Paraneoplastic syndromes occur in 7-15% of malignancies and involve substances secreted by tumors affecting distant sites. Common syndromes include endocrine disorders like Cushing syndrome from ACTH/cortisol overproduction. Hypercalcemia, the most frequent paraneoplastic syndrome, results from PTHrP secretion by cancers like breast and lung. Other syndromes involve inappropriate antidiuretic hormone or insulin secretion. These syndromes provide clues to underlying malignancies, impact prognosis, and challenge management. Recognition of tumor-induced hormonal imbalances is important for timely cancer diagnosis and treatment.

1. Paraneoplastic
Endocrine
Syndrome

2. Paraneoplastic Syndrome
• Definition: a syndrome due to
substances secreted by a tumour or its
metastases, with effects occurring
remotely from them
• may be idiopathic or involve
antibodies, hormones, cytokines

3. • Incidence: 7-15% of all malignancies
• no race or sex predilections
• occurs at any age
• commonly associated malignancies
include lung (especially small cell), breast
& stomach

4. Systems involved:
1. Neuromuscular eg. Eaton-Lambert
myasthenic syndrome
2. Endocrine (Cushing syndrome)
3. Cutaneous (acanthosis nigricans)
4. Rheumatological (hypertrophic
osteoarthropathy)

5. 4. Renal (nephrotic syndrome)
5. Gastrointestinal (diarrhoea)
6. Haematological (anaemia)
7. Miscellaneous (fever)

6. Importance:
• may be earliest manifestation of an
occult neoplasm
• present significant clinical problems
• mimic metastatic disease & confound
treatment
• parallel activity of associated tumour

7. Importance:
• usually appears in later stages of
disease
• associated with a poor prognosis
• only peptide hormones are secreted
ectopically, probably as they require
less cellular & metabolic
derangements than steroid hormones
synthesis

8. • WH Brown described the first case of
paraneoplastic endocrine syndrome in the
Lancet, 1928
• it was about tumour-induced adrenal
hyperplasia & preceded description of
Cushing disease by 4 years
• Hypercalcaemia is the most common
paraneoplastic syndrome
• Cushing syndrome, the most common
paraneoplastic endocrinopathy

9. Paraneoplastic Syndromes: Endocrinopathies
Clinical Syndromes
Endocrinopathies
Cushing syndrome
Major Forms of Underlying Cancer
Small cell carcinoma of lung
Pancreatic carcinoma
Causal Mechanism
ACTH or ACTH-like substance
Neural tumors
Syndrome of inappropriate
antidiuretic hormone secretion
Hypercalcemia
Small cell carcinoma of lung; intracranial
neoplasms
Squamous cell carcinoma of lung
Antidiuretic hormone or atrial natriuretic
hormones
Parathyroid hormone-related protein
(PTHRP), TGF-α, TNF, IL-1
Breast carcinoma
Renal carcinoma
Adult T-cell leukemia/lymphoma
Ovarian carcinoma
Hypoglycemia
Fibrosarcoma
Other mesenchymal sarcomas
Insulin or insulin-like substance
Hepatocellular carcinoma
Carcinoid syndrome
Bronchial adenoma (carcinoid)
Pancreatic carcinoma
Serotonin, bradykinin
Gastric carcinoma
Polycythemia
Renal carcinoma
Cerebellar hemangioma
Hepatocellular carcinoma
Erythropoietin

10. Hypercalcaemia
• Incidence: 10-20%
• Common tumour types: breast, lung & multiple myeloma
• tumour produces hypercalcaemia by:
1. direct metastatic bone destruction
2. humoral hypercalcaemia of malignancy (HHM)
3. local osteolytic hypercalcaemia (LOH)
4. calcitriol

11. Hypercalcaemia
• signs & symptoms:
• Constipation
• Fatigue
• Nausea
• Polyuria
• Polydipsia
• Weakness
• confusion
• seizures

12. Cause:
• synthesis & secretion of PTHrP by
tumour cells
• Incidence: 8-12.5%

13. Hypercalcaemia:
• Common tumour types:
1. squamous cell lung carcinoma
2. Breast
3. Esophagus
4. Head & neck

14. Associated with:
• male gender
• squamous cell
• bone metastases
• high tumour load
• advance stages

15. • PTHrP bears 60% homology with PTH
over first 13 amino acids at N terminal
• PTH-like activity of PTHrP is contained
within first 34 amino acids which
involves receptor binding & activation
• genes for PTH & PTHrP reside in
chromosomes 11 & 12 respectively

16. Hypercalcaemia:
• PTHrP level correlates with serum Ca level
• both PTHrP & PTH share a G proteincoupled receptor and stimulate adenylate
cyclase:
- bone resorption
- distal tubular calcium reabsorption
- proximal tubular phosphate reabsorption

17. Parathyroid Hormone Related Peptide

18. Calcium Metabolism

19. Hypercalcaemia:
• PTHrP appears to enhance ability of breast
cancer to erode bone & establish bone
mets and acts as an autocrine growth
regular for prostate Ca
• high proportion of patients with skeletal
mets & hypercalcaemia have high serum
PTHrP

20. • PTHrP >12pmol/L is associated with
lesser reduction in hypercalcaemia by
iv pamidronate & recurrence of
hypercalcaemia within 14days
• prognosis: very poor, median survival
of 1month

21. Hypercalcaemia:
• PTHrP is also produced by normal
tissue (eg. keratinocytes,
mammary & renal tubular cells)
but are undetectable in normal
individuals & cancer without HHM

22. Functions include:
• regulating Ca transport in lactating
breast & across placenta
• promote cartilage cell growth
• angiogenesis inhibitor

23. Hypercalcaemia:
• Common tumour types: multiple
myeloma, lymphoma, breast Ca
• osteoclast activating factor (OAF)
produced by tumour act locally to
stimulate osteoclast-mediated bone
resorption
• TNF- in myeloma, PG-E2 in breast Ca, IL-1,
IL-6, TGF-, , TNF-

24. Hypercalcaemia:
• Common tumour types: most Hodgkin’s,
1/3 of NHL
• usually responds to glucocorticoid therapy
• via calbindin-D:
- intestinal Ca absorption
- renal Ca reabsorption
-  Ca & phosphate mobilisation from bones

25. Hypercalcaemia: Treatment
1. IV drip
2. Furosemide after hydration
-  renal Ca clearance
3. IV Bisphosphonates (Pamidronate 90mg in 2hrs)
- inhibits osteoclast function & osteoclast
viability
4. Mithramycin:
- inhibits RNA synthesis in osteoclasts
- limited by hepato/nephrotoxicities & plt

26. 5. Corticosteroid
- blocks extrarenal synthesis of calcitriol by
inhibiting macrophage 1-hydroxylase activity
6. Calcitonin 4-8mcg/kg q12H:
- rapid onset
-  bone resorption &  renal Ca excretion
7. Gallium nitrate:
-  bone resorption
- slow onset, Ca more & longer than
bisphosphonate
- limited by nephrotoxicity

27. Hypercalcaemia: Treatment 3
8. ?human immunoglobulin fusion protein:
- blocks TNF receptor homologue & disrupts
signals essential for osteoclast activation &
survival
- inhibits osteoclastic bone resorption
9. Treat underlying cancer

28. Ectopic Cushing Syndrome:
• Cause: synthesis & secretion of ACTH and
its precursors by tumour cells
• Incidence: 15-20% of all Cushing syndrome
50% due to Ca lung
(27% small cell; 21% bronchial
carcinoids)

29. • Common tumour types: small cell,
carcinoid, ovarian, medullary carcinoma of
thyroid, pancreas, thymoma
• Interestingly, though more than half has
ACTH, only 1.6-4.5% of small cell cancer
patients develop ECS

30. In small cell carcinoma related ECS:
- degree of ACTH precursors > ACTH suggests
defective processing of POMC
- non-pulsatile ACTH secretion
- precursors correlate with cortisol levels
- error may arise due to cross reactivity with ACTH
assays
- rarely shows all classic signs of Cushing syndrome
due to aggressive tumour, short time exposed to
excessive corticosteroids & aberrant POMC
processing

31. Ectopic Cushing Syndrome:
In small cell carcinoma related ECS:
Clinical features: proximal myopathy (29-61%)
moon facies (40-52%)
- nearly all hypokalaemic & majority,
hyperglycaemic
- 64-87% present with extensive stage and
respond poorly to chemotherapy
Prognosis: median survival 4months, worse
with ECS

32. Ectopic Cushing Syndrome:
In carcinoid related ECS:
1. POMC is processed normally
2. ACTH > precursors
3. mimics pituitary overproduction of ACTH
4. may also produce CRH & contain
glucocorticoid receptor

33. Ectopic Cushing Syndrome:
In carcinoid related ECS:
• most have classic Cushingoid
appearance, attributed to indolent
nature & normal POMC processing
• Hypertension is prominent
• 50% has Hypokalemia

34. • Dexamethasone suppression &
metyrapone tests may mislead due to
glucocorticoid receptor expression
• Prognosis: relatively more aggressive
tumour (locally invasion & LN mets)

35. Ectopic Cushing Syndrome:
Treatment:
1. Inhibit steroid biosynthesis (eg. ketoconazole,
metyrapone)
2. Inhibit hormone secretion (eg. octreotide)
3. Surgical resection of tumour eg. carcinoid,
thymoma; and bilateral adrenalectomy
4. Chemotherapy

36. Syndrome of Inappropriate Antidiuretic
Hormone

37. Syndrome of Inappropriate Antidiuretic
Hormone:
• Cause: synthesis & secretion of ADH by
tumour cells
• Incidence: 7-16% of lung cancer
more common in extensive SCLC
• Common tumour types: small cell, brain
tumours, leukaemia, lymphoma and head
& neck tumours

38. • signs & symptoms: asymptomatic, fatigue,
headache, delirium, seizures
• euvolaemic, serum
hyponatraemia/hypoosmolality,
inappropriately concentrated urine
• exclude other causes eg. drugs (vincristine,
cisplatin, morphine etc), infection
(brain/lung), stroke etc

39. Syndrome of Inappropriate Antidiuretic
Hormone
• secretion not suppressed by serum
hypoosmolality
• <50% of lung cancer patients with elevated
ADH develop SIADH
• amongst tumour recurrence, 60-70%
develop SIADH too
• prognosis: associated with survival

40. Syndrome of Inappropriate Antidiuretic
Hormone
• Normally, ADH release alone is not sufficient to
cause hyponatraemia; with volume expansion,
natriuretic factor is secreted
• BG Campling et al demonstrated atrial natriuretic
peptide & ADH production in 70% & 9% respectively
of 23 small cell carcinoma cell lines
• Other natriuretic peptides (Brain NP, may also be
involved
• these contribute to hyponatraemia found in
syndromes of inappropriate diuresis due to SCLC

41. Syndrome of Inappropriate Antidiuretic
Hormone
Treatment:
1. Treat malignancy
- e.g chemotherapy for SCLC causes >80%
resolution of clinically manifest SIADH
2. Fluid restriction
3. Demeclocycline
- dose dependent & reversible  in
concentrating abilities of kidney

42. Non-Islet Cell Tumour Hypoglycaemia
• Cause: synthesis & secretion of high
molecular weight IGF-II by tumour cells
• 50% presented with hypoglycaemia
• Common tumour types: hepatocellular,
gastric, mesothelioma

43. • IGF-II has an amino acid sequence
homologous to proinsulin &
hypoglycaemic effects
• normal IGF-II is a 7.5kDa peptide but in
NICTH, abnormal processing of its
precursor leads to high MW IGF-II (1118kDa)
• contains O-glycosylated residues in first 21
positions of proIGF-II E-domain

44. Non-Islet Cell Tumour Hypoglycaemia
• IGF-II forms a binary complex with IGF
binding protein & crosses capillary barrier
• easy access to target tissue, elevated levels
of IGF-II & suppression of growth hormone
secretion at pituitary level by IGF-II
contribute to hypoglycaemia

45. • 53% association with hypokalaemia,
due to insulin-like activity of IGF-II
• IGF-I & IGF-II/IGF-I ratio supports
diagnosis
• following tumour removal, a
significant decrease in big IGF-II levels
& hypoglycaemia was seen

46. Conclusion
• Paraneoplastic syndrome is an
important part of tumour biology
• It may be the only manifestation of an
occult malignancy
• May be used to monitor treatment
response & tumour recurrence