paraneoplastic and ectopic hormone secretion and … and ectopic hormone secretion ... rare...
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Paraneoplastic and ectopic hormone secretion
and syndromes
SIADH
Disorders affecting multiple endocrine systems
Istvan Takacs, MD, PhD
Paraneoplastic and ectopic hormone secretion
and syndromes
SIADH
Disorders affecting multiple endocrine systems
Istvan Takacs, MD, PhD
Paraneoplastic syndromes:
Disorders that accompany benign or malignant tumors, but
are not directly related to the mass effects of invasion.
not depend on: size, localization, curability
They are more common than is generally appreciated
~ 20-25 % of the cancer
Eutopic hormone sources
expression of hormone from its normal tissue of origin
Ectopic hormone sources
expression of hormone from atypical tissue
most common type of tumors: SCLC and carcinoid
Endocrin tumors of the
gastrointestinal tract and pancreas
localisation Producing hormon
Carcinoid stomach, small intestine,
appendix, colonl-rectum;
+broncopulmonál
amins, polipeptids,
prostaglandins
Gastrinoma pancreas, duodenum, gastrin
Somatostatinoma pancreas,duodenum/jejunem somatostatin
GRFoma pancreas, jejunum, pulmo GRF
ACTHoma pancreas ACTH
VIPoma pancreas, nerological,
adrenal gland
VIP
Inzulinoma pancreas inzulin
Glucagonoma pancreas glucagon
1
Neuroendokrin cell concept
Intracitoplazmatic granulums
+ producing amins and peptids (exsist in neurons)
+ specific clinical signs of the tumors
Locations Gastointestinal tract (13 types are known)
pancreas,
lung,
urogenital tract
Formation from multipotens stem cell and not from the neurons
What can produce the neuroendokrin tumors?
Amins
serotonin, 5-hidroxitriptamin, norepinefrin, hisztamin, dopamin
Polipeptids
kallikrein, bradikinin, somatostatin, neuropeptid K, neurokinin A , ACTH,
GH, PP, motilin, VIP, gastrin, peptid YY, neurokinin B, glucagon,
béta endorfin, neurotensin, chromogranin A
Prosztaglandins
Used for immunocytochemical localization
neuron specific enolase, synaptopysin, chromogranin A
Epidemiology
~ 5 / 100 000 (NET)
2/3 gastrointestinal (jejuno-ileum; colon rectum)
1/3 lung
Incidence early ~ 10 %-al increasing
Classification
Forgut Midgut Hindgut
Location bronchial, stomach,
duodenum
jejunum, ileum,
appendix,
colon ascendent
colon descendent,
rectum
Histology argyrophil argentaffin argyrophil
Producing CgA, 5-HT,
AVP, hisztamin, ACTH,
GHRH, gasztrin,
szomatosztatin,
CgA, 5-HT, histamin,
tachykinins
prostaglandins
CgA, PP,
somatostatin
Clinical signs atypical carcinoid, ZE,
Cushing, acromegaly
multihormonal
metastasize to bone
typical carcinoid No endocrin sign
Clinical signs
Sporadic form
Inherited form
MEN 1
NF 1
von Hippel-Lindau
Carcinoid syindrome NET signs (classic classification)and/or
Diarrhoe 60-80 % (serotonin) - watery, with flushing, abdominal pain
Flush 50-70 % (bradykinin) – deep red, neck face upper body, 2-5min, hours
Pain 10-30 % (comb.)
Asthma 5-20 % (comb.)
Heart disease 10-40 % (comb.) – endocardium fibrosis, right side, pulmonic valve…
Pellagra 1-5 % (triptofán)
Fibrosis rare
Clinical signs
Sporadic form
Inherited form
MEN 1
NF 1 Recklinghausen disease
von Hippel-Lindau
Carcinoid syndrome NET signs (classic classification)and/or
Diarrhea 60-80 %
Flush 50-70 %
Pain 10-30 %
Asthma 5-20 %
Heart disease 10-40 %
Pellagra 1-5 %
Fibrosis rare
Bronchopulmonal (20-30%) CS – 15 %
Stomach (5%) I.- 0%; II. – O% (ZE); III. – rare
Small intestine (20 %) CS – liver met.
Appendix (5%) CS – rare
Large intestine, rectum (15%) CS – 0 (glucagon)
Diagnosis
Clinical signs Laboratory measurement Images
5-HIAA (3-15 mg/24H) (from 5HT)
coeliakia, Whipple disease
banana, kiwi, avocado, tomato
acetaminophen, naproxen
aspirin, heparin, L-DOPA
Triptofán
5OH triptofán
Serotonin
Serotonin platelet MAO
Aldehid dehid
5-HIAA
Kromogranin-A (CgA) (19–98 ng/ml)
NET, pheocromocytoma
kidney failure, CHF, hepatic failure,
prostate cancer, breast cancer, PHPT (hyperpalsia)
PPI !!!
+ 56-88%
+ 56-100%
Diagnosis
Endoscopy X-ray, MR Isotop technics
Gastroscopy
Endoscopic US
Colonoscopy
Bronchoscopy
Clinical signs Laboratory measurement Images
CT
MR
PET-CT (11C 5-HT)
111Indium-octreotid scintigraphy123I-MIBG
Harrison’s 17.edition 2357. oldal
Treatment
Surgary treatmentcurative – adjuvans treatment not necessary (< 2 cm)
Palliativ - + kryotherapy, mikrovawe, embolisation…
Drug treatmentSomatostatin – analogs (10/50)
octreotid, lanreotid (LAR 10-30 mg 4 weeks)
pasireotid, dopastatin
+ Interferon
pegilált 75-150 ug sc. weekly 3*
Chemotherapyetoposid, ciszplastin, 5-fluorouracil/doxorubicin
temozolomid-thalidomid
Treatment
Peptidreceptor radionukleotid treatment
90Y-DOTA-TOC
177Lu-DOTA-TOC (36/49)
131I-MIBG
Harrison 17th edition 618. page
1, Humoral hypercalcaemia of malignancy (HHM)
Ca ↑ in malignancy
Skeletal metastasis
Humoral reason20 % of all malignancy
Most common reasons:
lung
head
neck
skin
esophagus
breast
genitourinary tract
myeloma multiplex
lymphomas
60 %
1, Humoral hypercalcaemia of malignancy (HHM)
Mediated by:
PTHrp – binds to the PTH receptor
can be stimulated by mutations oncogens
frequently from bone metastatic lesions
not measured by PTH labor methods
vitamin D – 1-α hydroxylation in lymphomas
RANKL - DKK1
1, Humoral hypercalcaemia of malignancy (HHM)
Clinical manifestations
acute duration + high serum calcium (>3,5 mmo/l)
sometimes initial presenting feature of malignancy
fatigue, mental status changes, dehydration
Diagnosis
Ca ↑; P↓; PTH↓; urine Ca ↑
1, Humoral hypercalcaemia of malignancy (HHM)
Treatment
oncologic treatment – removal the tumor mass
low calcium diet
oral phosphorus should be given
forced diuresis with loop diuretic
iv. bisphosphonat 30-90 mg pamironate or 4-8 mg zoledronate
in lymphomas, myeloma multiplex: glucocorticoid
1, Humoral hypercalcaemia of malignancy (HHM)
Treatment
oncologic treatment – removal the tumor mass
low calcium diet
oral phosphorus should be given
forced diuresis with loop diuretic
iv. bisphosphonat 30-90 mg pamironate or 4-8 mg zoledronate
in lymphomas, myeloma multiplex: glucocorticoid
Paraneoplastic and ectopic hormone secretion
and syndromes
SIADH
Disorders affecting multiple endocrine systems
Istvan Takacs, MD, PhD
2, Syndrome of inappropriate antidiuretic hormone secretion
SIADH
ADH↑ limited, concentrated urine, >100 mOsm/kg
urine sodium elevated,
serum sodium low <120 mmol/l
serum osmolality low <275 mOsm/kg
Compensatory mechanism:
decreased thirst
suppression of aldosteron and ANP production
The neurohypophysis consists of a set of hypothalamic nuclei that house the perikarya of
the magnicellular neurons that are responsible for synthesis of oxytocin and vasopressin.
The axonal process of these unmyelinated neurons, which form the supraoptico-
hypophyseal tract and termini of these neurons within the posterior lobe of the pituitary.
CNS
bleeding, trauma, tu, encephalitis
Surgery stress
Malignoma
small cell bronchy, prostata, pancreas, thymus…
Infections: pneumonia, tbc, meningitis, AIDS
Drugs
vasopressin, oxitocin
clopropamid, carbamazepin, barbiturat,
vincristin, cyclophosphamid
ecstasy
SIADH (Syndrome of Inappropriate Antidiuresis)
Harrison 17th edition2222. page
2, Syndrome of inappropriate antidiuretic hormone secretion
SIADH
Most common malignancy in the background:
SCLC 50-78 % (5-15%)
carcinoid
lung cancer
head-neck cancer
genitourinary cancer
gastrointestinal cancer
ovarian cancer
Clinical manifestations
usually asymptomatic
sometimes initial presenting feature of malignancy
weakness, lethargy, nausea, vomiting,
confusion, mental status changes, seizures
lack of edema
2, Syndrome of inappropriate antidiuretic hormone secretion
SIADH
Harrison 17th edition 278. page
Usually ADH measurement
not necessary
2, Syndrome of inappropriate antidiuretic hormone secretion
SIADHTreatment
oncologic treatment – removal the tumor mass
fluid restriction
Demeclocycline 3-4*300 mg
conivaptan 2*20-120 mg
if Na<115 mmol/l or CNS symptoms occur
3% NaCl solution iv. + loop diuretic
rate of correction must be< 1 mmol/l / hour
1, Humoral hypercalcaemia of malignancy (HHM)
Treatment
oncologic treatment – removal the tumor mass
low calcium diet
oral phosphorus should be given
forced diuresis with loop diuretic
iv. bisphosphonat 30-90 mg pamironate or 4-8 mg zoledronate
in lymphomas, myeloma multiplex: glucocorticoid
3, Cushing’s syndrome caused by ectopic ACTH production
Ectopic ACTH ↑↑ 10-20 % of Cushing’s syndrome
~ 50 % SCLC
35 % carcinoid
10 % isle cell tumor
2 % phaeochromocytoma
1 % ovarian cc
Clinical manifestations
acute duration → not a classical picture
missing moon face, central obesity..
male > female
proximal myopathy, edema, depression, personality changes
hypokalemia (worsening fatique), diabetes mellitus
skin pigmentation
predisposition to infection (pneumocystis carinii, mycosis)
poor wound healing
3, Cushing’s syndrome caused by ectopic ACTH production
3, Cushing’s syndrome caused by ectopic ACTH production
Diagnosis:ACTH; cortisol
Harrison 17th edition 2256. page
Harrison 17th edition 2256. page
3, Cushing’s syndrome caused by ectopic ACTH production
Treatment
oncologic treatment – removal the tumor mass
adrenalectomy is not practical
block steroid synthesis + glucocorticoid replacement
ketoconazole 2*200-400 mg
metyrapon 4*250-500 mg
mitotane 4*1 g
1, Humoral hypercalcaemia of malignancy (HHM)
Treatment
oncologic treatment – removal the tumor mass
low calcium diet
oral phosphorus should be given
forced diuresis with loop diuretic
iv. bisphosphonat 30-90 mg pamironate or 4-8 mg zoledronate
in lymphomas, myeloma multiplex: glucocorticoid
4, Tumor induced hypoglycaemia caused by IGF II.
Excess production of IGF II. precursors binding to the insulin
and IGF-I rec.
mesenchymal tumors
haemangioperycitomas
hepatocellular tumors
adrenal carcinomas
Hypoglycaemia associated with fasting + Suppressed insulin level
Symptomatic treatment:
Frequent meal, glucose, glucagon, GH, glucocorticoids
1, Humoral hypercalcaemia of malignancy (HHM)
Treatment
oncologic treatment – removal the tumor mass
low calcium diet
oral phosphorus should be given
forced diuresis with loop diuretic
iv. bisphosphonat 30-90 mg pamironate or 4-8 mg zoledronate
in lymphomas, myeloma multiplex: glucocorticoid
5, Tumor induced osteomalatia
FGF 23 (phosphatonin)
PHEX gene product producing tumors
benign mesenchymal tumors (fibroma, haemangiopericytoma)
sarcoma
lung cancer
prostate cancer
P ; Ca; 25(OH)D3 ; PTH; 1,25(OH)2D3; octreotid scan
oncological treatment – removal the tumor mass
phosphate and vitamin D supplementation
somatostatin
Mary D Ruppe: Primer on Metabolic Bone Diseases and.. 317 o.
Harrison 17th edition 618. page
Paraneoplastic and ectopic hormone secretion
and syndromes
SIADH
Disorders affecting multiple endocrine systems
Istvan Takacs, MD, PhD
Multiple Endocrine Neoplasia (MEN) Type I.
„Wermer’s syndrome”
Autosomal dominant trait - 11q13
mutations of the MEN1 gene, encoding the tumor suppressor menin
Disease Associations in the MEN I.
1, Parathyroid hyperplasia or adenoma
2, Islet cell hyperplasia, adenoma or carcinoma
3, Pituitary hyperplasia or adenoma
4, Less common:pheocromocytoma, lipoma, carcinoid
Several features of this syndrome
have an impact on management:
1, disease process within a single organ is multicentric
2, hyperplasia is the initiating lesion followed by adenoma
3, neoplasia in one organ may affect in another organ
4, generally evolves over a 30-40 year period
MEN I.
1, Hyperparathyroidism
MEN I.
Clinically it does not differ substantially from the sporadic form
other familial disorders with hypercalcaemia:
familial parathyreoid hyperplasia
familial adenomatosus hyperparathyreoidism
familial hypocalciuric hypercalcaemia
MEN I.
2, Neoplasia of pancreatic islets
- pancreatic polypeptide (75-85 %) – inhibitor peptid no signs
- gastrin (60 %) – Zollinger Ellison syndrome
- inzulin (25-35 %) – inzulinoma, hypoglycaemia
- vasoactive intestinal peptide (3-5%) – Verner Morrison syndrome
- glucagone – (5-10 %) – hyperglycaemia, necrolytic migratory erythaema
- somatostatin (1-5%)
- rare: CRH, ACTH, GHRH,
one-third malignant !! hormonal assays, CT screening in 2-3 years
more then 80 %
3, Pituitary hyperplasia or adenoma
MEN I.
- prolactinoma
- acromegaly
/rarely due to GHRH production of islet tumor/
- Cushing disease
/rarely due to CRH production of islet tumor/
more then 50 %
Multiple Endocrine Neoplasia (MEN) Type II.
autosomal dominant trait – 10q11.2
mutations of the c-ret protooncogene
MEN II.
Disease Associations in the MEN II.A familial medullary thyroid carcinoma
MEN 2A + cutaneous lichen amyloidosis
MEN2A + Hirchschprung disease
Disease Associations in the MEN II.B
MEN II.
MEN IIA1, medullary thyroid carcinoma
2, pheocromocytoma (50 %)
3, hyperparathyroidism (15-20%)
MEN IIB1, medullary thyroid carcinoma
2, pheocromocytoma (50 %)
3, mucosal neurinomas + marfanoid habitus
MEN II.
MEN IIA1, medullary thyroid carcinoma
2, pheocromocytoma (50 %)
3, hyperparathyroidism (15-20%)
MEN IIB1, medullary thyroid carcinoma
2, pheocromocytoma (50 %)
3, mucosal neurinomas + marfanoid habitus
total thyreoidectomy in childhood
screening in every year
screening in every 2 year
Polyglandular Autoimmune
Sydrome (PGA)
PGA
Immun dysfunction affects two or more endocrin glands
and other nonendocrine immun disorders are present
rare disease (Finn, Sardinians, and Iranian Jews)
with decreased hormon production (except Graves disease)
PGA I. the autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy
(APECED) syndrome
rare autosomal recessive disorder – due to mutations in the autoimmune regulator
(AIRE) gene on chromosome 21q22.3
Mucocutan candidiasis
Hypoparathyroidism
Adrenal insufficiency
Hypogonadism
Alopecia
Hypothyroidism
Malabsorption
Chronic active hepatitis
Vitiligo
Pernicious anemia
PGA
PGA
PGA II.
much more prevalent than the type I syndrome
DR3; DR4
Adrenal insufficiency
Hypothyroidism
Type 1 diabetes
Hypogonadism
Graves’ disease
Myasthenia gravis
Vitiligo
Alopecia
Pernicious anemia
Celiac disease
Schmidt syndrome
PGA
PGA III.rare
Type 1 diabetes + autoimmun thyroid disease
or
Adrenal insuffuciency + Hashimoto’s thyroiditis
PGA
Treatment:
hormon replacement (except Graves disease)
Adrenal insufficiency – glucocorticoid, mineralocorticoid
Hypothyroidism - levothyroxin
Type 1 diabetes - insulin
Hypogonadism – ostrogen or androgen
Hypoparathyroidism – d-vit analog
calcium
glucocorticoid
thyroid hormon
massage
Paraneoplastic and ectopic hormone secretion
and syndromes
SIADH
Disorders affecting multiple endocrine systems
Istvan Takacs, MD, PhD