sign in sign up
<<
Home , Adrenal tumor, Neuroendocrine cell, Pituitary adenoma

The Role of the Endocrinologist in the Management of NETs

Lauren Fishbein MD, PhD, MTR Assistant Professor of Medicine at the University of Colorado Division of , Metabolism and Diabetes Division of Biomedical Informatics and Personalized Medicine

Keynote for the 8th Annual UPenn Focus on Neuroendocrine Tumors Patient and Caregiver Program March 8, 2019 Disclosures

I have no financial disclosures or conflicts of interest Overview

•Personalized/Precision Medicine

•What are endocrine ?

•What is a ?

• in neuroendocrine tumors We are all unique We are all unique

http://www.sciencephoto.com/media/209984/view Personalized/Precision Medicine

Mid-1990s - The promise of the Human Genome Project Personalized Medicine The Human Genome Project Completed

Feb. 2001 – The Human Genome Project was published! Personalized/Precision Medicine

The Right Treatment At the Right Dose Use a person’s DNA For the Right Patient At the Right Time For the Right Outcome Variation in DNA in Genes Can Predict Response to Medication

http://pharmaxchange.info/press/wp- content/uploads/2011/04/pharmacogenetics.gif Personalized/Precision Medicine

http://www.cihr-irsc.gc.ca/e/43707.html

Personalized/Precision Medicine

Tumor DNA

Use DNA to predict who will get disease and prevent disease Biobanks

• Many around the country Donate Genotype done Colorado Center for Personalized Medicine Return of results Ethical and Moral Questions

“There Is No Gene For The Human Spirit.

How do you hide when you're running from yourself?

Only one criterion : genetic perfection

Only the strong succeed” Legislation

• May 2008 law passed • Genetic Information Nondiscrimination Act (GINA)

• Protects Americans from discrimination based on information derived from genetic tests • Forbids insurance companies from discriminating through reduced coverage or pricing and prohibits employers from making adverse employment decisions based on a person’s genetic code • In addition, insurers and employers are not allowed under the law to request or demand a genetic test

www.ornl.gov Personalized/Precision Medicine

• Pros: • Transform healthcare with new predictive, diagnostic and prognostic tools • Will increase our ability to predict outcomes of drug therapy • Biomarkers will result in more focused and targeted drug development and focused prognostic markers • Improve health outcomes and make healthcare more cost effective

• Cons: • More money upfront • Must address range of public policy issues: healthcare payer, medical records privacy, etc Ultimate Goals

• Provide personalized medicine in preventing and/or treating complex diseases

• Provide individualized drug therapy

• Provide individualized disease risk assessment My personal journey

Endocrine and Endocrine Genetics

Bone https://s-media-cache-ak0.pinimg.com/736x/5e/eb/a4/5eeba4d996ec972d35980896fe5bb654.jpg Why Endocrinology?

•Take care of the whole person

Bone https://s-media-cache-ak0.pinimg.com/736x/5e/eb/a4/5eeba4d996ec972d35980896fe5bb654.jpg What does an Endocrinologist do?

Treats people with endocrine disorders and dysfunction: • adrenal disorders • pituitary disorders • disorders • diabetes • osteoporosis • • low testosterone • growth problems • puberty problems • endocrine cancers (adrenal, pituitary, endocrine , thyroid, NETs…) • endocrine cancer predisposition syndromes http://www.scribd.com/doc/29100896/Endocrine-System-Glands-and-Hormones How I see the role of the Endocrinologist in management of NETs?

Captain of the ship and part of the team What is the role of the Endocrinologist in management of NETs?

• Treat: • any hormone overproduction by a tumor • any hormone underproduction by a tumor or because of treatment of a tumor • Treat: • unrelated hormone/ issues which arise • Ex: bone health

• Endocrinologists also do screening and surveillance for hereditary endocrine cancer conditions • Any field as long they have knowledge and expertise Endocrine Glands Master Gland Metabolism Energy • Organs in our body that BP/HR make hormones Immune Gland

Gut/GI tract

Energy BP Metabolism Food breakdown and metabolism Signals for energy usage and stores

Lung

Female hormones Male hormones

https://s-media-cache-ak0.pinimg.com/736x/5e/eb/a4/5eeba4d996ec972d35980896fe5bb654.jpg What are some common hormones?

Common examples • Thyroid hormone • Estrogen • • Testosterone • FSH Hormones made by NETs

PNETS Pheo/Para

Insulin (/) Glucagon Gastrin Pituitary Vasoactive intestinal polypeptide (VIP)

GI-NETs Thyroid NETs ACTH NETs TSH Gastrin GH Glucagon Serotonin FSH/LH ACTH What is a hormone?

•Any thoughts? What is a hormone?

• Hormones are chemical messengers in the body • Send messages about a particular function from one cell to another

Pancreas

Hormone Hormones made by NETs

Pheo/Para PNETS Adrenaline (metanephrines/catecholamines) Insulin Glucagon Somatostatin Gastrin Pituitary Vasoactive intestinal polypeptide (VIP) adenomas

GI-NETs Prolactin Thyroid NETs ACTH Serotonin Lung NETs TSH Gastrin Calcitonin GH Glucagon Serotonin FSH/LH ACTH Pancreatic Neuroendocrine Tumors (PNETs)

• 10-15% of all PNETs are associated with genetic syndromes • Such as VHL, MEN1, NF1, TSC von Hippel Lindau Disease

• VHL gene • 1 in 36,000

• cancer and cysts • Retinal and CNS hemangioblastomas • Endolymphatic sac tumors • Pancreatic neuroendocrine tumors and cysts •

http://www. /5648/von-hippel-lindau-disease-signs-symptoms-treatment Multiple Endocrine Neoplasia Type 1

MEN1 gene Protein MENIN 0.01-2.5 per 100,000

3 P’s

• Pituitary • Parathyroid /adenomas • Pancreatic neuroendocrine tumors

• GI-NETS • Adrenal tumors • Thymic tumors • Bronchopulmonary tumors • Skin tumors Van Leeuwaarde et al. ERC 2017 Type 1

• NF1 gene • 1 in 2,800 - 3,500

• Café-au-lait spots • Neurofibromas • Lisch nodules in the eye • Armpit/groin freckling • Optic glioma • Skeletal dysplasia • First degree relative with NF1

• Pheochromocytomas • Pancreatic NETs

Dermquest.com and nfcenter.wustl.edu Pancreatic Neuroendocrine Tumors (PNETs)

• Tumors of the pancreatic islet cells

http://biocrine.com/wp-content/uploads/2011/09/DAD2.png http://quasargroupconsulting.com/anatomy/pancreaseCells.gif of pancreas

Exocrine pancreas

Endocrine pancreas Islet of Langerhans Functional vs Non-functional

• Non-Functional PNETS • No clinical syndrome • Majority of PNETs

• Functional PNETS • Hormone elevated in blood + clinical syndrome Histology of pancreas

Exocrine pancreas

Endocrine pancreas Islet of Langerhans Pancreas Hormones – Pancreas messengers

Releases enzymes to help breakdown food

http://quasargroupconsulting.com/anatomy/pancreaseCells.gif Exocrine pancreas – makes enzymes to digest food

http://www.animatedpancreaspatient.com/en-pancreas/view/m501-s4-exocrine-pancreatic-insufficiency-epi-slide-show Exocrine pancreas – makes enzymes to digest food

Lack of nutrients for our body

Can cause bloating and

http://www.animatedpancreaspatient.com/en-pancreas/view/m501-s4-exocrine-pancreatic-insufficiency-epi-slide-show Pancreas Hormones – Pancreas messengers

http://quasargroupconsulting.com/anatomy/pancreaseCells.gif PNETS

• Non-functioning tumors and PPoma

• (Zollinger Ellison Syndrome) • Stomach ulcers and diarrhea

• • Hypoglycemia – low blood sugar

• • High blood sugar and diabetes and specific rash called necrolytic migratory erythema

• VIPoma • Very watery constant diarrhea, low potassium and chloride

• • Gallstones, intolerance to fat in the diet and leads to fatty diarrhea Gastrin

Stomach Pancreas Acid

Small intestine

• Gastrinoma – Zollinger Ellison Syndrome – causes ulcers and diarrhea

• Main treatment is PPI Blood Blood sugar sugar Insulin Blood sugar Blood Blood sugar sugar Blood sugar

Pancreas Liver

Insulin Receptor

Muscle

• Insulinoma– low blood sugar, confusion, vision changes, unusual behavior, rapid heart beat, sweating, shakiness, amnesia, eating every few hours, waking up at night to eat to avoid symptoms. • Main treatment is Majority of PNETs are non-functional

• So why am I talking about the hormones?

• A pancreas that is not functioning well or is absent due to surgery, may make too little hormone and enzymes • We can replace these with medications Abnormal functioning pancreas

•Insulin is the main hormone of concern when absent • Insulin deficiency causes diabetes mellitus • We can replace insulin to control diabetes Abnormal functioning pancreas

•Absent exocrine pancreas is another concern • Absent enzymes cause bloating and discomfort because food cannot be digested well • We can control the symptoms with giving back the enzymes before each meal

http://www.animatedpancreaspatient.com/en-pancreas/view/m501-s4-exocrine-pancreatic-insufficiency-epi-slide-show GI-NETS

• About 10% of people with bowel NETs will have carcinoid syndrome

• Neuroendocrine cells make serotonin that cannot be broken down properly Serotonin

• (message signal from a ) plays a role in mood regulation, pain perception, GI function.

serotonin

Nerve ending Too much serotonin

https://pearlpoint.org/sites/default/files/styles/large/public/carcinoid_syndrome.png?itok=fIdBQO4s Somatostatin

Pancreas

Somatostatin Receptor

Slow motility

Somatostatin analogs help control carcinoid syndrome Decreases diarrhea and flushing Controls tumor growth in several NETs

Pituitary picture from https://s-media-cache-ak0.pinimg.com/236x/3d/45/12/3d4512b044af3b0e5877a78499114d4e.jpg Treatment with Telotristat

• Telotristat can decrease serotonin and decrease diarrhea not controlled with somatostatin analogs Hormones made by NETs

Pheo/Para PNETS Adrenaline (metanephrines/catecholamines) Insulin Glucagon Somatostatin Pituitary Gastrin adenomas Vasoactive intestinal polypeptide (VIP) Prolactin GI-NETs ACTH Thyroid NETs TSH Serotonin Lung NETs GH Gastrin Calcitonin FSH/LH Glucagon Serotonin ACTH and

• Neuroendocrine tumors in the and extra-adrenal ganglia, respectively

• The majority are “functional” but many are not

• 35-40% are associated with hereditary syndromes • NF1, VHL, MEN2, Hereditary Paraganglioma/Pheochromocytoma Syndrome (SDHx, FH, etc)

Petri et al British Journal of Surgery 2009 von Hippel Lindau Disease

• VHL gene • 1 in 36,000

• and cysts • Retinal and CNS hemangioblastomas • Endolymphatic sac tumors • Pancreatic neuroendocrine tumors and cysts • Pheochromocytomas

http://www. /5648/von-hippel-lindau-disease-signs-symptoms-treatment Neurofibromatosis Type 1

• NF1 gene • 1 in 2,800 - 3,500

• Café-au-lait spots • Neurofibromas • Lisch nodules in the eye • Armpit/groin freckling • Optic glioma • Skeletal dysplasia • First degree relative with NF1

• Pheochromocytomas • Pancreatic NETs

Dermquest.com and nfcenter.wustl.edu Multiple Endocrine Neoplasia Type 2

• RET gene • 1 in 40,000

• MEN2A • Medullary Hyperparathyroidism Pheochromocytomas • Often bilateral • Cutaneous lichen amyloidosis

• MEN2B • • Pheochromocytomas • Mucosal neuromas • Marfinoid habitus (tall and thin)

https://en.wikipedia.org/wiki/Multiple_endocrine_neoplasia Hereditary Paraganglioma - Pheochromocytoma Gene Typical Location Other Associated Syndromes of Pheo/Para Cancers SDHB Extra-adrenal  Succinate Dehydrogenase Head and neck Complex Subunit gene Adrenal mutations SDHC Head and neck  SDHB Chest -Kidney cancer  SDHC -GI Stromal SDHD Multiple head  SDHD Tumor and neck  -Pituitary Tumor SDHA Adrenal -Others?  SDHAF2 Extra-adrenal SDHA Extra-adrenal SDHAF2 Multiple head and neck Adrenaline

(metanephrines catecholamines)

Flight or flight response

• Pheochromocytoma – leads to high , rapid heart rate, sweating, , , , increased blood sugar • And some patients have no symptoms Adrenaline

(metanephrines catecholamines)

Nerve signaling

• Paraganglioma – leads to high blood pressure, rapid heart rate, sweating, headache, anxiety, tremors, increased blood sugar • And some are non-secreting

https://classconnection.s3.amazonaws.com/839/flashcards/464839/png/screen_shot_2012-01-18_at_2.18.07_pm1326932318702.png Treatment for PCC/PGL

• Surgical resection • Need pre-op blocking with special blood pressure medication called Adrenaline alpha adrenergic receptor blockers Alpha blocker • Blocks effects of high adrenaline medication

Alpha- receptor

Adapted from Fishbein et al. JCH 2013 Common questions

• “Can I survive with one ?”

• What about no adrenal glands?

http://cf.ydcdn.net/1.0.1.66/images/main/A5adrenalgland.jpg Adrenal Hormones androgen

Salt/water balance Male physical Control BP Controls , characteristics BP, metabolism, bone health, …

• Cortical sparing adrenalectomy sometimes used • We have medications to replace all of these hormones as needed Hormones made by NETs

PNETS Pheo/Para

Insulin Adrenaline (metanephrines/catecholamines) Glucagon Somatostatin Gastrin Pituitary Vasoactive intestinal polypeptide (VIP) adenomas Prolactin Thyroid NETs GI-NETs ACTH TSH Lung NETs Calcitonin Serotonin GH Gastrin Serotonin FSH/LH Glucagon ACTH Lung neuroendocrine tumors (bronchial carcinoids) Rarely functional but can be

Lung Carcinoid serotonin syndrome

ACTH cortisol

= neuroendocrine cells in the lung

Surgery is mainstay of treatment Ectopic Cushing’s Syndrome

• Any neuroendocrine cell can make ACTH and lead to ectopic Cushing’s • Most commonly seen from lung NET • Also seen from medullary thyroid cancer, PNET, pheo, etc Cortisol Actions Skeletal Muscle Release of amino acids Liver Blocks insulin dependent Gluconeogenesis glucose uptake (insulin Decrease glucose uptake resistance)

Inflammatory and Immune Cells Peripheral Adipose Tissue Potent immunosuppressant and Release of free fatty acids and glycerol anti-inflammatory effects Decrease macrophage activity Decrease T cell activity Heart Decrease Increases BP via vasoconstriction degranulation (antihistamine Increases adrenergic receptor responsiveness effect) Vascular Smooth Muscle Vasomotor tone Responsiveness to vasoconstrictors Bone Increases osteoclast activity Decrease calcium absorption Adrenal Medulla Epinephrine synthesis (activates PNMT enzyme)

Cushing’s

High cortisol Surgery is mainstay • Pituitary tumor of treatment • • Ectopic – ex. NET in a non Medical therapy is pituitary/adrenal location second line • Iatrogenic

https://www.pinterest.com/pin/397161260859434936 Medical treatments for Cushing’s

ACTH secretion inhibitors Pasireotide Cortisol Cortisol synthesis receptor inhibitors and blocker Adrenolytic agents Before treatment After treatment Hormones made by NETs

PNETS Pheo/Para

Insulin Adrenaline (metanephrines/catecholamines) Glucagon Somatostatin Gastrin Pituitary Vasoactive intestinal polypeptide (VIP) adenomas

Thyroid NETs Prolactin GI-NETs ACTH Calcitonin TSH Serotonin Lung NETs GH Gastrin FSH/LH Glucagon Serotonin ACTH Endocrine monitoring

• Absent pancreas or adrenal glands

• MIBG therapy – monitor thyroid hormone

• Metastatic disease to bone – think about bone health – calcium/vitamin D, bisphosphonate or denosamab

• Other things related or unrelated to NET: • Diet, nutrition • Menopause • Thyroid disease • Osteoporosis • Diabetes mellitus Psychologic impact

• VERY IMPORTANT

• Use examples from the MEN1 and MEN2 literature • Can be extrapolated to any NET Psychological Impact of MEN

219 patients with MEN Responsibility of Endocrinologists (and all experts) to teach other 101 with MEN1 providers about NETs Mean age 47.5

57% felt 51% felt 83% felt negative negative 54% felt 55% felt GP confident in impact on impact on negative did not discussing mental/ employment/ impact on understand condition emotional family life condition with career well-being specialist

Grey and Winter 2016 DOI:10.1530/endoabs.44.P121 AMENSupport Online QOL Survey

AMENSupport Group • MEN1 specific questionnaire Public URL – 2 surveys • PROMIS-29 (NIH 6 months outcomes measurement information system

449 accessed survey 320 completed (46% response rate)

238 met 74% in USA 97% Mean age 45; 207 completed 91% PHPT and eligibility 12% Europe Caucasian; mean age at full survey 74% PNET criteria 9% Canada 76% Female MEN1 dx 34

Goswami et al. Sugery 2017 AMENSupport Online QOL Survey

• 53% of patients traveled >50 miles for doctor appointments • 32% had >20 appointments per year

• Can be associated with more anxiety, depression, fatigue, and sleep disturbances

• ~30% of patients spend $100-500 per month out of pocket

• Role of Endocrinologist (all providers) is to recognize this and offer resources to help Goswami et al. Sugery 2017 Peipert et al. Surgery 2017 Feeling knowledgeable about disease improves quality of life scores!

• Study in MEN2 patients • Can extrapolate to any endocrine or NET

•Role of Endocrinologist (all providers) is to teach our patients!

Rodrigues et al Thyroid 2017 Neuroendocrine Tumors and Hormones

Gut/GI tract

Skin

Lung

https://s-media-cache-ak0.pinimg.com/736x/5e/eb/a4/5eeba4d996ec972d35980896fe5bb654.jpg Precision Medicine

(Screening and Prevention) Tumor characteristics

Examples in NET:

• PRRT • MIBG

-Tumor must be “avid” for drug to be used -Check this on a DOTATATE or MIBG scan before treatment

Can we find biomarkers to know who will respond best within that group? [email protected]

Surveillance of Asymptomatic Hereditary PCC/PGL Mutation Carriers Excluding patients with MEN2, VHL and NF1

Annual biochemistries and whole body imaging from base to pelvis every two years

Rednam et al. Clin Cancer Res 2017 MEN1 Genetic Testing Recommendations

Consider referral for MEN1 testing when there is a personal or family history in a first-degree relative of: • 2 or more MEN1-associated tumors in the same person • PNET, Gastrinoma, , HPTH, Thymic NET, Bronchial NET and Adrenal tumors • Gastrinoma • Multiple PNETs in the same person • diagnosed before age 30 • Multiple parathyroid adenomas • Parathyroid adenoma with family history of hyperparathyroidism or MEN1-associated tumors

Adapted from Hampel et al Genetics in Medicine 2014 Genotype/Phenotype Correlations

Ex 8, 10-11 Ex 13-14 Ex 15-16

Khatami and Tavangar Biomarker Insights 2018 MEN2 Genetic Testing Recommendations

Consider referral for MEN2 testing when there is a personal history of or in some cases family history of: • Medullary thyroid cancer • Pheochromocytoma (paraganglioma) • Diffuse ganglioneuromatosis of the GI tract • Parathyroid adenoma diagnosed before age 30 • Multiple parathyroid adenomas • Parathyroid adenoma with family history of hyperparathyroidism or MEN2-associated tumors • Oral or ocular neuromas

Adapted from Hampel et al Genetics in Medicine 2014 Glucagon

Blood sugar Blood Liver Bloodsugar Pancreas sugar Blood sugar Glucagon Receptor

• Glucagonoma – blood sugar too high causing diabetes, , blood clots and a specific rash called necrolytic migratory erythema. Vasoactive Intestinal Polypeptide Energy (VIP)

Liver Pancreas glycogen

VIP Receptor

Pancreas bicarb

• VIPoma – causes huge amounts of very watery diarrhea leading to , low potassium and chloride glucagon Somatostatin insulin Pancreas Pancreas

Somatostatin Receptor

Nerve

Decrease acid Slow motility Secrete pituitary hormones • Somatostatinoma – results in dysregulation of many endocrine hormones. Lowers insulin leading to diabetes. Slows GI motility which can lead to gallstones, intolerance to fat in the diet and leads to fatty diarrhea. Pituitary picture from https://s-media-cache-ak0.pinimg.com/236x/3d/45/12/3d4512b044af3b0e5877a78499114d4e.jpg Pituitary adenomas – associated with MEN1

High prolactin

• –breast discharge • - no menstrual period • – low estrogen/testosterone

~65% of MEN1 associated pituitary adenomas

http://www.scribd.com/doc/29100896/Endocrine-System-Glands-and-Hormones Medical Treatment for Prolactin Secreting Tumors

agonist – bromocriptine and cabergoline

Molitch Endocrinol Metab Clin N Am 35: 99-116, 2006 Gillam, Molitch, Lombardi and Colao; Endo Reviews 27(5): 485-534, 2006 Medullary thyroid cancer

Diarrhea Flushing calcitonin thyroid

= medullary thyroid cancer Surgery is mainstay of treatment