12. NET Flashcards
Define NET + describe NE cell distribution in the body
Neoplasms arising from cells of endocrine + nervous systems
Many kinds of NETs but treated as group due to common features;
- produce biogenic amines + polypeptide hormones
- special secretory granules
- appearance
NE cells found in many different areas;
- in endocrine glands
- diffusely distributed throughout body (relatively more common in GI + pulmonary systems)
- originally believed to be from neural crest
NETs are most common in intestine, pancreas + lungs
What are the characteristics of NETs?
Mostly benign, some malignant
Generally slow growing
Malignant may be very slow growing
What is a NE cell?
Cells with neural and endocrine influence;
- especially interaction b/n these systems
Describe NE cells of the GI tract + their history
Can be single or in small groups
Only 1% of GI epithelium = NE cells but quantitatively comprise largest endocrine organ
Were first described as the DNES (diffuse NE system);
- concept described NE cells as discrete endocrine organs, clusters of cells within other organs and single NE cells disseminated throughout other organs
Later described as APUD cells based on their characteristics;
- Amine (high amine content)
- Precursor Uptake (high uptake amine precursors)
- Decarboxylase (high content of enzyme amino decarboxylase for conversion of precursor to amine)
NE cells do have the ability to produce biologically active amines or peptides that act like neurotransmitters, hormones or paracrine regulators
What is the diffuse endocrine system + what are its subcategories? Give an example of each
Other organs + tissues (not organs of main endocrine system) containing cells that can secrete bioactive amines or peptide hormones
Neural types (derived from neural crest);
- adrenal medulla > catecholamines
- paraganglia
Epithelial type (separate endocrine gland or parts of);
- adenohypophysis (ant pit)
- Islets of Langerhans > clusters of endocrine cells in exocrine acinar pancreas
- parathyroid gland
- pineal gland
Unicellular glands incorporated in other epithelial cells;
- GI tract > glucagon cells disseminated throughout the villus of the intestine
- liver
- merkel cells of skin
- parafollicular cell of the thyroid gland (C cells)
- mammary glands
- urogenital system (M + F)
- respiratory system
- adipose tissue
What causes NET symptoms and allows detection? How do they present?
NETs synthesise peptides, amines + other chemicals;
- they secrete these peptides + chemicals producing syndromes
- syndromes depend on NET secretions which can vary
Can also be asymptomatic = accidental discovery
Difficult to diagnose as;
- non-specific symptoms
- uncommon diagnosis for common symptoms e.g. ulcers, diarrhea, flushing
- diversity of symptoms attributable to other problems
Give examples of some of the NE cell products of the GI tract
Enterochromaffin (EC)/Kulchitsky cells throughout GUT + LUNGS;
- serotonin (5HT)
STOMACH;
- somatostatin - universal shut off
- VIP - vasoactive intestinal peptide
- gastrin - acid secretion
PANCREAS;
- insulin + glucagon - glucose homeostasis
- pancreatic polypeptide - gastric motility + satiety
What are GEP-NETs?
NETs are more properly described as gastro-entero-pancreatic NETs (GEP-NETs)
Some others fall into non-GEP-NETs (outside GEP axis)
How common are GEP-NETs?
Rare;
- ~1200/yr in UK
- ~3/100,00/yr
Prevalence of small bowel NETs rising in NI 1988-2012
Annual incidence of carcinoid gut GEP-NETs highest followed by carcinoid lung
How are GEP-NETs subclassified?
Most GEP-NETs fall into 2 distinct categories;
- carcinoid tumours;
- secrete serotonin
- develop from enterochromaffin (EC)/Kulchitsky cells - pancreatic endocrine tumours (PETs);
- secrete peptide hormones
Great behavioural differences but similarities in cell structure
How are PETs subclassified? Describe some of the prominent symptoms
Insulinomas: hypoglycemia, sweating, palps, anxiety
Gastrinomas: peptic ulcer, diarrhea
VIPomas: diarrhea, flushing
Glucagonomas: necrolytic migratory erythema
Somatostatinomas: mild diabetes
PPomas: no symptoms
Others
Describe a gastrinoma and its pathophysiology
Gastrinomas are PETs that produce excess gastrin;
Gastrin is released by G cells of pyloric antrum of stomach, duodenum + pancreas in response to;
- stomach distension
- vagal stimulation through GRP (gastrin releasing peptide)
- catecholamines
Stimulates gastric acid production in parietal cells by;
- directly binding parietal cell
- binding EC-like (ECL) cell that signals parietal cell by releasing histamine
Excess acid leads to;
- peptic ulceration
- hyperperistalsis = diarrhea
- inhibition of lipase = steatorrhea
Excess acid can be controlled with H2 antagonists + proton pump inhibitors
Describe a glucagonoma + its associated symptoms
Glucagonoma= a PET (alpha cells) secreting excess glucagon
- NR <150ng/L
- glucagonoma 11000-18000ng/L
S+Ss;
- anemia
- weight loss (GNG + lipolysis to produce glucose)
- rash (necrolytic migratory erythema)
- formation of blood clots
- DM
What are enterochromaffin (EC)/Kulchitsky cells? What do they have in abundance?
EC cells are a type of NE cell occurring in the epithelia that line the lumen of the digestive + respiratory tract
They contain ~90% of the body’s serotonin (5HT)
Serotonin important in GI tract;
- in response to chemical/mechanical/pathological stimuli it activates;
- secretory + peristaltic reflexes
- vagal afferents (via 5-HT3 receptors) that signal to the brain
How are carcinoid tumours sub categorised?
FORE GUT;
- lung (carcinoid symptoms)
- resp tract
- stomach (epigastric pain reflux)
- duodenum (no S+S)
MID GUT; (carcinoid symptoms)
- jejunum
- ileum
- prox colon
HIND GUT; (no S+S)
- distal colon
- rectum
What is carcinoid syndrome?
Collection of symptoms associated with carcinoid tumours;
- diarrhea
- flushing
- sweats
- wheeze
- carcinoid heart disease
Only ~25% pts present with this
How can carcinoid tumours be classified using serotonin?
Mid gut = rich in serotonin containing granules + frequently associated with carcinoid syndrome
Fore gut = few serotonin granules
Hind gut = very few serotonin granules
Describe non GEP-NETs + give some examples
Non-GEP-NETs are NETs that fall outside the GEP axis
Include;
- Pheochromocytoma
- Paraganglioma
- MCT medullary cancer of thyroid
- Anterior pit tumours
- Parathyroid tumour
- Small cell lung cancer
What is a pheochromocytoma?
Rare catecholamine-secreting tumour derived from chromaffin cells in adrenal medulla;
- chromaffin cells produce mainly adrenaline
- non-GEP-NET
Tumours arising outside the adrenal gland = extra-adrenal pheochromocytomas or paragangliomas
Excess catecholamine can be life threatening
Describe medullary cancer of the thyroid
MCT is a cancer of the parafollicular cells (C cells) located in the thyroid gland;
- C cells produce calcitonin (Ca metab)
- non GEP-NET
Thyroid tumour + elevated CT (normal thyroxine) = MCT
What are the at risk groups and the risk factors for GEP-NETs?
Risk groups?
- rare
- M = F
- 40-50 years
- family history pancreatic cancer
- certain genetic syndromes
Risk factors;
- diabetes
- cirrhosis of liver
- infections of GI tract
- smoking
Eg Steve Jobs, GEP-NET islet cell
List the complex familial endocrine cancer syndromes that may lead to NETs
Multiple endocrine neoplasia type 1 (MEN1) MEN2 Von Hippel Lindau disease (VHL) Neurofibromatosis type 1 (NF1) Carney syndrome Familial paraganglioma syndromes (PLGs)
Describe MEN + its categories
Multiple Endocrine Neoplasia;
- characterised by occurence of tumours involving 2 or more endocrine glands in a single pt
- autosomal dominant inheritance
- onset 15-40 years
2 major forms;
- type 1
- type 2
Describe MEN1 + associated NET risk organs
Wermer’s syndrome
Cr 11q13: MEN1 gene - menin tumour suppressor
- germ line + somatic mutations
1 in 30000 carry gene
90% with MEN1 show disease by 50 years
NETs in; (3 Ps!)
- parathyroid adenoma (80-95%)
- pituitary ant. adenomas (5-20%)
- PETs (20%)
Describe MEN2 + associated NET risk organs
Sipple’s syndrome
Cr 10q11.2: RET proto-oncogene - encodes RTK
1 in 20000 carry gene
NETs in; (1M, 2Ps!)
- MCT
- pheo
- parathyroid
Describe the 2 hit theory of Knudson in MEN1
People born with MEN1 have 1 mutated copy of MEN1 gene in each cell (germ line)
During lifetime other copy is mutated in a small number of cells (somatic mutation);
- no functional copies of MEN1 gene in select cells
- cells divide uncontrollably > tumours form
Describe Von Hippel Lindau (VHL) + its associated tumours
VHL syndrome = autosomal dominant inherited disorder characterised by the formation of tumours + cysts in many different parts of the body
1 in 36000
Assoc with;
- pheo
- pancreatic islet cell tumours
Describe neurofibromatosis 1 (NF1) + its associated tumours
Autosomal dominant inherited disorder
1 in 5000
Associated with NETs, e.g. pheo, gastrinoma + carcinoid but rare
What methods are used to diagnose NET?
Clinical presentation suspicion
Biochemistry;
- blood + urine: tachykinins, e.g. neurokinin A, 5HIAA
- urine: plasma catecholamines, 5HT
- immunoassays
- peptide screens: specific (gastrin), general (CgA + PP)
- stim tests: clonadine
Scans;
- PET, CT, CAT, MRI, US
- Octreotide/SRS scintigraphy
- MIBG scintigraphy
- FDOPA PET/CT
Biopsy/Surgery
Describe octreotide/SRS scintigraphy use in NETs
Somatostatin receptor testing/ octreotide scan
Normal NE cells express somatostatin receptors;
- binding shuts down cell activity
Radiolabelled somatostatin analogues are used to find NETs (abn proliferations of NEs)
- e.g. of radiolabel = indium-III
- injected IV + detected by gamma camera
High affinity somatostatin receptors are expressed in 88-100% of carcinoid tumours (primary + metastasis)
Can be used to diagnose, evaluate treatment + look for recurrence (MRD)
Describe MIBG scintigraphy use in NETs
MIBG = iobenguane, a noradrenaline analogue + radiopharmaceutical
- acts as a blocking agent for adrenergic neurons
If radiolabelled can localise to pheos, neuroblastomas + paragangliomas;
- FDOPA PET/CT scan ~100% sensitive for pheos vs 90% for MIBG but FDOPA availability rare
Can be used in NET treatments combined with I-131 to deliver targeted radiation to cells
What biochemical markers can aid NET diagnosis?
General NET markers; Chromogranin A (CgA blood test); - best marker for NETs - not raised in benign Pancreatic polypeptide
Specific NET markers;
- gastrin if gastrinoma suspected, etc
Plasma/urinary tachykinins;
- neurokinin A used to determine progression of mid gut carcinoid (MGC) disease - v important for treat
- 5HIAA (serotonin metabolite) raised in carcinoid EC cells secreting serotonin
Urinary plasma catecholamines;
- raised in pheo
Discuss the use of 5-HIAA as a biomarker for carcinoid NETs
5-HIAA/5-hydroxyindoleacetic acid
- serotonin metabolite
Carcinoid tumours sometimes secrete large amounts of serotonin into the blood;
- causes various forms of carcinoid syndrome
- growth promoting effect on cardiac myocytes = tricuspid valve disease syndrome by prolif of myocytes onto valve
Test;
- sensitivity 73%
- specificity 100% (if no drug/food interference)
Some food contains significant amounts of serotonin;
- avoid 3 days prior to + day of collection
- basically fruit + nuts
Discuss the biochemical tests for pheochromocytoma
First line = measure 24hr secretion of catecholamines (adrenaline/noradrenaline) in urine collection
If normal but still strongly suspected use clonadine test;
- clonadine = alpha adrenergic receptor agonist
- selectively stimulates receptors in brain that monitor catecholamine levels in blood
- if detect high level then turn off catecholamine production via neg feedback loop
Clonadine should trick brain into turning off catecholamine production - if catecholamines still present they are from a secreting tumour, i.e. pheo
