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.
Figure 18.1 Some non-endocrine tumours frequently associated with aberrant hormone secretion. Renal adenocarcinomas may also secrete erythropoietin, causing polycythaemia, but this is not ectopic secretion because this hormone is a normal product of the kidney. ACTH, adrenocorticotrophic hormone; ADH, antidiuretic hormone; hCG, human chorionic gonadotrophin; PTHrP, parathyroid hormone-related peptide. aCarcinoid tumours also secrete vasoactive amines (see p. 303).
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.
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.
|Serum: sodium||144 mmol/L|
|Blood: glucose||10.2 mmol/L|
|Plasma (0900 h): cortisol||1520 nmol/L|
|ACTH||460 ng/L (normal <80 ng/L)|
|High-dose dexamethasone suppression test: 09:00 h plasma cortisol after dexamethasone 2 mg, 4 times daily for 2 days||1500 nmol/L|
A discrete mass was present in the left lower zone on chest radiography.
The greatly elevated plasma cortisol and adrenocorticotrophic hormone (ACTH) concentrations are typical of ectopic ACTH secretion. Plasma ACTH concentrations are generally much higher than those seen in Cushing’s disease, except when a carcinoid or thymic tumour is responsible. As ACTH secretion is not under normal feedback control, the hypercortisolaemia is not suppressed by dexamethasone.
With ectopic ACTH secretion, the clinical presentation is typically dominated by the metabolic sequelae of excessive cortisol secretion, as in this case. These include hypokalaemia with alkalosis, which exacerbates the physical weakness due to steroid-induced myopathy, glucose intolerance, sometimes sufficient to cause frank diabetes, and hypertension. Osteoporosis predisposes to crush fractures of the vertebrae, and the presence of secondary tumour deposits may also give rise to back pain. The classic somatic manifestations of Cushing’s syndrome are often absent, a reflection of the very rapid progression of the condition in most cases. ACTH-secreting carcinoid and thymic tumours are an exception: the clinical syndrome in these cases may closely resemble Cushing’s disease, even to the extent that ACTH secretion, and hence that of cortisol, is suppressible by dexamethasone.
Ectopic antidiuretic hormone (ADH) secretion
A case of this syndrome is described in Case history 2.3. The secretion of ADH (vasopressin) by the tumour is uncontrolled and thus likely to be greater than the body’s normal requirements, resulting in water retention with dilutional hyponatraemia. When this is mild and develops slowly, it is often asymptomatic. However, severe hyponatraemia is associated with water intoxication, which can be fatal. The clinical features (drowsiness, confusion, fits and coma) may mimic those of cerebral metastases. Ectopic ADH secretion is most commonly seen with small cell carcinomas of the bronchus, but other tumours may be responsible (e.g. carcinoid tumours, breast cancer and pancreatic adenocarcinomas). A similar syndrome results from the inappropriate secretion of ADH that can occur in a variety of non-malignant diseases (see p. 27).
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.
Case history 18.2
An elderly man presented with loin pain and increasing thirst. Examination of the urine showed haematuria but no glycosuria.
|Serum: calcium (corrected)||3.2 mmol/L|
|alkaline phosphatase||80 U/L|
|parathyroid hormone||below detection limit of the assay|
Imaging showed an irregularly enlarged left kidney with a distorted pelvicaliceal system. Arteriography demonstrated an abnormal circulation in the left kidney, strongly suggestive of a tumour. Skeletal survey and isotopic bone scan showed no evidence of metastatic disease and a chest radiograph was normal.
At operation, a tumour was found in the upper part of the left kidney. The patient underwent nephrectomy and made an uneventful recovery. Following the operation, his plasma calcium concentration decreased and subsequently remained normal.
The combination of hypercalcaemia and hypophosphataemia is compatible with excessive parathyroid hormone (PTH) secretion, although the plasma phosphate may be normal or even raised if there is renal impairment. The absence of detectable PTH suggests that secretion of the hormone by the parathyroid glands is suppressed, as would be expected were the hypercalcaemia to be due to some agent other than PTH. True ectopic secretion of PTH is very rare. In most cases, hypercalcaemia of malignancy is due to the secretion of PTHrP by tumours. This substance, which has some N-terminal amino acid sequence homology with PTH, binds to PTH receptors and has similar actions to PTH itself, but is not detected in most assays for PTH.
This condition is discussed in detail in Chapter 11. It is only rarely due to ectopic insulin secretion by non-β-cell tumours. Tumour-associated hypoglycaemia is usually associated with large mesenchymal tumours, such as retroperitoneal sarcoma, and is often due to the secretion of insulin-like growth factors (somatomedins) by the tumours.
Other paraneoplastic endocrine syndromes
Gynaecomastia may occur in patients with bronchial carcinomas, as a result of secretion of human chorionic gonadotrophin (hCG). Precocious puberty may develop in male children with hepatic tumours secreting hCG, but this is very rare. Secretion of erythropoietin is responsible for the polycythaemia that can occur in association with uterine fibromyomata and the rare tumour, cerebellar haemangioblastoma. Secretion of erythropoietin by adenocarcinomas of the kidney can cause polycythaemia, but this is not ectopic secretion because the kidneys are the normal source of this hormone. Some cases of acromegaly have been shown to be due to tumoral secretion of growth hormone-releasing hormone (GHRH, see pp. 117 and 128).
Paraneoplastic syndromes are common, but it must be remembered that an endocrine syndrome in a patient with a tumour may be due to coexistent endocrine disease and not necessarily to the secretion of a hormone or other factor by the tumour. There are also several non-endocrine paraneoplastic syndromes. Some of these may be immunologically mediated (e.g. the Lambert–Eaton syndrome, see p. 271), but the cause of others (e.g. paraneoplastic cerebellar syndrome) is uncertain.
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.