Gastroenteropancreatic and Bronchopulmonary Neuroendocrine Tumors

Overview

Gastroenteropancreatic and Bronchopulmonary Neuroendocrine Tumors

Overview

Edda Gomez-Panzani, M.D.

2 EGP MD

The genes are the coded messages in a cell that guide its behavior; they are packed in bundles called chromosomes

http://dels-old.nas.edu/plant_genome/images/DNA.jpg

Genes and chromosomes

Fluo

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ent I

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ybrid

izat

ion

(FIS

H) i

dent

ifica

tion

of H

uman

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osom

es

3 EGP MD

Normal cell cycle

http://www2.le.ac.uk/departments/genetics/vgec/diagrams/22-Cell-cycle.gif

http://www.cbp.pitt.edu/faculty/yong_wan/images/main_cell_cycle.jpg

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Sometimes, mutations occur. Mutations are changes in the genes that result in the cells changing their behavior.

These changes can involve losses, alterations or gains in the important cell control systems related to growth, interaction with other cells and even cells’ life span

Once damage occurs, it can be:Reversed

Removed

Toleratedhttp://www.cancer.gov/PublishedContent/Images/images

/documents/2bb8687b-eb2b-4e62-ba30-a0572dee414e/cancer10.jpg

Errors during the cell cycle

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Mutations

Muhammad Mahdi Karim (www.micro2macro.net)Own work by uploader, http://bjornfree.com/galleries.htmlAuthor=Bjørn Christian Tørrissen Date=2010-04-10

http://forums2.gardenweb.com/forums/load/annuals/msg070249178518.html

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Apoptosis (Programmed Cell Death)Some times, when the damage is significant and it cannot be repaired or removed, the cell goes through a process of programmed cell death called apoptosisApoptosis: A normal, genetically regulated process leading to the death of cells and triggered by the presence or absence of certain stimuli, as DNA damage www.dictionary.com

http://www.microbiologybytes.com/virology/kalmakoff/baculo/pics/Apoptosis.gif

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How does cancer develop?

http://mediconweb.com/wp-content/uploads/2011/02/cancer-cell-mutation1.jpg

When a mutation cannot be repaired and the abnormal cells continue to multiply and become resistant to death (apoptosis), cancer occurs

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Mutations

http://msucares.com/news/print/sgnews/sg11/sg110824.htmlPhoto by Gary Bachman

http://forums2.gardenweb.com/forums/load/annuals/msg070249178518.html

9 EGP MDhttp://www.beliefnet.com/healthandhealing/images/Cancer_cell_division.jpg

Lymphatic orBlood Vessel

Metastatic Spread

Disseminated Disease

Different cancers behave differently depending on the type of cell involved and the degree of uncontrolled cell growth

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Looking at degrees of cell growth

http://www.gistsupport.org/media/Understanding Pathology Report/mitoses-marked-575pix.jpg

Ki-67Immunohistochemical stain that identifies cells in any non-resting stage of the cell cycle (anything but GO). The result is given as the percent of cells that have entered the cell cycle.

Mitotic countHow many cells are undergoing mitosis (cell division)

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Merkel cell tumors (skin)

Anterior pituitary gland• Adenoma

Endocrine tumors in miscellaneous sites

• Ovary, cervix, endometrium

• Breast• Prostate• Medullary thyroid

carcinoma• Kidney• Larynx, paranasal

sinuses, salivary glands

Pheochromocytomas and

Paragangliomas

Bronchopulmonary and Thymic endocrine tumors

• Thymic carcinoid• Tumorlets• Typical and atypical lung

carcinoid • Small cell lung cancer• Large cell lung cancer

GI endocrine tumors• Carcinoid Tumors• Undifferentiated NE

carcinomas

Pancreatic endocrine tumors• Non-functional• Insulinoma• Gastrinoma• VIPoma• Glucagonoma• Somatostatinoma• ACTH-oma

Neuroendocrine Tumors (NETs)

NEUROENDOCRINE

TUMORS

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Neuroendocrine Tumors (NETs) – Incidence

0

1

2

3

4

5

6

19731974197519761977197819791980198119821983198419851986198719881989199019911992199319941995199619971998199920002001200220032004

Inci

denc

e pe

r 100

,000

Year

Yao C. J. et al. J. of Clin Onc. 2008. 26;18:3063-3072.

SEER9 SEER13 SEER17

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Gastro-Entero-Pancreatic (GEP) and Bronchopulmonary (BP) NETs – Incidence

0

0.2

0.4

0.6

0.8

1

1.2

1.4

1.6

197319751977197919811983198519871989199119931995199719992001200320052007

LungSmall IntestineRectumPancreas

Inci

denc

e pe

r 100

,000

YearYao C. J. et al. J. of Clin Onc. 2008. 26;18:3063-3072 and Age-adjusted incidences for NETs from the SEER (1973-2007) tumor registry database.

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Classification of GEP and BP NETsPathological classificationWhere do they come from

Foregut (bronchus, lung, thymus, stomach, first portion of duodenum, pancreas and ovary) – 41%Midgut (second portion of the duodenum, jejunum, ileum, appendix and ascending colon) – 26%Hindgut (transverse colon, descending colon and rectum) – 19%

What do they makeFunctional» Classified by the peptide predominantly

secreted» Can change secretory patterns over time

Non-Functional

Yao C. J. et al. J. of Clin Onc. 2008. 26;18:3063-3072.

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Carcinoid TumorsNon-Functional PNETsInsulinomasGastrinomasVIPomasGlucagonomasSomatostatinomasMixed islet cell/exocrine

Gastroenteropancreatic 60.5%

27.3%BP

12.2%

Other

GEP and BP NETs

Adapted from Handbook of Gastroenteropancretic and Thoracic Neuroendocrine Tumors. Edited by Martyn Caplin and James Yao. 2011. With permission from J. Yao.

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GEP NETs Clinical Manifestation Functional vs. Non-Functional

At least 13 gut neuroendocrine cells exist, all of which produce various bioactive peptides or amines (ie. serotonin, somatostatin, substance P, melatonin, histamine, gastrin, ghrelin, cholecystokinin, GLP, motilin, neurotensin, VIP etc.)

>70% not truly nonfunctional:• Pancreatic polypeptide• Neurotensin• Ghrelin• NSE• Chromogranins• Human Corionic Gonadotropins

Motlin IM, et al. Lancet Oncology 2008;9:61-72.Metz D. and Jensen R. Gastroenterology 2008;135-1469-1492

FUNCTIONAL NON-FUNCTIONAL

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GEP-NETs

Tumor Incidence per 106

persons per yearPrimary location Malignant (%)

Carcinoid1 20-50 Gastrointestinal: 67%Bronchopulmonary: 25%

Other: 8%

70-100

0.5-1.5

1.2

0.05-0.2

0.01-0.1

Very rare3

Very rare3

Gastrinoma2 Pancreas: 60%Duodenum: 30%

Other: 10%

Insulinoma2 Pancreas 99-100% 5-15

VIPoma2 Pancreas: 90%Other: 10%

80

Glucagonoma2 Pancreas 99-100% 60

Somatostatinoma2 Pancreas: 56%Duodenum/jejunum: 44%

60

GRFoma2

60-90

Pancreas: 30%Lung: 54%

Jejunum: 7%Other: 13%

30

1 Modlin et al. Cancer 2003 ;97(4):934-9592 Metz D. and Jensen R. Gastroenterology 2008;135-1469-1492.3 < 0.1/million

PNETs

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GEP-NETsTumor Peptide Symptoms/Syndrome

Carcinoid SerotoninTachy and bradykinins

Carcinoid syndrome

Insulinoma Insulin Hypoglycemia

VIPoma VIP Verner-Morrison

Glucagonoma Glucagon DM, NME*, cachexia

Somatostatinoma Somatostatin Bile stones, steatorrhea, DM

GRFoma GH releasing factor Acromegaly

Gastrinoma Gastrin Zollinger-Ellison Syndrome: Abdominal pain, diarrhea, GERD, ulcers

* Necrolytic migratory erythema

Head 30.4%

Uncinate 0.6%

Tail 47.6%

Neck 5.4% Body 16%

Localization of 168 Pancreatic NE neoplasms (Mass General). Vagefi et. Al. Arch Surg. 2007;142:347-354.

20 EGP MD©Edda Gomez-Panzani

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Siegfried Obendorfer 1907

Carcinoid (Karzinoide)

Adenoma Carcinoid Carcinoma

Benign Tumors Malignant Tumors

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Origin of Carcinoid tumors: Enterochromaffin cells

Crypts of Lieberkühn

Kulchitzsky cells

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Intestinal Carcinoid tumors

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Local effects - Carcinoid Tumor in Distal Ileum

Common findings:Mural thickeningConsiderable desmoplastic reactionSubstantial kinking

Radiographics 2007;27:236-236©2007 by Radiological Society of North America

Intestinal obstructionFrom primary tumorFrom sclerosing reaction in the surrounding mesentery

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Serotonin Production by Carcinoid Tumors

Wikipedia.org

PlateletsCNS GI Carcinoid syndromeCarcinoid crisis

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Functional vs. Non-Functional

What role does the liver play?

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The liver

From: Biomedical CommunicationsArizona Health Sciences Center

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Liver metastases

Systemic Circulation

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Carcinoid Syndrome

The occurrence and severity of the syndrome is directly related to tumor bulk in an area that drains into the systemic circulationIn the vast majority of cases this correlates to hepatic metastases

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Syndrome without liver metastases

Exceptions include:» Peritoneal carcinomatosis» Primary ovarian carcinoids» Broncopulmonary carcinoids

Peritoneal carcinomatosis arising from appendiceal tumor

Glockzin et al. World Journal of Surgical Oncology2009 7:5 doi:10.1186/1477-7819-7-5

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Serotonin and Carcinoid TumorsForegut carcinoids have few serotonin granules (ie. Lung, Stomach, Pancreas)

Mid-gut carcinoids are rich in serotonin containing granules and arefrequently associated with carcinoid syndrome (small bowel, appendix)

Hind-gut carcinoids have very few serotonin granules (distal colon and rectum)

Freq

uenc

y

> 50%

10- 50%

< 10%

Asymptomatic

Gustafsson B. et al. Current Opinion in Oncolocy 2008;20:1-12.

Carcinoid Syn

drome

Pain/Discomfort

Bleeding

Obstructio

n

Palpable Mass

Weight Loss

Asymptomatic

Carcinoid Syndrome

Pain/Discomfort

Bleeding

Obstructio

n

Palpable Mass

Weight Loss

Freq

uenc

y

> 50%

10- 50%

< 10%

COLON AND RECTUMSMALL BOWEL

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Carcinoid Syndrome

In 10% of patients with carcinoid tumors1954 – Thorson and Waldenstrom

Malignant carcinoid of the small intestineMetastases to the liverPeripheral vasomotor symptoms (flushing)DiarrheaValvular disease of the right side of the heart (pulmonary stenosis and tricuspid regurgitation without septal defects)BronchoconstrictionAbdominal pain

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Frequency of Carcinoid Syndrome by Primary Organ site location of Carcinoid Tumor

Freq

uenc

y

> 50%

10- 50%

< 10%

Stomach

Small Intestin

e

Appendix

Colon and

Rectum

Adapted from Gustafsson B. et al. Current Opinion in Oncology 2008;20:1-12.

Bronchopulm

onary

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Most Frequent Signs/Symptoms of Carcinoid Syndrome

0

10

20

30

40

50

60

70

80

90

100

Flushing

DiarrheaValvular Heart Disease

Cramping

TelangiectasiaWheezing

Edema

Cyanosis

PellagraArthritis

Creutzfeldt W, Stockmann F. World J Surg. 1996; 20:126-131

Per

cen

t

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Carcinoid Syndrome - Flushing

Flushing (~92%)Caused by vasodilatationMay be brief (ie. 2-5 min) or may last for several hoursMay be accompanied by tachycardiaPrecipitated by:

Stress (physical and/or mental)InfectionAlcoholCertain foods (spicy)Drugs (ie. Catecholamines, calcium, pentagastrin etc.)

Creutzfeldt. W. World J Surg. 1996;20(2):126-31.

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Carcinoid Syndrome - Diarrhea

Diarrhea (~78%)

Serotonin and Substance P stimulate small bowel and colonic motility

Post-prandial transit times in the small bowel and colon have been reported (von der Ohne et al.) to be 2 to 6 times faster in carcinoid patients than in healthy individuals. Fasting colonic times are normal.

Malabsorption can result in fluid and electrolyte imbalance, malnutrition, pellagra etc.

May be accompanied by borborygmi, cramping and or pain

Walter Sutton’s sketch of the GI system- 1905. Clendening Medical Library, Univ. of Kansas Med. Ctr.

Creutzfeldt. W. World J Surg. 1996;20(2):126-31.

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Carcinoid Syndrome – Carcinoid Heart Disease

Valvular Heart Disease (~52%)Most often in the presence of consistently high levels of 5-HIAA

Excess serotonin (5-HIAA) stimulates proliferation of fibroblasts, myofibroblasts and a matrix-rich fibrous stroma devoid of elastic fibers covered by endothelium

This proliferation results in the formation of plaques that are deposited primarily on the tricuspid and pulmonary valves causing them to thicken and retract

Eventually the patient develops right sided ventricular failure which accounts for approximately 20-30% of deaths in patients with carcinoid tumors

Creutzfeldt. W. World J Surg. 1996;20(2):126-31.

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Carcinoid Syndrome – Telangiectasia

Telangiectasia (~25%)

Small dilated blood vessels near the surface of the skin or mucous membranes, measuring between 0.5 and 1 millimeter in diameter

Lesions can develop anywhere on the body but are commonly seen on the face around the nose, cheeks and chin.

Creutzfeldt. W. World J Surg. 1996;20(2):126-31.

39 EGP MDWikipedia.org

Tryptophan, an essential amino acid, is required for the synthesis of niacin (B3) In the presence of a functional carcinoid tumor tryptophan is diverted from niacin to serotonin synthesis resulting in niacin deficiencyNiacin deficiency leads to Pellagra

Carcinoid Syndrome –Pellagra

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Carcinoid Syndrome – Pellagra

Pellagra (~7%)Pelle agra (pelle=skin; agra= rough).Symptoms:

Diarrhea, dermatitis, dementia and deathPhotosensitivityAggressionRed skin lesionsAlopeciaEdemaGlossitis

Treatment:Niacinamide (niacin produces flushing) 200-500 mg daily in divided doses

Creutzfeldt. W. World J Surg. 1996;20(2):126-31.

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DyspneaPalpitationsLow blood pressureFatigue/AstheniaDizzinessMyopathyChanges in mental state

Other Signs/Symptoms of Carcinoid Tumors

Creutzfeldt. W. World J Surg. 1996;20(2):126-31.

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Carcinoid CrisisImmediate onset of a debilitating and life-threatening condition associated with carcinoid syndrome

May occur spontaneously or may be precipitated by anesthesia, chemotherapy, infection, stress, catecholamines, tumor manipulation or embolization procedures

Symptoms include prolonged severe flushing, diarrhea, hypotension/hypertension, tachycardia, severe dyspnea, peripheral cyanosis and sometimes hemodynamic instability, hyperthermia and bronchospasm.

Most often seen with large tumor load, high levels of circulating serotonin, elevated CGA and 5-HIAA

Appropriate precautions include immediate therapy and close monitoring before, during and after surgical treatment.

Oberg K. Williams Textbook of Endocrinology; 10th Ed. Saunders; 2003;1857-1876.

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Natural History of Carcinoid Tumors

0 2 4 6 8 10 12 14 16 18 20

Primary Tumor Growth

Metastases

Death

Vaguesymptoms

Diagnosis:Irritable Bowel

Menopause

NETDiagnosis

Years

Vinik A., Amer J Dig Dis. Sci., 1989;34:14-27

Flushing

Diarrhea

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The problem, however, remains that diagnostic

investigation is usually initiated by

symptomatology, and in the vast majority of

patients, symptomatology is indicative of

metastasis.

Modlin IM, Kidd M, et al. Current status of gastrointestinal carcinoids. Gastroenterology 2005;128:1717-51.

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50% of NETs Present with Regional or Distant Metastases at Diagnosis

Yao C. J. et al. J. of Clin Onc. 2008. 26;18:3063-3072.

50% 27%

23%

Localized Metastatic

Distant metastases

Regional spread

SOURCE: SEER Database

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Extent of Disease at Diagnosis by Site of Origin

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Rectum Lung Jejunum/Ileum

DistantRegionalLocalized

Ext

ent o

f Dis

ease

(%)

92%

8%

49%

51%71%

29%

Given the time it takes to make the diagnosis, the probability of metastatic disease, is dramatically increased

Median age at diagnosis for NETs: Rectum - 56 years, lung - 64 years and jejunum/ileum - 66 years

Yao C. J. et al. J. of Clin Onc. 2008. 26;18:3063-3072.

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13335121516

343535

71

135

0

30

60

90

120

150

Liver

Mesente

ry

Retroperi

toneu

m

BonePer

itoneu

mOva

ryThor

ax

Supraclavic

ularSkin

Retro-orb

ital

Epicard

ialBrea

stBrai

n

Sites of Metastatic Dissemination of Midgut NETs

Strosberg J et al. Survival and prognostic factor analysis of 146 metastatic neuroendocrine tumors of the midgut. Neuroendocrinology 2009;89:471-6.

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Origin of Pancreatic Islet Cell Tumors

GRFoma 54%

Gastrinoma 30%Somatostatinoma 44%

GRFoma 7%

GRFoma 33%Somatostatinoma 56%

Gastrinoma 60%VIPoma 90%

Glucagonoma >99%Insulinoma >99%

1Metz D. and Jensen R. Gastroenterology 2008;135-1469-1492. 2 Modlin. I. et al. Cancer 2003;97(4):934-959

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Insulinomas – 17% of all PETs

Insulinoma Insulin

Hyperinsulinemia• Neuroglycopenia (90%)

• Amnesia or coma (47%)• Confusion (80%)• Visual changes (59%)• Convulsions (17%)• Altered consciousness (38%)

• Sympathetic overdrive (60-70%)• Weakness (56%)• Sweating (69%)• Tremors (24%)• Palpitations (12%)• Hyperphagia (14%)

• Obesity (<50%)Metz D. and Jensen R. Gastroenterology 2008;135-1469-1492

Whipple triad•Episodic (symptomatic) hypoglycemia

•CNS dysfunction temporally related to hypoglycemia (measured at the time the symptoms were present)

•Dramatic reversal of CNS abnormalities by glucose administration

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Gastrinomas – 15% of all PETs

Gastrinoma Gastrin

Zollinger-Ellison syndrome (ZES)• Ulcers• GERD• Diarrhea• MalabsorptionHypergastrinemia

(fasting 97-99%)

Metz D. and Jensen R. Gastroenterology 2008;135-1469-1492

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VIPomas – 2% of all PETs

VIPomas VIP

Diarrhea• Electrolyte disturbances

• Hypokalemia (70-100%)• Dehydration (45-95%)• Hyperglycemia (20-50%)• Hypercalcemia (25-50%)• Hypochlorhydria (35-76%)• Flushing (15-30%)

Metz D. and Jensen R. Gastroenterology 2008;135-1469-1492

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Glucagonoma – 1% of all PETs

Glucagon

Hyperglucagonemia• Glucose intolerance (DM)• Weight loss• Necrolytic migratory erythema

Metz D. and Jensen R. Gastroenterology 2008;135-1469-1492; Echenique-Elizondo. Pancreas 2004;5(4):179-185.

Glucagonoma

• Hypoaminoacidemia• Chelitis• Normocytic anemia• Vein thrombosis• Neuropsychiatric manifestations angularchelitis.net

Courtesy of Prof. Raimo Suhonen

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Non-functional NETs – ~33%

Most secrete amines and peptides but do not result in an identifiable clinical syndromeLocal mass effects: obstruction and painRemoval of the primary tumor has been reported to prolong survival in all patients (median 1.2 vs. 8.4 years; p<0.001) and in those with metastases (1.0 vs. 4.8 years; p<0.001)

Franko J, Wentao F et al. J Gastrointest Surg; 2012; 14:541-548

Ashley S and Lauwers G. N Engl J Med 2002;347:1783-1791

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Comprise ~20% of all lung cancersR. Laennec’s report (published posthumously in 1831) of an intrabronchial mass could be the first written description of a BP carcinoid

René-Théophile Hyacinthe Laënnec

Bronchopulmonary (BP) Neuroendocrine Tumors

Clinical presentationCoughHemoptysisObstructive pneumonia<5% Carcinoid syndrome

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Bronchopulmonary (BP) Neuroendocrine Tumors

WHO (2004) histologic classification:Low-grade typical carcinoid tumor (TC) – G1Intermediate-grade atypical carcinoid tumor (AC) – G2High-grade large-cell neuroendocrine carcinoma (LCNEC) – rare (<3%) – G3High-grade small-cell lung carcinoma (SCLC) – most common – G4

SRS sensitivity in detection of BP-NETs: 93-87% for primary tumors and 59% for metastases

5 year survival:TC ~88-90%AC ~50-60%

Gustafsson B. et. Al. Cancer 2008;113:5-21

58 EGP MD