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FCDS Annual ConferenceBoca Raton Marriott at Boca Center
July 28, 2016Steven Peace, BS, CTR
Anatomy and Physiology of the (Neuro)Endocrine SystemWHO Classification, Tumor Grade and Tumor Markers
Signs & Symptoms, AJCC/UICC TNM 7thedPlus…NCCN Treatment Guidelines
Neuroendocrine Tumors
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The (Neuro)Endocrine System – Anatomy & Physiology
WHO Classification for NETs and Endocrine Carcinomas
NETs of the Pancreas, GI Tract, Thyroid, and Lung
Are All NETs Reportable?
New Terms and Histology Codes
Tumor Grade and Other Markers
AJCC/UICC TNM Staging
Treatment Guidelines
Questions
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3Source: www.biologyjunction.com and education-portal.com
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4Source: images.flatworldknowledge.com
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5Source: images.flatworldknowledge.com
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6Source: Gray654 – Gray’s Anatomy (public domain)
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DEFINITION: “Stroma” is the supportive framework of an organ, gland or other structure that is usually composed of connective tissue. The stroma is distinct from the “parenchyma”, which is the of the key functional tissue or elements of that organ that makes the organ, gland or structure do what is intended to do. It holds things together.
Stroma/Connective Tissue Includes: soft tissue, muscle, bone, tendons, mesentery, fibrous tissue, fatty tissue, lymphatic tissue, subcutaneous tissue, blood vessels, lymph vessels, and even nervous system tissues that lie outside the brain and CNS (autonomic and peripheral nervous systems), and even the tissues of the pleural cavity, peritoneum and retroperitoneum including the omentumand mesentery.
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The endocrine system works alongside of the nervous system to form the control systems of the body. The nervous system provides a
very fast and narrowly targeted system to turn on specific glands and muscles throughout the body. The endocrine system, on the
other hand, is much slower acting, but has very widespread, long lasting, and powerful effects. Hormones are distributed by glands
through the bloodstream to the entire body, affecting any cell with a receptor for a particular hormone. Most hormones affect cells in several organs or throughout the entire body, leading to many
diverse and powerful responses.
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The (Neuro)Endocrine System Includes
The Endocrine System (glands and organs) PLUS
The Diffuse Neuroendocrine System
The Diffuse Neuroendocrine System or Diffuse NES is made up of scattered neuroendocrine cells distributed throughout
the body - each location serving different function – no organ/gland
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Diffuse NES Examples: Digestive NES cells – regulate release of digestive enzymes Digestive NES cells – regulate intestinal movements Respiratory NES cells – regulate respiratory function Adrenal Medulla and Paraganglia (organ) – regulate blood
pressure and heart rate – produce both epinephrine and neuro-epinephrine
Neuroendocrine cells are also found in non-neuroendocrine glands
Neuroendocrine cells are also diffusely scattered in skin, thymus, prostate, and other glands and tissues
Pancreatic Islet Cells of the Pancreas Gland – Islets of Langerhans – produce insulin to regulate sugar levels in the body and bloodstream
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Neuroendocrine Tumors or NETs are often referred to by a different names – some of this is historical – some habit.
Some NETs are benign tumors but some highly malignant Neuroendocrine Tumors known widely by another name:
Merkel Cell Carcinoma Medullary Thyroid Carcinoma Carcinoid Tumor (low-grade NET) Pheochromocytoma/Paraganglioma PanNET – Pancreatic Neuroendocrine Tumor Poorly Differentiated Large Cell Carcinoma (high-grade NET) Poorly Differentiated Small Cell Carcinoma (high-grade NET) ACTH-dependent or ACTH-independent Cushing Syndrome
Mitotic Index, Ki-67 Index, Hormone Functionality - Indicators
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NeuroECTODERMAL Tumors are also called NETs
This type of NET includes rare pediatric brain tumors and Ewing Sarcoma that develop from undeveloped and/or non-differentiated embryonal neural tissue of the ectoderm or tiesues that become brain and CNS. CNS PNET – primitive neuroectodermal tumor of CNS PPNET – peripheral primitive neuroectodermal tumor – Ewing ‘s
DNET – dysembryoplastic neuroepithelial tumor and not related to other NETs noted above.
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The classification and reporting of tumors of the pancreas can be confusing in part due to the latest terminology associated with tumors arising in the pancreas, and complicated by the mixed
nature of benign, borderline, in-situ and invasive neoplasms and various histologic subtypes associated with pancreatic neoplasms.
In 2010 the World Health Organization (WHO) published the latest WHO Classification of Tumors of the Pancreas.
ALL in-situ and invasive (malignant) neoplasms of the pancreas are reportable. However, some reportable neoplasms are
associated with terminology registrars may not immediately recognize as reportable malignancy.
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ICD-O-3 Description Reportable8150/3 Cystic Pancreatic Endocrine Neoplasm (CPEN) Y
8453/2 Intraductal Papillary Mucinous Neoplasm (IPNM) Y8503/2 Intraductal Tubule-Papillary Neoplasm (ITPN) Y8470/2 Mucinous Cystic Neoplasm (MCN) Y8246/3 Neuroendocrine Carcinoma Y8240/3 Neuroendocrine Tumor, Grade 1 (NET GR1) Y8249/3 Neuroendocrine Tumor, Grade 2 (NET GR2) Y8452/3 Solid Pseudo-Papillary Neoplasm (SPN) Y
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Non-Invasive and Invasive Pancreatic Neoplasms Often Missed
References: 2010 WHO Classification of Tumours of the Pancreas; Pathologe. 2011 Nov;32 Suppl2:332-6. doi: 10.1007/s00292-011-1515-2; Ann Surg. 2004 May; 239(5): 651–659), 2011 ICD-O-3 Updates, 2015 SEER Program Coding and Staging Manual, and NCI SEER Ask A SEER Registrar.
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15Source: www.nccn.org/neuroendocrine.pdf
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Speel EJM et al. Am J Pathol. 1999;155:1787–1794 and Rindi G, et al. Ann NY Acad Sci. 2004;1014:1-12
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“Functional” Neuroendocrine Tumors are NETs that
produce an excess of hormones that can lead to a variety of
hormone-related symptoms including facial or body
flushing, diarrhea or bronchospasms. Over the long-term
the chronic over/under expression of hormones can lead to
other life-threatening conditions such as carcinoid heart
disease – fibrous heart & valves, diabetes, weight gain,
diarrhea, sudden growth of hands or feet, etc.
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Examples of “Functional” Hormone-Producing NETs Insulinoma – tumor produces excess/insufficient insulin Glucagonoma – interferes with production of glucose which then
causes problems with high blood sugar and worsening diabetes Gastrinoma – increased production of gastrin leading to ulcers Somatostatinoma – disrupts multiple hormone balances leading to
diabetes, gallstones, and inability to digest fats VIP-oma – disrupts vasoactive intestinal peptide – severe diarrhea GRF-oma – produce excessive amounts of growth hormone
release factors – leads to sudden growth of feet and hands ACTH-oma – produce excessive amounts of the hormone ACTH.
Too much ACTH increased production of steroids which lead to weight gain, depression, increased risk of infection, skin changes.
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NETs in the GI Tract develop in the neuroendocrine cells of the connective tissues in and around the GI Tract and may
grow inward or outward.
NETs in the GI Tract stimulate hormone-producing endocrine cells resulting in the overproduction of
vasoactive peptide hormones [serotonin (5-HT), histamines and tachykinins) causing a constellation of symptoms
“carcinoid syndrome” – flushing, fatty diarrhea, bronchospasms, and “dumping” syndrome.
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Endocrine Neoplasms are tumors of Endocrine Organs Pancreas Testis Ovaries
Endocrine Neoplasms are tumors of Endocrine Glands Pineal Gland Pituitary Gland Thyroid Gland Thymus Gland Adrenal Glands Parathyroid Glands
Endocrine Neoplasms are not necessarily NETs
20Source: www.magazinehealth.com/endocrine
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Tumors that arise in the Diffuse Neuroendocrine System REPEAT: The Diffuse Neuroendocrine System or Diffuse
NES is made up of scattered neuroendocrine cells distributed throughout the body - each location serving different function – no organ/gland – and rare neoplasms. Merkel Cell Carcinoma Medullary Thyroid Carcinoma Carcinoid Tumor (low-grade NET) Pheochromocytoma/Paraganglioma PanNET – Pancreatic Neuroendocrine Tumor Poorly Differentiated Large Cell Carcinoma (high-grade NET) – not lung Poorly Differentiated Small Cell Carcinoma (high-grade NET) – not lung ACTH-dependent or ACTH-independent Cushing Syndrome
Mitotic Index, Ki-67 Index, Hormone Functionality - Indicators
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22Source: www.nccn.org/neuroendocrine.pdf
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Pain Asthma Diabetes Gallstones Stomach ulcers Severe diarrhea Sudden food allergies Facial or body “flushing” Anxiety and/or Depression Other functional bowel disease Hypoglycemia (low blood sugar) Sudden growth of the hands and feet (acromegaly)
23Source: www.mja.com.au/Volume 193 Number 1
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CgA or Chromogranin – Most Important NET Marker Elevated in 60%-80% of functional and non-functional NETs
5-HIAA – 5-hydroxyindoleacetic acid A product of the breakdown of serotonin
Excess Hormone Levels in Blood Human Growth Hormone Glucocorticoid Steroids Somatostatin Serotonin Insulin Gastrin ACTH
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25Source: www.mja.com.au/Volume 193 Number 1
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26Source: www.med.harvard.edu
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27Source: NCCN Guidelines for Neuroendocrine Tumors -Version 2.2016
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28Source: NCCN Guidelines for Neuroendocrine Tumors -Version 2.2016
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Use Specific TNM Chapter NET Ampulla NET Colon NET Rectum NET Small Intestine NET Stomach Exocrine/Endocrine Pancreas Merkel Cell Carcinoma
If no Specific TNM NET Chapter Use the Site/Organ/Organ System of Origin to stage Lung, Thyroid, Prostate, etc.
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Note 1: No Tis - AJCC does not include a Tis category for Neuroendocrine Tumors (NET) of the colon. WHO 4th edition reclassification of some NETs to non-invasive behavior may impact TNM Staging in 7th edition since no Tis exists currently.
Note 2: The assignment of the T category codes for NETs of the colon/rectum is based on tumor size and extension.
Note 3: Ignore intraluminal extension to adjacent segment(s) of colon/rectum or to the ileum from the cecum; intramucosal, code depth of invasion or extra-colonic spread as indicated.
Note 4: Nodes are either positive or negative
Note 5: Mets are either present or absent.
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Nodes are either Positive or Negative – N0 or N1 Distant Metastasis are either Positive or Negative – M0 or M1
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Site-Specific Factors for NET Neoplasms
Mitotic Count - # mitosis/10HPFNote 3: Record mitotic count to the nearest tenth as documented in the pathology report. For example, a mitotic count of 3/10 HPF would be coded = 030.
Serum CgA (Chromogranin A - Lab Value)Note 2: Record to the nearest nanogram/milliliter (ng/ml) the highest CgA lab value documented in the medical record prior to treatment. For example, code a pretreatment CgA of 400 ng/ml = 400
Urinary 5-HIAA (5-Hydroxyinidoleacetic Acid – Lab Value)Note 2: Record to the nearest milligram (mg) the highest 5-HIAA lab value documented in the medical record prior to treatment. For example, code pre-treatment 5-HIAA of 550 mg over 24 hours = 550
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33Source: NCCN Guidelines for Neuroendocrine Tumors -Version 2.2016
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34Source: NCCN Guidelines for Neuroendocrine Tumors -Version 2.2016
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35Source: NCCN Guidelines for Neuroendocrine Tumors -Version 2.2016
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36Source: NCCN Guidelines for Neuroendocrine Tumors -Version 2.2016
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37Source: NCCN Guidelines for Small Cell Lung Cancer -Version 1.2016
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38Source: ASCO.org and American Cancer Society
Standard Chemotherapies for GI Tract Tumors such as fluorouracil and oxaliplatin have limited efficacy.
Octreotide (Sandostatin) may slow tumor growth in patients with NET of mid-gut that has metastasized.
Lanreotide (Somatostatin analogue) may slow tumor growth in patients with NET of mid-gut that has metastasized.
Bevacizumab (Avastin) can help limit the growth and spread by stopping angiogenesis, the process of making new blood vessels, which “starves” the tumor.
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39Source: FDA Approvals and Indications for Use
FDA approvals and indications for use for Sandostatin Do not classify or code this as “hormone therapy” for NETs. Sandostatin can be used off-label as an orphan drug for
NETs – when this occurs code as “Other Therapy”. The Novartis website for Sandostatin is specific about how
the drug is to be used and indications. They do not make any claims of anti-neoplastic activity…only symptom management. One of its functions is to "switch off" the secretion of growth
hormone by the pituitary gland. Somatostatin also inhibits the release of serotonin, gastrin,
vasoactive intestinal peptide, secretin, motilin and pancreatic polypeptide.
These actions are what helps to control the symptoms of flushing and diarrhea in carcinoid tumors and Vasoactive Intestinal Peptide (VIP) secreting adenomas.
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40Source: Canadian Cancer Society and US FDA
Everolimus (Afinitor) has demonstrated some benefit
Sunitinib (Sutent) has also demonstrated some benefit
Sunitinib is also used to target GIST with some benefit
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41Source: American Cancer Society
Tumor Ablation and/or Tumor Embolization
Radiofrequency ablation (RFA), which uses high-energy radio waves to heat the tumor and destroy cancer cells.
Ethanol (alcohol) ablation, where concentrated alcohol is injected directly into the tumor to kill cancer cells.
Microwave thermotherapy, where microwaves transmitted through a probe placed in the tumor are used to heat and destroy the cancer cells.
Cryosurgery (cryotherapy), which destroys a tumor by freezing it using a thin metal probe. This method sometimes requires general anesthesia (where you are deeply asleep and not able to feel pain).
Trans-arterial (liver) embolization (TAE), which attempts to block or reduce the blood flow to cancer cells in the liver
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CDC Information about NET and GIST Neoplasms
American Cancer Society and Canadian Cancer Society
NCI Physician Data Query for Healthcare Professionals
WHO Classification of Tumors of Endocrine Organs, WHO, 2004
WHO Classification of Tumors of the Skin, WHO, 2006
WHO Classification of Tumors of the Digestive System, WHO, 2010
WHO Classification of Tumors of Lung, Pleura, Thymus, WHO, 2015
NCCN Evidence Based Treatment Guidelines, NCCN, 2016
American Society of Clinical Oncology, ASCO, 2016
AJCC/UICC Cancer Staging Manual, 7th edition
H. Lee Moffitt Cancer Center, Jonathan Strosberg, MD42
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