Paraneoplastic and ectopic hormone secretion and … and ectopic hormone secretion ... rare autosomal recessive disorder –due to ... Paraneoplastic and ectopic hormone secretion

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