Paraneoplastic Endocrine Syndrome

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Paraneoplastic Endocrine Syndrome

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Paraneoplastic Endocrine Syndrome

  1. 1. Paraneoplastic Endocrine Syndrome
  2. 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. 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. 4. Systems involved: 1. Neuromuscular eg. Eaton-Lambert myasthenic syndrome 2. Endocrine (Cushing syndrome) 3. Cutaneous (acanthosis nigricans) 4. Rheumatological (hypertrophic osteoarthropathy)
  5. 5. 4. Renal (nephrotic syndrome) 5. Gastrointestinal (diarrhoea) 6. Haematological (anaemia) 7. Miscellaneous (fever)
  6. 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. 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. 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. 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. 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. 11. Hypercalcaemia • signs & symptoms: • Constipation • Fatigue • Nausea • Polyuria • Polydipsia • Weakness • confusion • seizures
  12. 12. Cause: • synthesis & secretion of PTHrP by tumour cells • Incidence: 8-12.5%
  13. 13. Hypercalcaemia: • Common tumour types: 1. squamous cell lung carcinoma 2. Breast 3. Esophagus 4. Head & neck
  14. 14. Associated with: • male gender • squamous cell • bone metastases • high tumour load • advance stages
  15. 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. 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. 17. Parathyroid Hormone Related Peptide
  18. 18. Calcium Metabolism
  19. 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. 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. 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. 22. Functions include: • regulating Ca transport in lactating breast & across placenta • promote cartilage cell growth • angiogenesis inhibitor
  23. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 34. • Dexamethasone suppression & metyrapone tests may mislead due to glucocorticoid receptor expression • Prognosis: relatively more aggressive tumour (locally invasion & LN mets)
  35. 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. 36. Syndrome of Inappropriate Antidiuretic Hormone
  37. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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

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