Metabolic aspects of malignant disease

Chapter 18 Metabolic aspects of malignant disease


The clinical signs and symptoms in patients suffering from cancer are often directly related to the physical presence of the tumour. For example, the tumour may destroy essential normal tissue, cause obstruction of ducts or exert pressure on nerves. Systemic manifestations, including cachexia and pyrexia, are also frequently present, and indeed may be the only evidence of the presence of a tumour. In some patients, the clinical features may be those of an endocrine syndrome. This would be expected with a tumour of endocrine tissue such as an insulinoma (producing hypoglycaemia) or an adrenal carcinoma (producing Cushing’s syndrome), but often occurs with tumours not obviously of endocrine origin.

In many cases, these syndromes are caused by the secretion of a hormone by the tumour. This has been termed ectopic hormone secretion, because the hormone is not secreted from its normal site, while ‘eutopic hormone secretion’ describes secretion from the endocrine gland. However, it seems likely that, in many cases, these tumours arise from cells normally capable of hormone secretion but which are present in only very small numbers in the non-neoplastic tissue. ‘Aberrant’ rather than ‘ectopic’ hormone secretion may be a more accurate term for this phenomenon. Tumours can be associated with other systemic manifestations, for example a cerebellar syndrome, arthropathy, etc. The term paraneoplastic syndromes encompasses all the systemic manifestations of cancer not directly related to the physical presence of the primary tumour, whether or not they are due to a hormone.

This chapter discusses paraneoplastic endocrine syndromes, certain familial endocrine syndromes and also tumour markers, that is, substances that may be present in the circulation in malignant disease and whose concentrations can be measured as an aid to the diagnosis or monitoring of tumours.

Paraneoplastic endocrine syndromes

Origins and classification

These syndromes are due to the secretion of peptide hormones or other humoral factors, which are coded for by genes and translated from mRNA. All somatic cells contain a full complement of genes, and aberrant hormone secretion could be explained either by novel expression of a gene that is not normally expressed in the cells from which the tumour arises, or by re-expression of a gene that is expressed during development in a stem cell from which the tumour cells are ultimately derived. The fact that these syndromes tend to be associated with certain tumours, notably small cell carcinoma of bronchus, and that some tumours give rise to predominantly only one syndrome, favours the second explanation.

Small cell carcinoma of the bronchus is an example of an APUD tumour. This term, derived from amine precursor uptake and decarboxylation, was originally used to describe tumours of neuroectodermal origin sharing similar amine-handling characteristics. In fact, the principal products of most of these tumours are low molecular weight peptides (many of them hormones). However, paraneoplastic endocrine syndromes also occur in association with tumours that do not arise from APUD cells and, apart from their ability to secrete hormones, no single distinctive property has been shown to be common to all non-endocrine tumours associated with these syndromes.

Hormone secretion by tumours does not always cause an endocrine syndrome. This may be because insufficient is secreted to cause a persistently raised plasma concentration (particularly as normal secretion of the hormone may be suppressed) or because the principal secretory product is an inactive precursor of the hormone.

Some tumours associated with aberrant hormone secretion are listed in Figure 18.1. The most frequently encountered paraneoplastic endocrine syndromes are dilutional hyponatraemia, hypercalcaemia and Cushing’s syndrome. Calcitonin secretion is thought to be common, but is clinically silent.

Cushing’s syndrome

Cushing’s syndrome is the condition that results when tissues are exposed to supraphysiological concentrations of glucocorticoids. It is discussed in detail in Chapter 8.

Ectopic secretion of adrenocorticotrophic hormone (ACTH) by non-endocrine tumours is common. Evidence of it has been found in up to 50% of patients with small cell bronchial carcinomas, although massive secretion, giving rise to the typical features as shown by Case history 18.1, is uncommon. ACTH is produced by post-translational modification of the precursor, pro-opiomelanocortin (POMC), and both this precursor and other products of the POMC gene (see p. 121) may be secreted in some cases. Alternative splicing may produce unusual forms of ACTH that are metabolically active but may not be detectable in biochemical assays.

With bronchial carcinomas, the prognosis is usually very poor unless the tumour is suitable for surgical excision. As discussed on p. 145, medical treatment may provide symptomatic relief.

image Case history 18.1

A retired warehouseman presented with muscle weakness and back pain. He had also lost 5 kg in weight in the previous two months and had recently been passing more urine than usual. He had smoked 25–30 cigarettes a day for many years, but had generally enjoyed good health. On examination, in addition to the weakness and signs of weight loss, he was found to have glycosuria and was hypertensive, but his appearance was otherwise normal and no abnormal physical signs were elicited.

Tumour-associated hypercalcaemia

Hypercalcaemia is common in malignant disease. When bony metastases are present, dissolution of calcium from bone by the metastases themselves may contribute to hypercalcaemia. However, there is in general a poor correlation between the extent of metastatic bone involvement and the severity of any hypercalcaemia; also, hypercalcaemia can occur in the absence of detectable metastasis. Although hypercalcaemia can affect renal function adversely and decrease calcium excretion, it should suppress parathyroid hormone secretion by the parathyroid glands. This would be expected to decrease renal tubular calcium reabsorption, and allow excretion of calcium mobilized from bone. However, there is often renal calcium retention owing to the involvement of humoral factors in the hypercalcaemia of malignancy. Parathyroid hormone-related peptide (PTHrP) is most frequently responsible.

Hypercalcaemia is common in haematological malignancies, particularly myeloma, and is due to the release of osteoclast-activating cytokines (e.g. interleukin-1, tumour necrosis factor β (TNFβ)) by the tumours. Osteoclasts may also be activated by prostaglandins produced by tumour metastases in bone, for example metastases from breast carcinoma.

image Case history 18.2

An elderly man presented with loin pain and increasing thirst. Examination of the urine showed haematuria but no glycosuria.

Other metabolic complications of malignant disease

Metabolic complications in patients with malignant disease are not always due to aberrant hormone secretion. They may be due to some other effect of the tumour, or develop as a consequence of treatment.

Renal failure can occur for many possible reasons. Causes include obstruction of the urinary tract, hypercalcaemia, direct infiltration of the kidneys (e.g. by lymphoma), Bence Jones proteinuria (in myeloma), antibiotics, cytotoxic drugs and the tumour lysis syndrome. This latter is the result of massive necrosis of tumour cells during treatment with cytotoxic drugs. Features include hyperkalaemia, hyperuricaemia, hyperphosphataemia and hypocalcaemia. It is particularly likely to occur with large, chemosensitive tumours such as some lymphomas, and with leukaemias, and can cause acute renal failure. Preventive measures include the maintenance of adequate hydration, giving allopurinol to inhibit uric acid synthesis, and careful monitoring of fluid and electrolyte status. Some drugs (e.g. rasburicase) that may be given to promote uric acid breakdown in vivo continue to act in vitro after a specimen of blood is withdrawn and may produce a spuriously low value when the concentration of uric acid is measured.

Hypomagnesaemia (often accompanied by hypokalaemia) is a particular complication of treatment with cytotoxic drugs that affect the proximal renal tubules, such as cisplatin, which is frequently used in ovarian cancer. Massive renal loss of potassium can occur in patients requiring treatment with amphotericin for fungal infections, which can develop as a result of the immunosuppressive effect of some tumours and cytotoxic drugs.

Apr 3, 2019 | Posted by in BIOCHEMISTRY | Comments Off on Metabolic aspects of malignant disease
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