectal Surg 2006; 19: 45– 48. Carcinoid and Neuroendocrine Tumors of the Colon and Rectum
JAMA Oncol 2017 vol 3(10) pp 1335‐ 1342. Trends in the Incidence, Prevalence, and Survival Outcomes in Patients With NETs in the US. Dasari A, Shen C, Halperin D, et al.
JAMA Oncol 2017 vol 3(10) pp 1335‐ 1342. Trends in the Incidence, Prevalence, and Survival Outcomes in Patients With NETs in the US. Dasari A, Shen C, Halperin D, et al.
Seminars in Onc 2018‐ 08 vol 45(2) pp 249‐ 258. Epidemiologic trends in NETs ‐ An examination of incidence rates and survival of specific patient subgroups over the past 20 years. Sackstein PE, O’Neil DS, Neugut AI, et al.
Carcinoid Tumors Symptoms and Carcinoid Syndrome
Carcinoid tumor symptoms • Most carcinoid tumors in the colon are asymptomatic at the time of diagnosis endoscopically • Most symptoms are usually vague • Often related to mass effect of the tumor • Typical symptoms are present in less than 10% of cases • Symptoms include • • • Abdominal pain Weight loss Bleeding Obstruction Constipation Frequently NONE • Hepatic metastasis usually necessary to manifest typical symptoms Clin Colon Rectal Surg 2006; 19: 45– 48. Carcinoid and Neuroendocrine Tumors of the Colon and Rectum
Carcinoid Syndrome • Symptoms thought to arise from release of serotonin and other vasoactive amines into the systemic circulation • Symptoms include • • Cutaneous flushing Diarrhea Wheezing Eventually right sided valvular heart disease NEJM 1999‐ 03 vol 340(11) pp 858‐ 68. Carcinoid Tuomors
Carcinoid Syndrome Carcinoid Heart Disease • Occurs in up to 70% of patients • Frequently results in death • Right sided heart disease • Plaque like deposits of fibrous tissue on the valves as well as right atrium and right ventricle • Most commonly from midgut carcinoids with metastasis Adv Surg 2011 vol 45 pp 285‐ 300. Recent advances in the diagnosis and treatment of gastrointestinal carcinoids. Valentino J, Evers BM.
Carcinoid Tumors Diagnosis
Carcinoid - Biochemical Screening • Most commonly used tests • Urinary 5‐hydroxyindole acetic acid (5‐HIAA) • Serum Chromogranin A • Widely available Clin Colon Rectal Surg 2006; 19: 45– 48. Carcinoid and Neuroendocrine Tumors of the Colon and Rectum
Carcinoid - Biochemical Screening • Newer markers may improve the diagnosis and prognostication • pancreastatin • neurokinin A • plasma 5‐HIAA • Not as widely available Endocr Pract 2015‐ 05 vol 21(5) pp 534– 545. AACE‐ACE Disease State Clinical Review – Diagnosis And Management Of Midgut Carcinoids. Liu EH, Solorzano CC, et al.
Carcinoid - Biochemical Screening • Urinary 5‐hydroxyindole acetic acid (5‐HIAA) • Widely available • Specificity ~88% • Detects about 84% of midgut carcinoids, but not as good foregut or hindgut • Certain foods and medications can affect serum serotonin and urinary 5‐HIAA Clin Colon Rectal Surg 2006; 19: 45– 48. Carcinoid and Neuroendocrine Tumors of the Colon and Rectum Endocr Pract 2015‐ 05 vol 21(5) pp 534– 545. AACE‐ACE Disease State Clinical Review – Diagnosis And Management Of Midgut Carcinoids. Liu EH, Solorzano CC, et al.
Carcinoid – Biochemical Screening Urinary 5 -hydroxyindole acetic acid (5 -HIAA) • High serotonin concentrations occur with the ingestion of bananas, kiwis, pineapple, plantains, plums, and tomatoes • Moderate elevations with avocado, black olives, spinach, broccoli, cauliflower, eggplant, cantaloupe, dates, figs, nuts, grapefruit, and honeydew melon • Drugs that increase u 5‐HIAA: acetanalid, phenacetin, reserpine, glyceryl guiacolate (found in many cough syrups), and methocarbamol • Drugs that decrease u 5‐HIAA: chlorpromazine, heparin, impiramine, isoniazid, levodopa, monoamine oxidase inhibitors, methenamine, methyldopa, phenothiazines, promethazine, and tricyclic antidepressants • Need to do a thorough diet and medication history Endocr Pract 2015‐ 05 vol 21(5) pp 534– 545. AACE‐ACE Disease State Clinical Review – Diagnosis And Management Of Midgut Carcinoids. Liu EH, Solorzano CC, et al.
Carcinoid - Biochemical Screening • Serum Chromogranin A • Best overall marker of NETs • Sensitivity and specificity range from 70‐ 100% • Variability between labs, so serial measurements should be done at the same lab • Often elevated 50‐ 100% above normal • Serum level may be indicative of tumor burden and thus carry prognostic significance in midgut NETs Clin Colon Rectal Surg 2006; 19: 45– 48. Carcinoid and Neuroendocrine Tumors of the Colon and Rectum Endocr Pract 2015‐ 05 vol 21(5) pp 534– 545. AACE‐ACE Disease State Clinical Review – Diagnosis And Management Of Midgut Carcinoids. Liu EH, Solorzano CC, et al.
Carcinoid - Biochemical Screening Serum Chromogranin A • Elevated levels of Cg. A have been reported in patients using proton‐pump inhibitors, in patients with renal or liver failure, malignant hypertension, and in those with chronic gastritis Endocr Pract 2015‐ 05 vol 21(5) pp 534– 545. AACE‐ACE Disease State Clinical Review – Diagnosis And Management Of Midgut Carcinoids. Liu EH, Solorzano CC, et al.
Carcinoid - Biochemical Screening • Pancreastatin • • • Post translational processing product of Cg. A Negative prognostic indicator when elevated Correlates to the number of liver metastasis Potentially useful marker for diagnosis and monitoring Unaffected by proton pump inhibitors Endocr Pract 2015‐ 05 vol 21(5) pp 534– 545. AACE‐ACE Disease State Clinical Review – Diagnosis And Management Of Midgut Carcinoids. Liu EH, Solorzano CC, et al.
Endocr Pract 2015‐ 05 vol 21(5) pp 534– 545. AACE‐ACE Disease State Clinical Review – Diagnosis And Management Of Midgut Carcinoids. Liu EH, Solorzano CC, et al.
Carcinoid - Imaging • CT Scan or MRI • CT most commonly used imaging study due to being widely available and standard protocols • Due to long life span, repeated radiation from CT can be an issue • MRI most useful for liver mets, small bowel difficult to see due to motion • Detection rate ~80% with no significant difference between CT and MRI in detection rates • Classic triad of calcified mass, spiculation, and stranding suggesting localized fibrosis Clin Colon Rectal Surg 2006; 19: 45– 48. Carcinoid and Neuroendocrine Tumors of the Colon and Rectum Endocr Pract 2015‐ 05 vol 21(5) pp 534– 545. AACE‐ACE Disease State Clinical Review – Diagnosis And Management Of Midgut Carcinoids. Liu EH, Solorzano CC, et al.
Carcinoid - Imaging • Octreoscan scintigraphy • Single photon emission CT (SPECT) • Most (80%) NETs express somatostatin receptors • 111 In‐pentetreotide (Octreoscan) is the most widely used (pentetreotide – somatostatin analogue) • Sensitifity 80‐ 90% • Advantage of scanning entire body • Median detection rate ~89% • Disadvantages • Insensitive for tumor < 1 cm • Lower sensitivity • Inconvenient for patient – IV injection of tracer, then scans 4 hr and 24 hr later Clin Colon Rectal Surg 2006; 19: 45– 48. Carcinoid and Neuroendocrine Tumors of the Colon and Rectum Endocr Pract 2015‐ 05 vol 21(5) pp 534– 545. AACE‐ACE Disease State Clinical Review – Diagnosis And Management Of Midgut Carcinoids. Liu EH, Solorzano CC, et al.
Carcinoid - Imaging • PET • Previously of limited utility as most NETs are well differentiated and have a low metabolic rate • Newer technologies make it more feasible • 68 Ga‐somatostatin PET – • new and emerging • offers greater sensitivity and resolution of images • undergoing clinical trials in US, only available at a few specialty centers Clin Colon Rectal Surg 2006; 19: 45– 48. Carcinoid and Neuroendocrine Tumors of the Colon and Rectum Endocr Pract 2015‐ 05 vol 21(5) pp 534– 545. AACE‐ACE Disease State Clinical Review – Diagnosis And Management Of Midgut Carcinoids. Liu EH, Solorzano CC, et al.
Carcinoid Tumors Treatment
Carcinoid - Treatment • Surgical resection • Incidental discovery at time of appendectomy • Somatostatin analogues octreotide and lanreotide are highly efficacious for symptomatic improvement and tumor control • Traditional chemotherapies ineffective due to slow growing nature of most NETs • New/emerging treatment ‐ peptide receptor radiotherapy (PRRT), SA is chelated to a beta emitting cytotoxic isotope, 90‐Yttrium or 177‐Lutetium Endocr Pract 2015‐ 05 vol 21(5) pp 534– 545. AACE‐ACE Disease State Clinical Review – Diagnosis And Management Of Midgut Carcinoids. Liu EH, Solorzano CC, et al.
Carcinoid – Treatment Endoscopic • Endoscopic Mucosal Resection (EMR) vs Endoscopic Submucosal Dissection (ESD) • 2013 systematic review and meta‐analysis suggested ESD was more effective at achieving “complete resection” • Subsequent systematic review and meta‐analysis disputed this • Low level of available evidence Colorectal Dis 2013‐ 03 vol 15(3) pp 283‐ 91. EMR vs EMD for rectal carcinoid tumours ‐ a systematic review and meta‐analysis. Zhong DD, Shao LM, Cai JT. Expert Rev Gastroenterol Hepatol 2015‐ 05 vol 9(5) pp 659‐ 69. Endoscopic resection of submucosal tumors. Longcroft‐Wheaton G, Bhandari P.
Carcinoid - Treatment www. carcinoid. com/hcp‐resources, accessed 10/28/2019
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References • Clin Colon Rectal Surg 2006; 19: 45– 48. Carcinoid and Neuroendocrine Tumors of the Colon and Rectum • J Clin Oncol 2008; 26(18): 3065 ‐ One Hundred Years After Carcinoid. Epidemiology of and Prognostic Factors for Neuroendocrine Tumors in 35, 825 Cases in the United States • World J Gastrointest Endosc 2011; 3(7): 133‐ 139 ‐ Management of early gastrointestinal neuroendocrine neoplasms • NEJM 1999‐ 03; 340(11): 858‐ 68. Carcinoid Tuomors • Am Fam Physician 2006; 74: 429‐ 34. Carcinoid Tuomors • Hum Pathol 2004‐Dec; 35(12): 1440‐ 51. Siegfried Oberndorfer: origins and perspectives of carcinoid tumors • Frankf Z Pathol 1: 425‐ 429, 1907. Obendorfer S: Karzinoide tumoren des dunndarms
References • Adv Surg 2011 vol 45 pp 285‐ 300. Recent advances in the diagnosis and treatment of gastrointestinal carcinoids. Valentino J, Evers BM. • Endocr Pract 2015‐ 05 vol 21(5) pp 534– 545. AACE‐ACE Disease State Clinical Review – Diagnosis And Management Of Midgut Carcinoids. Liu EH, Solorzano CC, et al. • Colorectal Dis 2013‐ 03 vol 15(3) pp 283‐ 91. EMR vs EMD for rectal carcinoid tumours ‐ a systematic review and meta‐analysis. Zhong DD, Shao LM, Cai JT. • Expert Rev Gastroenterol Hepatol 2015‐ 05 vol 9(5) pp 659‐ 69. Endoscopic resection of submucosal tumors. Longcroft‐Wheaton G, Bhandari P. • JAMA Oncol 2017 vol 3(10) pp 1335‐ 1342. Trends in the Incidence, Prevalence, and Survival Outcomes in Patients With NETs in the US. Dasari A, Shen C, Halperin D, et al. • Seminars in Onc 2018‐ 08 vol 45(2) pp 249‐ 258. Epidemiologic trends in NETs ‐ An examination of incidence rates and survival of specific patient subgroups over the past 20 years. Sackstein PE, O’Neil DS, Neugut AI, et al. • www. carcinoid. com/hcp‐resources, accessed 10/28/2019
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