אנדו Flashcards
2019 NENs NEW Classification?
G1- cell monomorphism, Ki67≤3%
G2- cell monomorphism, 3% < Ki67 ≤ 20%
G3- cell monomorphism, 20% < Ki67 (≤ 55%)
10% G4-small cell & large cell NE carcinomas
cell pleyomorphism, necrosis, invasion,
(20%) 55% < Ki67 ≤ 100%
MIB1 stains nucleolus of cells differentiating- city named ‘kill’
carcinoid nomenclature?
“Carcinoid Syndrome“ - serotonin secreting neoplasm
neuroendocrine tumors of the lung-
typical - G1
atypical - G2
NETs classification?
NF-NETs 75%
```
F-NETs 25%
Insulinoma
Gastrinoma)
Glucagonoma
VIPoma
Carcinoid Sdr.
Cushing Sdr.
Hypercalcemia
Acromegaly
~~~
NETs LAB?
Non-specific:
Chromogranin A (CgA) 65% of all NEN
PPI, H2RAs: feedbeck CgA ↑, stop PPI 3w before unless gastrinoma
Neuron Specific Enolase (NSE)- aggressive tumours
PP- pancreatic tumors in MEN-1
(pro) Calcitonin - Medullary carcinoma, PNETs
Alk.Phos, PLT
Specific:
5-HIAA, a serotonin metabolite (carcinoid)
Insulin & C-Peptide & hypoglycemia (insulinomas)
Fasting serum gastrin & PH<2 (gastrinomas, ZES)
Glucagon (glucagonoma)
VIP (VIPoma)
Not for screening!!!!
Molecular Imaging of NETs?
DOTA-TATE PET-
inject TATE (ss analogue), bound to DOTA (chimeric molecule) 🡪 detect all SSTR2 cells
(+optional therapy of SS analogue)
will be shown in liver (homogenic grey), spleen (vascular, endothel), kidney (excretion)
all else is pathological
FDG- most common PET CT
glucose-radio-active- Fluorine uptake, high metabolic demands
-Low sensitivity in G1&G2
-complementary to Ga-DOTA-PET
Current Therapies for GEP NETS?
Surgical resection: Curative or Palliative (Debulking)
Intestinal NET- Somatostatin Analogues 1st line (85%) Everolimus- mTORi PRRT Interferon alpha
Pancreatic NET- Somatostatin Analogues 1st line (85%) Everolimus, Sunitinib (TKI) PRRT Chemotherapy (G3)
Somatostatin?
1st line inhibitory functions: endocrine/exocrine secretions neurotransmission motor and cognitive functions intestinal motility endocrine cell proliferation
Long acting- Octreotide LAR (IM) or Somatuline Autogel (SC) every 4w
Pan-receptor ligand (1-5 at same time) - Pasireotide or SOM230, daily or weekly
> 90% of NENs express SSTR
SSTR2, SSTR5, and SSTR1 are most frequently
Effective Symptom Relief (secretory)
REDUCTION in Diarrhoea Frequency
REDUCTION in Flushing Frequency
Most side effects are transient
PRRT Peptide Receptor Radionuclide Therapy - Eligibility Criteria?
Coupling a radioisotope to a molecule which would specifically bind to tumor cells & deliver an effective radiation dose to the tumor- TATE (SS analogue)
2nd line
Metastatic/locally advanced/inoperable NETs
20% diseases regression
65% stop advancement
more adverse effects: Acute and subacute-Usually self-limiting. Long term Renal failure - rare MDS or leukemia (2%)
insulin lvls at hypoglycemia measurement?
C-peptide
low if exogenic insulinemia
high if endogenous insulinemia
Insulinoma diagnosis?
fast glucose 72h gold standart (in all endocrine do imaging after initial suspicion and DD)
high index of suspicion
blood glucose ≤ 2.2mmol/l (≤40 mg/dl)
insulin ≥6µU/l (≥36pmol/l ) & C-peptide ≥200 pmol/l;
מדידים או גבוהים
HRCT/MRI; EUS/IOUS; 68Ga-DOTATATE, 68Ga-exendin-4
Insulinoma treatment?
surgery - treatment of choice (laparoscopic, IOUS)
ablation (RFA)
medical therapy (unable/ unwilling for surgery, or for metastatic disease):
self monitoring of glucose
glucose infusion
diazoxide - usually a 1st line drug
glucocorticoids - effective in refractory cases
somatostatin analogues (SSAs) - inhibit insulin secretion (!!paradoxical effect via action on GH & glucagon - worsening hypoglycemia in some patients) 50% check before administration!
malignant insulinoma: SSAs; chemotherapy , PRRT, TKI (sunitinib) or mTOR inhibitors (everolimus);
Insulinoma characteristics?
the most common F-PNETs
“Rule of 10” (multiple, malignant, MEN1, ectopic [not in pancreas]).
Clinically Whipple’s triad-
Symptoms of hypoglycemia
Low glucose level ≤2.2mmol/l (≤40mg/dl)
Relief of symptoms with glucose administration
Gastrinomas & Zollinger-Ellison Syndrome (ZES) characteristics?
Gastrinoma triangle (70% duodenum; 20% pancreas; 10% LN)
Sporadic (80%), hereditary (20%, MEN1)
Malignant 60-90%
Clinically, symptoms d/t gastrin-related high gastric acid output (ZES) ± tumor mass
diagnosis:
elevated fasting gastrin (~90-98% patients, after stopping anti-acid drugs, if possible); pH<2.
localization: HRCT/MRI, EUS, SRI
Gastrinomas & Zollinger-Ellison Syndrome (ZES) Treatment?
surgical excision in localized disease
systemic therapy:
PPI always
SSAs, 1st line; then
advanced :
PRRT, or
Targeted therapy: TKI (sunitinib) or mTOR inhibitor (everolimus), or
capecitabine-temozolomide (CAP-TEM), or
liver metastates:
TACE; RFA
Glucagonoma characteristics?
7% of F-pNETs usually large (>5 cm) and metastatic (~80% liver) at presentation
clinical Glucagonoma Syndrome: necrolytic migratory erythema (NME) new/uncontrolled DM (75-95%) abdominal pain, anorexia, diarrhea thromboembolism (~30%) neurologic: ataxia, dementia, optic atrophy
Glucagonoma diagnosis?
fasting plasma glucagon >500pg/ml (50-150)
localization: HRCT/MI; EUS; SRI
Glucagonoma treatment?
surgical excision in localized disease
systemic therapy:
PPI always
SSAs, 1st line; then
advanced :
PRRT, or
Targeted therapy: TKI (sunitinib) or mTOR inhibitor (everolimus), or
capecitabine-temozolomide (CAP-TEM), or
liver metastates:
TACE; RFA
u5HIAA sampling?
דיאטה 3 ימים לפני ותוך כדי האיסוך ללא דברים שדומים לסרוטונין.
אבוקדו, בננות, וניל, בטונים, קפה שוקו וכו
Carcinoid Syndrome initial treatment?
(HD) SSA & zolendronic acid
CRF:
diuretics, low salt diet
Carcinoid Syndrome characteristics?
19% F-NETs originating in SI, lung, pancreas, ovary…
Associated with high serotonin (5HIAA)
Diarrhoea, flushing, bronchospasm
30-60% CHD - increased mortality
Carcinoid crisis - life-threatening
Risk Factors for CHD Development & Progression in Carcinoid Syndrome?
High circulating serotonin
High u5HIAA (>300 µmol/24h or >30mg/24h)
Prolonged exposure
≥3 diarrhea /day
Overexpression & activation of 5HTRs (mainly 5HT2BR) in cells (fibroblasts, smooth muscle cells, etc.)
Approach to a Patient with CS & CHD - Principles of Therapy?
1st - Decrease Hormonal Levels
1st line- Somatostatin Analogues (SSA, also high dose)
+-Serotonin synthesis (TH) inhibitor - Telotristat Ethyl
Considered Individually: (PRRT), OR mTOR inhibitor - Everolimus), OR NF-α (rarely used), OR Locoregional (TACE/SIRT), surgical debulking), OR
2nd - Identify & Treat Right HF
3rd - Decide on Valve Replacement (NET MDT)
Medullary Thyroid Carcinoma (MTC) characteristics?
parafollicular C-cells of the thyroid, neural crest origin
F-NET:
Calcitonin (most common);
Carcinoembryonic antigen (CEA)
ACTH, Substance P, Gastrin
Two types:
Sporadic 25% 50-60y
Familial [AD]: Multifocal and bilateral MEN IIA/IIB Familial MTC >95% germline RET (Tyrosine kinase receptor coder) 20-30y 🡪 found early 🡪 better prog.
Medullary Thyroid Carcinoma (MTC) clinical presentation?
50-60% nodal involvement when detected
Compressive symptoms (dyspnea, dysphagia)
Hoarseness (RLN)
Paraneoplastic syndromes (Cushing’s)
Diarrhea-Calcitonin causes increased secretion of electrolytes into the intestine
Medullary Thyroid Carcinoma (MTC) treatment?
- Locoregional:
Surgical resection ± EBRT
Or
Vandetanib for unresectable symptomatic or progressive - Symptomatic, distant metastases:
Consider palliative resection
Ablation (RFA, TACE) or Vandetanib
3. Asymptomatic, distant metastases: Observe or Consider resection (if possible) Ablation (RFA, TACE) or Vandetanib if PD
- Disseminated Symptomatic Disease
Clinical Trial (preferred) Or EBRT for Focal Symptoms
or
Vandetanib Or Consider other TKIs
or
Dacarbazine (DTIC)-based chemotherapy (RET mute)
Bisphosphonate or Denosumab for bone metastases
Diagnostic Pathway in NET?
Clinical Symptoms/ Incidental Finding 🡪 Lab
tests 🡪 Imaging anatomic/ functional 🡪 Histo-pathology 🡪 Prognostic stratification 🡪 Therapeutic
Decision
Acromegaly - Signs and Symptoms?
GH Excess: Frontal Bossing Chin Protrusion Enlargement of hands and feet Thick skin Skin tags Sweating Sleep Apnea Carpal Tunnel Syndrome Glucose intolerance Osteoarthritis Colonic Polyps macroglossia
Tumor-related: Headache Visual field defect Loss of pituitary function- Gonadotrophins TRH - hypothyroid ACTH - Addison’s Diabetes insipidus (very rare unless apoplexy)
Regulation of GH Secretion?
SS is the main inhibitor, regulated by: sleep🡪 acetylcholine↑ 🡪 ↓ arginine 🡪 ↓ dopamine (more then GH)🡪 ↓ alpha androgenics, opiates, GABA🡪 ↓ glucose 🡪 ↑ GH 🡪 ↑ IGF-1 🡪 ↑
GH direct regulators: GRH 🡪 ↑ TRH 🡪 ↑ T3 🡪 ↑ dopamin 🡪 ↓ glucose 🡪 ↑ (BUT SS ↑↑↑) IGF 🡪↓ stress 🡪 ↑
Diagnose Acromegaly?
1st-
IGF-1 (Insulin-like Growth Factor 1)
IGF-BP3 (IGF binding protein 3)
1-2hr postprandial GH
2nd. Normal- Acromegaly Excluded
2nd. abnormal:
Oral Glucose Tolerance Test (OGTT)
normal- GH will go down in a blink, Acromegaly Excluded
abnormal 🡪 GH normal or even rise 🡪 Acromegaly diagnosis
↓
3rd. pituitary MRI
Normal🡪 Somatostatin receptor Scan 🡪 Site-specific CT/MRI 🡪 TREATMENT
Abnormal 🡪 treatment
Growth-Hormone Excess Etiology?
98%: GH-producing pituitary tumor
2%: Ectopic GHRH secretion Small cell lung cancer Bronchial or intestinal carcinoid tumors Pancreatic islet cell tumor Pheochromocytoma
0%: Ectopic GH secretion exceedingly rare
Acromegaly with large pituitary tumor “collateral damage”?
- Pituitary-Adrenal axis:
cortisol insufficiency
Fasting morning cortisol > 350 nmol/l 🡪 deficiency is highly unlikely - hypothyroidism
TSH may be low, normal or slightly elevated
(if high 🡪 probably non functional 🡪 no TRH 🡪 No processing 🡪 no functionality
FT4 is low
- Pituitary gonadal axis
LH, FSH, Sex hormones - Diabetes Insipidus- rare if no apoplexy
- Visual field defect
Acromegaly: Treatment options?
surgery
micro 82% , Recurrence 5-10%
macro 47%, Recurrence 100%
Dopaminergics- Cabergoline, 10-20%
Effect minimal and may be transient
Radiotherapy 75% (20 years)
Neuro deficits- allmost none
Somatostatin analogs- 50-65% Gallstones Monthly injections 80+% reduce IGF1 levels 30-50% normalize IGF1
GH receptor antagonist- Pegvisomant
Normalization of GH 90%
Normalization of IGF1 80-90%
Acromegaly: Treatment Algorithm?
Pituitary Adenoma
↓
< 1cm 🡪 Transphenoidal surgery
> 1cm:
🡪 non invasive 🡪 Consider preoperative somatostatin analog + Transphenoidal surgery
↓
Post prand GH >1 mcg/l And/or IGF-1 elevated?
↓
somatostatin analog or dopaminergic
🡪 invasive 🡪 somatostatin analog or dopaminergic ↓ GHR, antagonist or dopaminergic ↓ Combination therapy ↓ Radiation Therapy
Post-prand GH <1 mcg/l and IGF-1 normal
↓
Annual Follow-up
Differential Diagnosis of Hyperprolactinemia?
macroprolactinoma 🡪usually Prolactin levels > 5,000
Stalk compression, medications, hypothyroidism and stress 🡪 usually prolactin levels < 2,000 and virtually always less than 5,000 mIU/l.
Microprolactinomas and mass lesions compressing the pituitary stalk frequently present with similar prolactin levels.
Hyperprolactinemia: Clinical Presentation?
Women: Amenorhea 57-90 % Galactorrhea 30-80 % Headache 40 % Visual field defect<25 % Hirsutism 19 %
Men: Decreased libido 75-100 % Impotence 68-100 % Headache 70 % Visual field defect 36-70 % Galactorrhea 10-30 % Gynecomastia 4-50 %
Prolactinoma: Results of Treatment?
Surgery:
Microprolactinoma 60-80% -Recurrence 50%
Macroprolactinoma 10-30% -Recurrence 100%
Radiotherapy -Normalization of PRL after ~10 years
Medical Therapy
Microprolactinoma >90%
Macroprolactinoma 50-80%
Clinical Evaluation of Hyperprolactinemia?
Increased fasting, resting prolactin levels
< 5,000 mIU/l:
“Non-functioning” macroadenoma-
Surgery and/or Radiation
Cortisol, thyroid and testosterone replacement
> 5,000 mIU/l:
Dopaminergic Therapy
Dopamine agonist therapy will normalize prolactin and lead to tumor regression in most patients with macro- and micro-prolactinomas
Hormone Replacement Therapy in Panhypopituitary Patient?
Adrenal Cortex:
Emergency (Stress)
Hydrocortisone 50-100 mg IV every 8 h.
Maintenance - cortisone in various ways
Thyroid:
Levothyroxin 100-200 mcg/d
Maintain T4 level in upper normal range
Gonadal Steroids:
Estrogen/Progesterone or Testosterone
ADH: Desmopressin (DDAVP)
Growth Hormone
Non-Functioning Macroadenoma of Pituitary Treatment?
- Hormonal Replacement
- Surgical
Most cases
Dopaminergic for prolactinoma - Radiation
Small effect
High probability of pituitary dysfunction
Low probability of secondary tumor
May have long-term subtle neurologic effects
4.Medical
Steroids for hypophysitis
Specific treatment for granulomatous disease
Thyrotoxicosis etiology?
primary hyperthyroidism, Endogenous overproduction of thyroid hormone :
grave’s disease
toxic multinodular goiter
toxic adenoma
without hyperthyroidism, Release of pre-formed hormone from damage to the gland:
subacute thyroiditis
silent thyroiditis
amiodaron, radiation, infraction of adenoma
secondary hyperthyroidism: TSH secreting pituitary adenoma Thyroid hormone resistance syndrome HCG-mediated hyperthyroidism – β-HCG shares α subunit with TSH Gestational thyrotoxicosis
Excess levothyroxine administration
Features Unique to Graves’ Disease?
- אוושה בבלוטה – האזנה לבלוטה > ניתן לשמוע אוושה, עקב זרימת דם מוגברת בתוך הבלוטה.
- אופתלמופתיה
- דרמופתיה – עיבוי של העור באזור הטיביה, מאוד נדיר (זה היה נראה בעיקר לפני שהיו לנו דרכים למדוד יתר פעילת של הבלוטה ולטפל)
- שינוי ציפורניים – מאוד מאוד נדיר.
thyroid hormones characteristics?
> 99% of Thyroid Hormone is Bound
Bound hormones are inactive, only the free portion is biologically available to tissues
T4- T0.5= 7d 100% production by thyroid
T3- T0.5= 12-18h 20% production by thyroin, 80% in periphery by conversion of T4
TBP- 80% of bound thyroid hormone
Increase: Estrogen, Acute Hepatitis, Drugs
Decrease: Androgens, Glucocorticoids, NS, Cirrhosis
Graves’ Disease LAB?
LOW TSH (negative feedback) HIGH T3, T4
no further testing needed (book says) but:
Radioactive Iodine Uptake and Scan- increased diffuse uptake (normal around 30%)
Thyroid Ultrasound- elevated blood flow
Tests of thyroid autoimmunity?
TPO Ab – Thyroid Peroxidase Ab
very sensitive- graves 50% and hashimoto 80%
Thyroglobulin Ab 30%
TRAb – TSH receptor Ab
specific for graves
TSI – Thyroid Stimulating Ig
specific for graves- 90%
graves treatment?
Symptomatic relief -
book- Beta blockers (propranolol at high doses decreases peripheral conversion of T4 to T3)
(short T0.5 so…)
1. Antithyroids: methimazole first line PTU: in thyroid storm and 1st trimester -[inhibits T4→T3 (high dose)] relapse 60% adverse: Agranulocytosis- discontinue ATDs in case of fever or sore throat acute hepatitis
- surgery
adverse:
Hypoparathyroidism
RLN paralysis
Intraop thyroid storm, bleeding
Lifelong L-T4
3. Radioiodine adverse: Pregnancy/breastfeeding Radiation protection issues Ophthalmopathy Lifelong L-T4
Graves’ Ophthalmopathy?
CASC – score >=3 points, max 7
Activation of TSH-R and IGF-1R leads to inflammatory environment, fibroblast proliferation and increased cytokines/chemokines 🡪 prostaglandin and GAG infiltration/inflammation within the orbit 🡪 ophthalmopathy
can happen without thyroid problem
risk factors: Age Sex Genetics/Ancestry: Highest in Caucasians; lowest in Asians Smoking: Increases GO progression and decreases therapy efficacy TSH receptor Thyroid dysfunction Radioactive iodine therapy (RAI)
Graves’ Ophthalmopathy - Treatment?
Treat underlying thyroid hormonal imbalance:
Radioactive iodine should be avoided
mild- glucocorticoid therapy should follow RAIodine administration
Smoking cessation
Selenium supplementation
Immunosuppressive therapy-
Glucocorticoids: IV methylprednisolone pulse therapy with 500 mg x 6w followed by 250 mg/week X 6w
Teprotumumab (anti-IGF-1)
second line agents: CellCept, anti-IL-6, anti-B cell mAb, orbital radiation
Decompressive surgery
DD of Thyroiditis?
acute (more rare):
bacterial , fungal
I131 treatment
amiodarone (has iodine in it)
subacute: viral silent (including postpartum) mycobacterial infection drugs- interferon, amiodaron
chronic:
autoimmunity- hashimoto, atrophic, Riedel’s
parasitic
traumatic
Thyroiditis LAB/imaging?
TSH LOW (negative feedback) T4 +3 elevated Thyroglobulin ↑ ESR ↑ (מוגבר בדלקת) TPO Ab negative
Nuclear Medicine Imaging-
no uptake- RAIU< 5%
Thyroiditis treatment?
no antithyroids! inhibits production of new hormone; they do not interfere with pre-formed hormone release.
Beta-blockers- drugs of choice
symptomatic relief and suppression of tachyarrhythmia
Use NSAIDS (Advil or nexin) or corticosteroids prn for pain management
Natural course of thyroiditis?
pathogenesis: destruction of thyroid and hormones spill to blood
↓
thyrotoxic 🡪 hypothyroid (easy) 🡪 recovery
TSH ≥ 10 (mU/L) or symptomatic:
50-100 mcg of L-T4 for 6-8 weeks and TFTs should be reassessed thereafter
acute iodine load thyroid response?
normal thyroid-
wolf chaikoff effect (organification of iodine↓, massive emptying)
defective thyroid-
jod-basedow effect (massive deposition)
Amiodarone-Induced Thyroid Dysfunction?
39% iodine by weight
Very long half life! (50-100 days)
Acutely inhibits T4 release (Wolf-Chaikoff effect)
Inhibits 5’ deiodinase 🡪 reduces FT3 with normal-elevated T4 and transient TSH elevation
Can cause hypothyroidism (13% )
More common in those with TPO Ab +
No need to discontinue drug, simply treat hypothyroidism
Can cause hyperthyroidism (2%) (AIT) - 2 forms:
Type 1- increased T4/T3 synthesis -underlying thyroid pathology (Jod-Basedow effect)
Type 2- (destructive thyroiditis) resulting in excess release of T4/T3 without increased hormone synthesis
Treat with high dose ATDs or thyroid surgery (type 1) or steroids (type 2)
Amiodarone-Induced Thyroid evaluation?
Thyroid Nuclear Medicine Scan- Not helpful
Procore had saturated the thyroid
Ultrasound-
high blood flow, nodes 🡪 Type 1 AIT
Amiodarone-Induced Thyroid Treatment?
has type 1 AIT-
Discontinuing amiodarone if possible – remember t½ is long
high dose methimazole (ATD)
Beta blockers for symptom control
type 2 AIT
steroids and BB without methimazole
DD of hypothyroidism?
primary-
hashimoto, 131 treatment, drugs (thyroiditis), surgery, infiltration (amyloidosis, sarcoidosis)
transient- thyroiditis
secondary-
hypopituitarism
hypothalamic disease
hypothyroidism LAB?
high TSH
low T3+4
TPO Ab positive (HASHIMOTO)
Treatment of Hypothyroidism?
Levothyroxine (L-T4) (BETTER T0.5 THAN T3)
Full dose replacement ~ 1.6 mcg/kg
Slow replacement in Elderly (>75Y), CAD
Liothyronine (L-T3)
short half life and fluctuating levels
Follow up TSH 6w
Subclinical Hypothyroidism treatment?
When TSH is ≥ 10
When symptomatic
Pregnant women should be treated from the first trimester as it may affect pregnancy outcome
Always repeat the test prior to starting therapy!!
Toxic nodule?
ברוב המוחלט של המקרים נודולה פעילה לא ממאירה
רוב הנודולות לא ממאירות
mostly Activating mutation of TSH-R
הטיפול – יוד רדיואקטיבי (ולפעמים מתימזול)
