Oncology - Paraneoplastic complications Flashcards
What are paraneoplastic syndromes?
Cancer produces illness through direct effects (e.g. local invasion) and the release of biologically active substances. Diseases produced by the latter are termed “paraneoplastic syndromes” the most common of which are:
- anaemia
- cachexia
- tumour induced hypercalcaemia
- SIADH
- Cushing’s syndrome
- Hypoglycaemia associated with production of insulin like growth factors
What is the pathogenesis of paraneoplastic complications?
Paraneoplastic syndromes arise from a variety of mechanisms, many of which are still unknown:
(i) release of normal cellular proteins, in increased amounts (e.g. ectopic hormone production)
(ii) cytokine production
(iii) autoantibody production, which typically result in neurological disorders
(iv) via abnormal metabolism of steroids, the production of enzymes or the expression of foetal proteins
What is the most common form of anaemia encountered in cancer? What mechanisms underly this?
The majority of anaemia relates to the “anaemia of chronic disease”, whereby the inflammatory response associated with malignancy leads to the production of a number of cytokines that suppress the bone marrow. These include:
- disturbance of normal iron metabolism by TGF beta, IL-1, IL-6 and interferon gamma. These may act through increasing the levels of hepcidin, which suppresses iron uptake and utilisation
- TNF alpha (whose levels can be greatly increased in patients with cancer) antagonising the effects of EPO on the bone marrow. Sufficient levels of Hb can be achieved in about 50% of patients by giving exogenous EPO
- in rare patients malignancy induces an autoimmune haemolytic anaemia
- rarer still, malignancy can induce renal cell aplasia
Other causes of anaemia include iron deficiency (esp. GI) and those with folate deficiency (those with rapidly dividing tumours)
What causes cachexia in cancer patients?
The weight loss and malaise associated with cancer relate to the tumour burden, but also to the production of cytokines such as TNF or cachexin. Steroids and progesterones may have a useful symptomatic role.
What are the features of SIADH?
SIADH results in hyponatraemia, renal sodium loss, hypervolaemia and inappropriately high urine osmolarity. Clinically, this may only produce biochemical disease but it may also produce symptoms related to the hyponatraemia: tiredness, mental clouding, delirium, and coma.
List the causes of SIADH?
This can be remembered by the aid memoire SIADH:
Surgery
Intracranial (infection, head injury, cerebrovascular disease)
Alveolar (pus, cancer)
Drugs ABCD (analgesics, barbiturates, cyclophosphamide/ carbamazepine/ chlorpromazine, diuretic: thiazides)
Hormonal (hypothyroid, Addison’s)
What is the mechanism of SIADH in cancer?
The mechanism of SIADH in cancer is two fold:
(i) reflex release by central nervous system tumours, drugs or co-existing lung disease, and
(ii) ectopic hormone release by the tumour, as in small cell lung cancer and more rarely tumours of the duodenum, pancreas, thymus and lymphomas. A precursor molecule is split to produce ADH and neurophysin.
How should SIADH be treated?
The underlying disease should be aggressively treated; fluid restriction is the mainstay of treatment. Refractory cases may respond to demeclocycline, which induces nephrogenic diabetes insipidus.
What tumours cause hypercalcaemia?
Cancer causes hypercalcaemia by 2 main mechanisms:
1) Tumour induced hypercalcaemia (TIH)
2) Hypercalcaemia from boney metastasis
TIH is associated wth production of parathyroid hormone related protein (PTHrP) which is homologous to PTH and may activate the PTH receptor. Solid tumours causing TIH include squamous cell lung cancer, gynaecological, and genitourinary cancers. Multiple myeloma and HTLV associated lymphoma are the most common haematological malignancies causing TIH. The latter in part because of vitamin D production within the tumour.
Boney metastasis is the main other differential for hypercalcaemia, usually from breast, prostate, thyroid or renal cell carcinomas. This develops in 10-20% of patients with disseminated malignancy. Bony metastasis are the most common cause of malignancy related hypercalcaemia, cause hypercalcaemia by releasing TNF alpha, prostaglandins and other paracrine agents that activate osteoclasts.
How is malignant hypercalcaemia treated?
Treatment involves correcting the volume depletion that all hypercalcaemic patients have (caused by calcium induced diabetes insipidus). Bisphosphonates are useful in TIH, but PTHrP related hypercalcaemia is often refractory. Steroids are used for steroid responsive tumours, e.g. multiple myeloma and lymphoma.
Name some other causes of hypercalcaemia that should be considered alongside malignancy
GRIM FED Granulomas (TB, sarcoidosis) Renal failure Immobility Malignancy
Familial (familial hypocalciuric hypercalcaemia)
Endocrine PATH (phaeochromocytoma, Addison’s disease, thyrotoxicosis, hyperparathyroidism)
Drugs (thiazides, lithium, vitamins A and D, milk alkali syndrome)
What cancers cause Cushing’s syndrome and how common is it?
Cushing’s syndrome is classically produced by ectopic ACTH production by small cell lung carcinoma. Overall, 40% of patients with SCLC secrete polypeptides, most of which are non functional, e.g. the precursor molecule to ACTH is often present in these tumours but only about 4% possess the biological activity of ACTH. Overall only 2-3% of patients with SCLC have Cushing’s syndrome. When the syndrome is acute and prominent, it is typically associated with hirsuitism, acne and hypokalaemia. It needs medical control both in its own right AND because it increases the toxicity of chemotherapy.
How does cancer cause hypoglycaemia?
Hypoglycaemia occurs in cancer by 3 main mechanisms:
1) massive size of slow growing tumour - e.g. mesenchymal sarcomas, lymphomas or mesotheliomas often secrete “big” IGF factor II
2) IGF typically from hepatic or adrenal carcinomas
3) insulin secretion by insulinomas, with the rare but classic presentation of fasting hypoglycaemia, commonly associated with neuropsychiatric sequelae and relentless weight gain
What neurological paraneoplastic syndrome are anti-Yo, anti-Hu, anti-Ri and anti-Tr antibodies associated?
Cerebellar syndrome.
These antibodies are associated with cerebellar cortical degeneration, most commonly seen with carcinoma of the lung, breast, or ovary. The cerebellar syndrome has prominent involvement of eye movements, is extremely disabling, and precedes the diagnosis of the underlying cancer. The prognosis is poor and is not reversible with successful treatment of the malignancy. MRI is typically normal, and the diagnosis is one of exclusion. Toxic, metabolic, degenerative and rare differentials such as CJD and HIV should be considered.
What is the Lambert-Eaton myasthenic syndrome?
This is a paraneoplastic condition characterised by symmetrical muscle weakness, hyporeflexia and autonomic dysfunction with improvement in strength on reinforcement. Eye involvement (unlike in myasthenia gravis) is RARE. Nerve evoked acetylcholine release at neuromuscular junction is reduced. Serum antibodies against voltage gated calcium channels occur.
