Neuroendocr Lecture

7/27/2019 Neuroendocr Lecture

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GASTROENTEROPANCREATICNEUROENDOCRINE TUMOURS

PROF DR : ABDEL RAHMAN A MOKHTARInternal Medicine Mansoura University


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DEFINITION AND CHARACTERS:

Gastroenteropancreatic neuroendocrine tumours (GEP-NETs) are considered to berare, heterogeneous and complex neoplasms.

They include the pancreatic (PNETs) and gastrointestinal (GI) neuroendocrinetumours (GI-NETs) or carcinoids, which share their origin of cells from the diffuseneuroendocrine system , but further show many differences regarding

pathogenesis, clinical behaviour and prognostic outcome.Characteristic for GEP-NETs is their ability to produce bioactive substances

Based on the clinical symptoms and syndrome caused by these peptides, theycan be divided into functioning (F-NETs) and non-functioning tumours (NF-NETs).

Although GEP-NETs are generally more indolent than carcinomas, the majority aremalignant, showing aggressive tumour behaviour and presenting with metastasesat diagnosis.

GEP-NETs can occur sporadically, or as part of a hereditary syndrome such asmultiple endocrine neoplasia syndrome type 1 (MEN-1), von-Hippel Lindau

disease (vHLD), neurofibromatosis type 1, or tuberous sclerosis.


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GEP-NETs arise from cells of the diffuse neuroendocrine system (DNES) and untilrecently were believed to derive from migrated neural crest cells.

In fact, they actually derive from local multipotent GI stem cells, rather than

by migration of the neural crest cells, and hence are endodermal in originThe gut DNES cells are remarkably heterogeneous and consistof 14 different types of cells making it the largest endocrine organ inthe body.

The secretion of bioactive amines is regulated by mechanical and chemicalstimuli. Adenyl cyclase,b-adrenoceptors, and pituitary adenylate cyclase activating

polypeptide are activating pathwaysWhereasSomatostatin (via somatostatin receptor 2),acetylcholine (muscarinic

acetylcholine receptor M4), and c-aminobutyric acid (GABA) (via GABA-Areceptors) are inhibitory signals.It is the secretion of these bioactive amines that make these tumors unique

in their biological characteristics


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NOMENCLATURE ISSUES

Endocrine versus neuroendocrineOriginally, the concept of neuroendocrine neoplasia reflected the hypothesis thatthe cells from which these tumors were derived originated from the embryonicneural crest. This concept was disproved years ago, causing some authorities toadvocate abandoning the term neuroendocrine in favor of endocrine.

However, the neoplastic cells also possess features of neural and epithelialcells, and for this reason, the most recent edition of the WHOclassification of tumors of the digestive system has once againrecommended the use of neuroendocrine

Tumor instead of neoplasmCertainly, all of the entities under discussion are neoplastic, and neoplasm istherefore a more accurate term than tumor, which means onlya mass. However, neuroendocrine tumor (NET) has achieved widespreadacceptance in many systems and will be used here in stead of the more correct

but less accepted alternative, neuroendocrine neoplasm.


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Carcinoid tumor (from the German karzinoide or cancer -like)

In 1907, Oberndorfer introduced this term for neuroendocrine tumours with arelatively benign course.Increasing knowledge about these tumours, however, led to the conclusion thatcarcinoids also encompass low-grade and high-grade malignant tumours.

Therefore, Soga et al. called the term carcinoid a misnomer

In fact, this term has been used for different goals;whereas pathologists label all tumours with neuroendocrine features as

a carcinoid, clinicians use carcinoid for serotonin -producing tumoursthat lead to the carcinoid syndrome.


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Therefore, Capella et al.suggested replacing carcinoid by neuroendocrine tumour to include all tumours withneuroendocrine features, but also realised that abandoning this term completely wouldbe too confusing, and therefore proposed to utilise it for the specification of a NET with serotonin production or producing any other substance

which may lead to the carcinoid syndrome.

Hence, the current nomenclature systems such as the European NeuroendocrineTumor Society(ENETS) and the World Health Organization (WHO) embrace the

term GEP -NETs for tumors of epithelial origin occurring in thegastrointestinal (GI) tract with neuroendocrine differentiation.


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CLASSIFICATION :


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GI NEUROENDOCRINE

TUMORSPancreatic NETs Insulinoma Glucagonoma VIPoma Pancreatic

polypeptidoma

Foregut Thymus Esophagus Lung

Stomach Duodenum

Midgut Appendix Ileum Cecum Ascending

colon

Hindgut Distal largebowel

Rectum

Other NETS


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Differentiation and Grading ISSUES

Differentiation

refers to the extent thatneoplastic cells resemble their non-neoplastic counterparts

GRADE : refers tothe inherent biologic

aggressiveness of thetumor


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Yao JC et al. J Clin Oncol . 2008;26:3063-3072.

INCIDENCE OF NETS INCREASING


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INCREASING INCIDENCES OF NET

Increased incidence of carcinoid tumours, US population 1973 2005Overall increase recorded for all primary sites during this period. Data from SEER

database, US National Cancer InstituteModlin et al. Lancet Oncol 2008; 9: 61 72


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NETS ARE THE SECOND MOST PREVALENTTYPE OF GI MALIGNANCY

2x more prevalent

than pancreatic cancer

]

1. National Cancer Institute. SEER Cancer Statistics Review, 1975-2004. http://seer.cancer.gov/csr/1975_2004. 2. Modlin IM, Lye KD, Kidd M.Cancer . 2003;97(4):934-959.

]


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EPIDEMIOLOGIC NOTES FOR THE CLINICIAN

1) It is imp ortant to real ise that GEP-NETs frequent ly oc cur as or together wi th a second pr imary m al ignancy.The presence of a simultaneous second primary or metastatic malignancy must bethoroughly examined, as several case reports describe the existence of a second tumour synchronous with a carcinoid lesion.

For example, gastrointestinal stromal tumours (GIST) are frequently seen in combinatiowith (gastric) carcinoids.

Therefore, alertness for synchronous (neuroendocrine) tumours among clinicians isadvocated.

2) Pat ients su ffer ing fro m heredi tary s yn drom es suc h as MEN-1, vHLD,neurof ibro m atosis type 1 or tub erous sc lerosis , are a t increased r isk fo r a GEP-NET . So, members from hereditary GEP-NET disorder familiesshould be checked for such tumours, preferably by genetic counselling and, if possible,DNA profile, or by measurement of markers for these or associated tumours.


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3) A no ther d iff icul ty in d iagn os ing GEP-NETs ar ises as these tumours show a relatively high frequency of ectopic occurrence.

For example, gastrinomas, which are usually located in the pancreaticoduodenalregion and lymphnodes, have been reported on ectopic locations suchas ovaries, biliary tract, kidneys, stomach and liver.

Some authors believe that it is uncertain whether these ectopic locations compriseprimary gastrinomas rather than metastases of occult primaries.

GEP-NETs have been reported in rare locations such as the oesophagus, gallbladder and biliary ducts, Meckels diverticulum, ampulla of Vater, genital tract and skin.

Lack of awareness that neuroendocrine lesions can also occur on these unusual sitesresults in the consequence that these tumours are frequently misdiagnosed or

overlooked.

Therefore, it is recommended that when imaging is not successful in detecting aneuroendocrine tumour in the usual sites, an intensive search for occult tumours atunusual sites should be started.

Additionally, it is important to realise that
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PRESENTATIONASYMPTOMATIC . VAGUE SYMPTOMS,CARCINOID SYNDROME.GASTROINTESTINAL NET.PANCREATIC NET..FUNCTIONING & NONFUNCTIONING.BRONCHIAL NET.METASTATIC DISEASE.
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NONSPECIFIC SYMPTOMS OFTEN LEAD TO A DELAYED DIAGNOSIS

1. Modlin IM, Moss SF, Chung DC, Jensen RT, Snyderwine E. J Natl Cancer Inst . 2008;100(18):1282-1289.

Presents toprimary care

Vague abdominal

symptoms

May be diagnosedas IBS

May be referredto specialists for evaluation whensymptoms donot resolve

Referred tomultiplespecialists

Symptomsbecome worseor patient

consultsfor another reason

Diagnosisremains unclear

Seen bygastroenterologistor other specialistwho orders imaging

A referral leadsto a scan or patient

scanned for another reason

Liver metastasis or primary lesion isvisualized

May be anincidental finding

Surgeon,pathologistperform biopsyor resection

Biopsy provides diagnosis of NET

Patient is referred tosurgical oncologist,medical oncologist,or endocrinologist

Treatment dependson stage, histology,symptoms

Estimated time to diagnosis: 5 to 7 years 1


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Vague abdominalsymptoms

Primary tumor

Flushing

Metastases

Diarrhea

Death

NETS ARE OFTEN DIAGNOSED LATE

Time

Vinik A, Moattari AR. Dig Dis Sci . 1989;34[Suppl]:14S-27S.


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CARCINOID SYNDROME About 50% of patients with carcinoid

syndrome have cardiacabnormalities caused by chronicexposure of the heart valves toserotonin, which causes fibrosisand thickening of the tricuspid andpulmonary valves, resulting in

regurgitation or, less commonly,stenosis.

Right heart failure andcongestive cardiac failure can result.

.Ascites and oedemacan also occur. The consequenthepatic congestion results in adecreased capacity of the liver todegrade hormones, which further exacerbates symptoms and can result

in acute decompensation.


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Gastrointestinal NETs

Small-bowel carcinoids are frequently asymptomatic or present with vagueabdominal symptoms that can be mistaken for irritable bowel syndrome.

Some patients present with intermittent or acute bowel obstruction.Production of serotonin or other bioactive amines is a typical

feature of small-bowel carcinoids, and local secretion causes mesentericfibrosis that predisposes to bowel obstruction or can compress mesenteric vessels,resulting in bowel ischaemia and malabsorption.

Most gastric, appendiceal and rectal carcinoids present as incidentalfindings.

These tumours are usually non-functioning and remain asymptomatic untiladvanced.


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Pancreatic NETsNon-functioning pancreatic NETsmay grow for a long time withoutcausing symptoms.When large enough, obstruction of bile or pancreatic

ducts may causeobstructive jaundice or symptoms due to pancreatic enzyme insufficiency, such

as diarrhoea.

About half of pancreatic NETs are functional producing a


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About half of pancreatic NETs are functional , producing arange of hormones resulting in characteristic syndromes .


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Bronchial NETsBronchial carcinoid tumours can cause

Recurrent pneumonia from airway obstruction,Pleurisy, haemoptysis and shortness of breath.

A small proportion of these tumours produce serotonin or similar bioactive hormones, resulting in carcinoid syndrome, or ACTH,

resulting in Cushings syndrome.


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Metastatic diseaseCommon sites of metastatic diseaseinclude :- Local or distant lymph nodes,-Liver, bone and peritoneum.-In females the ovary can be a site of metastatic disease.

Some patients present with symptoms of fatigue and weight loss.

Unlike other malignancies in which untreated metastatic disease is usuallyrapidly progressive, even widely spread metastatic NETs can be indolent,sometimes referred to as cancer in slow motion.

It is not uncommon for it to present initially as a cancer of

unknown primary, as the burden of metastatic disease can be large, whilethe primary site remains small and difficult to locate.


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INVESTIGATION

CgA is an acidic glycoprotein
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CgA is an acidic glycoproteinexpressed in the secretory granulesof most normal and neoplasticneuroendocrine cell types.


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CHROMOGRANIN A (CGA): A VALUABLE DIAGNOSTICAND PROGNOSTIC TOOL

Highly elevated serum CgA and/or immunohistochemical (IHC) staining of tumor for CgA is diagnostic of NETs

Offers 85% sensitivity and 96% specificity for NETs1

CgA can be used to monitor treatmentresponse

More sensitive than radiology for measuringprogression 2

References: 1. Campana D, Nori F, Piscitelli L, et al. J Clin Oncol . 2007;25(15):1967-1973. 2. Eriksson B, berg K, Stridsberg M. Digestion . 2000;62(suppl 1):33-38.


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CHALLENGES PRESENT WITH CGA TESTING

Other conditions can cause elevated CgARisk of false positivesSevere hypertensionGastric acid suppression (PPIs) Renal insufficiencyChronic atrophic gastritis.

CgA values vary considerablyBetween different types of NET

Test kits not universally standardizedDifferent standards, units of measuresDifferent antibodiesDifferent detection system


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IF SUSPICION OF ASPECIFIC SYND ,TESTS FORHORMONEEXCESSES AREINDICATED

5 HIAA (24 HR URINE COLLECTION)


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5 HIAA (24-HR URINE COLLECTION)SEROTONIN (BLOOD, MORE VARIABLE)

5-HIAA = 5-hydroxyindoleacetic acid

5-Hydroxyindole acetic acid (5-HIAA) is the urinary breakdownproduct of serotonin and can be measured using a 24-hour urinecollection in patients with features of carcinoid syndrome.

Some foods, including pineapples, bananas, eggplants, tomatoes,avocados and walnuts contain high levels of serotonin, which can

increase urinary levels of 5-HIAA, and should be avoided three daysbefore collection.

5-HIAA can also be increased in patients with untreatedmalabsorption such as in coeliac disease.

A variety of medications can also increase or decrease 5-HIAAlevels.CgA measurement is more sensitive and is increasingly replacing use of urinary 5-HIAA


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OTHER MARKERS IN FUNCTIONAL TUMORS

Gastrinoma

Gastrin

Glucagonoma

Glucagon

Insulinoma

Insulin

Pro-insulin

C-peptide

VIPoma

Vasoactiveintestinalpeptide

Fasting measurements when possible


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EchocardiographyCarcinoid heart disease is seen in a high proportion of patients withlongstanding carcinoid syndrome,and echocardiography is needed to assess this.

Specific features are thickening of valvular cusps and chordae, whichresults in regurgitation or stenosis (usually of the tricuspid valve) leadingto right ventricular dilation and reduced function, as well as right atrialdilation


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DIAGNOSTIC

ALGORITHM


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DIAGNOSTICALGORITHM


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DIAGNOSTICALGORITHM


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TREATMENTGiven the complexity and heterogeneity of this disease, therapy isindividualised based on several factors, including:

Disease extent.

Rate of growth determined by temporal change on imaging and histological

grade/proliferative index. Level of SSTR expression .

Disease -related symptoms with regard to the primary lesion or metastatic deposits.

Patient comorbidities.


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TREATMENT OPTIONS

Surgery (curative vs debulking)Radiofrequency ablationChemo-embolizationSomatostatin analogue (hormonal treatment)Chemotherapy or other medical therapy(targeted kinase inhibitors)Biologic therapy.Radionuclide therapy


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The two current ly avai lable


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SSAs are oc treot ide (Sandostatin100- 500 g [a short-acting preparation]

and Sandostatin LAR 10-30mg [a long-acting repeatabledepot preparation]) and lanreotide(Lanreotide Autogel 60,90, 120mg [a depot preparation]).The short-acting is SChas a half-life of 1.5-2 hours andis used for the treatment of breakthroughsecretory symptoms.

The depot preparations are given once every four weeks by deep SC or IM injections and are used for long-term control.These agents do have adverseeffects, including: Nausea. Cramping. Diarrhoea. Steatorrhoea. Cardiac conduction abnormalities. Endocrine dysfunction hpothyroidism,hypo- and hyperglycaemia).

Cholelithiasis in up to 50% of patients (although cholecystitisdevelops in fewer than 5%).Patients undergoing surgicalresection of NETs should beconsidered for prophylactic

cholecystectomy to facilitatelater use of SSAs.


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RADIOFREQUENCY ABLATION


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CHEMOEMBOLISATION


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CHEMOEMBOLISATION


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PEPTIDE RECEPTOR RADIONUCLIDE THERAPY The use of beta particle emitters ,Indium111,Y-90 and lutetium-177 (Lu-177).

The last 2 in the form of Y-90 andLu-177 DOTATATE (LuTate) arenow preferred and havedemonstrated excellent objectiveresponse rates(about 70%) with low toxicity.High-energy beta particles fromY- 90 can travel up to a centimetrein tissue whereas lower-energy

particles from Lu-177 travel1-2mm.Both result in crossfire, whereby each cell irradiates its neighbours,resulting in efficient radiationdelivery to aggregations of cancer cells.


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Q i


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Quiz


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QUIZ


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QUIZ


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QUIZ


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