Metabolic Aspects of Malignant Disease - Comprehensive Notes

Metabolic Aspects of Malignant Disease

Objectives

• List common endocrine paraneoplastic syndromes and the associated hormone secretions.

• Describe biochemical abnormalities in hypercalcaemia of malignancy.

• List biochemical abnormalities of ectopic vasopressin secretion.

• List metabolic complications of malignant disease.

• Describe biochemical and clinical features of the carcinoid tumours.

• List the glandular involvement in multiple endocrine neoplasia.

• List common tumour markers employed in the work-up of patients suspected of malignancy.

Introduction

• Paraneoplastic syndromes (PNS) are rare clinical syndromes due to the systemic effects of tumours.

• They are not directly related to the physical presence of the primary tumour.

• They are due to the secretion of peptide hormones or other humoral factors by tumours.

• Early diagnosis improves prognosis and enables monitoring and early detection of recurrence.

Tumours Associated with Hormone Secretion

• Small cell carcinoma of bronchus:

  • ACTH (and precursors): Cushing syndrome

  • Vasopressin: Dilutional hyponatraemia

• Squamous cell carcinoma of bronchus:

  • PTHrP: Hypercalcaemia

• Breast carcinoma:

  • hCG: Gynaecomastia

  • Calcitonin: None

• Carcinoid tumours:

  • ACTH: Cushing syndrome

  • Vasopressin: Dilutional hyponatraemia

• Renal cell carcinoma

  • PTHrP: Hypercalcaemia

• Mesenchymal tumours:

  • Insulin-like growth factors: Hypoglycaemia

Effects of Malignancy

• Directly related to the physical presence of the tumour.

• Systemic manifestations (cachexia and pyrexia).

• Endocrine disturbances.

• Ectopic hormone secretion.

Cachexia and Fever

• Cachexia: Syndrome of generalized weakness and wasting of the body due to severe chronic illness.

  • Due to cytokine release: TNF alpha (tumour necrosis factor alpha).

  • There is alteration in carbohydrate, protein and fat metabolism.

  • TNF-α is responsible for the increase in gluconeogenesis, loss of adipose tissue and proteolysis, while causing decrease in protein, lipid and glycogen synthesis.

  • Deficient food intake, loss of protein, malabsorption.

• Fever is related to interleukins and release of endogenous tissue pyrogens.

Common Endocrine Paraneoplastic Syndromes

• Hypercalcaemia of malignancy.

• Ectopic vasopressin (antidiuretic hormone) secretion.

• Cushing Syndrome.

• Tumour associated Hypoglycaemia.

Hypercalcaemia of Malignancy

• Occurs in up to 10% of all patients with advanced cancer.

• Hypercalcemia is mediated by different mechanisms such as the ectopic production of the parathyroid hormone-related peptide (PTHrP) by tumour cells, local osteolytic hypercalcaemia, and excess of extrarenal vitamin D.

• Patients manifest as generalized weakness, lethargy, nausea, vomiting, altered mental status, bradycardia, acute renal failure, hypertonia, and hypertension.

• Common in squamous cell tumours and small cell lung cancers (SCLC), also tumours including GI-NETs.

• Bony metastases: dissolution of calcium from bone, prostaglandins produced by tumour metastases in bone e.g. breast carcinoma.

• There is often renal calcium retention caused by the involvement of humoural factors. Parathyroid hormone-related peptide (PTHrP) is most frequently responsible.

• Osteoclast activation: osteoclast-activating cytokines (e.g. interleukin-1, tumour necrosis factor β (TNFβ)) by the haematological tumours e.g. myeloma causing localized bone resorption.

• Lymphomas can produce 1,25-dihydroxycholecalciferol leading to increased absorption of calcium from the gut and hypercalcaemia.

Ectopic Antidiuretic Hormone (ADH) Secretion

• Frequently seen in Small cell lung carcinoma (10% to 45% ).

• SIADH is also seen in 2–4% of non-SCLC patients, including those suffering from prostate, breast, adrenal cancer and lung carcinoids.

• Characterized by hypo-osmotic, euvolemic dilutional hyponatremia.

• Clinical manifestations vary from mild symptoms such as nausea, anorexia, fatigue, headache, weakness, and memory difficulties and lethargy to severe symptoms like confusion, seizures, respiratory depression, and coma.

• Laboratory findings are positive for hyponatraemia, decreased serum osmolality, and increased urine osmolality(continued natriuresis, inappropriately concentrated urine).

• 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 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.

HYPONATREMIA

• Serum osmolality Normal (280-295 mOsm/kg):

  • Isotonic hyponatremia

    • Hyperproteinemia

    • Hyperlipidemia (chylomicrons, triglycerides, rarely cholesterol)

• Low (<280 mOsm/kg):

  • Hypotonic hyponatremia

    • Volume status

      • Hypovolemic

        • UNa+ < 10 mEq/L

          • Extrarenal salt loss

            • Dehydration

            • Diarrhea

            • Vomiting

        • UNa+ > 20 mEq/L

          • Renal salt loss

            • Diuretics

            • ACE inhibitors

            • Nephropathies

            • Mineralocorticoid deficiency

            • Cerebral sodium-wasting syndrome

      • Euvolemic

        • SIADH

        • Postoperative hyponatremia

        • Hypothyroidism

        • Psychogenic polydipsia

        • Beer potomania

        • Idiosyncratic drug reaction (thiazide diuretics, ACE inhibitors)

        • Endurance exercise

        • Adrenocorticotropin deficiency

      • Hypervolemic

        • Edematous states

          • Heart failure

          • Liver disease

          • Nephrotic syndrome (rare)

          • Advanced kidney disease

• High (>295 mOsm/kg):

  • Hypertonic hyponatremia

    • Hyperglycemia

    • Mannitol, sorbitol, glycerol, maltose

    • Radiocontrast agents

Cushing Syndrome

• Cushing syndrome is the condition that results when tissues are exposed to supraphysiological concentrations of glucocorticoids.

• Malignancy-associated causes include both adrenal and non-adrenal tumours.

• Ectopic secretion of adrenocorticotrophic hormone (ACTH) by NETs (Neuroendocrine tumours) is common.

• Evidence of it has been found in up to 50% of patients with small cell bronchial carcinomas, although massive secretion, causing the typical features is uncommon.

• Arises from tumor secretion of adrenocorticotropic hormone or corticotropin releasing factor =production and release of cortisol from the adrenal glands.

• Clinically: hypertension, muscle weakness, and generalized oedema, weight gain, centripetal fat distribution

• Patients may present with hypokalaemic metabolic alkalosis, elevated cortisol level and elevated ectopic adrenocorticotropic hormone (ACTH) due to tumor cells

• The diagnosis of ectopic secretion is confirmed by the high-dose dexamethasone suppression test, imaging (CT of the thorax/abdomen/pelvis) and tumour markers.

• Bilateral inferior petrosal sinus sampling may be necessary to definitively exclude a pituitary source.

Tumour-Associated Hypoglycaemia

• It is only rarely due to ectopic insulin secretion by non–β-cell tumours

• It is more often associated with large mesenchymal tumours , such as retroperitoneal sarcoma, and is due to the secretion of insulin-like growth factors (somatomedins) by the tumours.

• Massive infiltration of the liver by solid tumours can impair gluconeogenesis resulting in hypoglycaemia.

Other Paraneoplastic Endocrine Syndromes

• Gynaecomastia may occur in patients with bronchial carcinomas, as a result of secretion of human chorionic gonadotrophin (hCG).

• 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 renal cell carcinomas can cause polycythaemia, but this is not ectopic secretion because the kidneys are the normal source of this hormone.

• Acromegaly from tumoural secretion of growth hormone–releasing hormone

• Severe phosphate wasting leading to tumour-induced osteomalacia is a rare feature of some mesenchymal tumours that secrete fibroblast growth factor 23

Other Metabolic Complications of Malignant Disease

• Acute or chronic kidney disease 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 (TLS).

• 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 commonly used in ovarian cancer

• Massive renal loss of potassium can occur in patients who require treatment with amphotericin for fungal infections, which can develop as a result of the immunosuppressive effect of some tumours and of cytotoxic drugs

Tumour Lysis Syndrome

• 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

• 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 - false negative results

Carcinoid Syndrome

• Gastroenteropancreatic neuroendocrine tumours (GEP-NET) arise from neuroendocrine cells derived from the embryological gut

• They commonly produce hormones and other peptides

• Clinical features typical of excessive secretion

• Around half of GEP-NETs are carcinoid tumours, which are most frequently found in the appendix and ileocaecal region but can also occur elsewhere in the gut, gallbladder, biliary and pancreatic ducts, and in the bronchi

• They are of low-grade malignancy: although they frequently invade local tissue, distant metastases are rare

• Pellagra-like skin lesions caused by nicotinic acid deficiency are an occasional feature of the carcinoid syndrome. The major amine secreted by intestinal carcinoid tumours (derived from embryonic midgut) is serotonin.

• Bronchial carcinoids (derived from foregut) tend to produce 5- hydroxytryptophan because they often lack the decarboxylase enzyme.

• All carcinoid tumours may also produce histamine and kinins, which are important in the symptomatology of the carcinoid syndrome

• Furthermore, the secretion of peptide hormones (e.g. ACTH) is often demonstrable and may contribute to the clinical presentation.

• Syndrome occurs as a result of release of vasoactive amines , such as serotonin, and peptides, such as ACTH, from the tumour into the circulation.

• It is usually seen only with bronchial tumours , which liberate their products directly into the systemic circulation, or when tumours in the gut have metastasized to the liver.

• Serotonin (5-hydroxytryptamine [5HT]) is synthesized from tryptophan, an essential amino acid

• In patients with carcinoid syndrome, 50% of dietary tryptophan (rather than the usual 1%) may be metabolized by this pathway, diverting tryptophan away from protein and nicotinic acid synthesis.

Metabolic Pathway

L-tryptophan
Tryptophan hydroxylase
L-5-Hydroxytryptohan
Aromatic L-amino acid decarboxylase
5-hydroxytryptamine (Serotonin, 5-HT)
Monoamine oxidase
5-hydroxyindole acetaldehyde
Aldehyde dehydrogenase
5-hydroxindole acetic acid (5-HIAA)

Carcinoid Syndrome Diagnosis

• The usual screening test for carcinoid syndrome is measurement of 24 h urine 5- hydroxyindoleacetic acid (5-HIAA, a metabolite of 5-HT)

• Chromogranin A may be a more sensitive (but less specific) marker for the condition

• In patients with suspected bronchial carcinoid, but normal 5-HIAA secretion, measurement of whole blood serotonin may secure the diagnosis.

• Some hormones produced by gastroenteropancreatic neuroendocrine tumours (GEP-NET) and the clinical features associated with their excess secretion.

• About 50% of GEP-NETs are carcinoid tumours. The non-carcinoid types are most commonly found within the pancreas but may occur anywhere along the gastrointestinal tract or, rarely, elsewhere.

• The clinical manifestations depend on the predominant hormone secreted. Many GEP-NETs also produce chromogranins, which can be useful tumour markers.

Multiple Endocrine Neoplasia (MEN)

• They are familial disorders, with an autosomal dominant inheritance, in which tumours (benign or malignant) or hyperplasia develop in two or more endocrine glands.

• MEN 1 is caused by an inactivating mutation of the MEN1 tumour suppressor gene: genetic studies can help to identify affected family members, who require yearly screening.

• MEN 2 is caused by an activating germline mutation in the RET proto-oncogene: family members should be screened for the mutation and, if affected, should be offered prophylactic surgery e.g. thyroidectomy to prevent the development of medullary cell carcinoma.

• Although rare, it should always be considered in young people presenting with hyperparathyroidism or other associated endocrine disorders.

Glands Affected in Multiple Endocrine Neoplasia

• MEN Type 1:

  • parathyroids

  • pancreatic islets

  • anterior pituitary

• MEN Type 2a

  • thyroid (medullary cell carcinoma)

  • adrenal medulla (phaeochromocytoma)

  • parathyroids

• MEN Type 2b

  • thyroid (medullary cell carcinoma)

  • adrenal medulla (phaeochromocytoma)

  • parathyroids (rarely)

  • various somatic abnormalities:

    • Marfanoid habitus

    • mucosal neuromata

    • pigmentation

    • café-au-lait spots

Tumour Markers

• The concentrations of many tumour markers are raised in a variety of cancers and can be raised in benign conditions

• Normal plasma concentrations do not exclude cancer

• The most appropriate use of most tumour markers is for serial monitoring of patients after treatment, although even this is dependent on whether further treatment is available for an individual patient

Ideal Tumour Marker

• An ideal secreted tumour marker could be used for:

  • screening

  • diagnosis

  • prognosis

  • treatment monitoring

  • follow-up to detect recurrence

α-Fetoprotein (AFP)

• A glycoprotein of molecular mass 67 kDa

• It is synthesized by the yolk sac and the fetal liver and gut

• In the foetus it is a major plasma protein, but concentrations fall rapidly within the first few months after birth

• Increased plasma concentrations of AFP are seen in normal pregnancy due to transfer into the maternal circulation (prenatal diagnosis of Down syndrome)

• AFP is a valuable marker for hepatocellular carcinomas (HCCs) and testicular germ cell tumours

• AFP concentrations are elevated in the majority of patients with cirrhosis and HCC

• AFP lacks specificity: can occur in cirrhosis in the absence of malignancy.

• AFP does not appear to be of value prognostically

• In histologically confirmed liver cancer, serial measurements are valuable in monitoring treatment response

• The normal hepatic regeneration that occurs after partial hepatic resection may cause a transient increase in AFP

• In patients with non-seminomatous germ cell tumours (NSGCTs) of the testes, AFP measurements are valuable in assessing prognosis, in staging and in monitoring therapy

• A very high concentration indicates a massive tumour load and a poor prognosis

• A rapid fall to normal after orchidectomy implies that the disease was limited to the testis

• Remission is achieved in 80% of patients with metastatic NSGCT, using a combination of surgery and chemotherapy

• The efficacy of treatment can be assessed from the decline in plasma AFP concentration, which reflects the decrease in tumour mass

• Remission: repeated measurements are essential

• A rise in concentration : recurrence of the tumour

• A rise in concentration, even if within “normal range”, should raise the suspicion of tumour recurrence

• Tumours may lose the ability to secrete AFP, so clinical assessment remains an important

• Around 30% of all testicular tumours are NSGCTs

• More common are seminomas (40%): these do not secrete AFP, although some secrete hCG

Carcinoembryonic Antigen (CEA)

• Present in elevated concentrations in the plasma of 50% of patients with colorectal cancer (>80% if hepatic metastasis present)

• Concentrations may be raised in other malignancies, including pancreatic, breast and lung tumours, as well as in a variety of non-malignant conditions, including liver disease of various types, pancreatitis and inflammatory bowel disease , and in some people who smoke heavily.

• CEA is neither sufficiently specific nor sensitive to be used in screening for colorectal carcinoma

• CEA concentrations in plasma correlate poorly with tumour bulk, which limits the usefulness of measurements in monitoring treatment

• After surgical resection of a tumour, plasma CEA concentration can be expected to fall.

• However, although a subsequent rise suggests a recurrence, recurrence is not always heralded by a rise, because tumours may lose the ability to secrete CEA.

Carbohydrate Antigen Markers

• High-molecular-weight glycoproteins

• Better for monitoring rather than for screening or diagnosis (not tumour specific)

• An exception is CA125 , a protein marker for ovarian cancer.

• A normal concentration of CA125 does not exclude ovarian cancer

• Increased concentrations can be found in benign conditions (e.g. endometriosis), in ascites and in non-ovarian malignancies, especially those that affect the pleura or peritoneum.

• Serial measurements are valuable in monitoring patients after surgical resection of a tumour.

• An inadequate fall in concentration during chemotherapy suggests treatment failure

• Treatment response monitoring:
  CA19-9 for adenocarcinoma of pancreas and possibly colorectal and gastric carcinomas

• Plasma CA19-9 concentrations are elevated in >80% of patients with carcinoma of the exocrine pancreas, but only occasionally in benign disease.

• Potential value of CA19-9 is reduced by the fact that pancreatic cancer tends to present late and that 5–10% of the population does not express the antigen.

• CA15-3 for breast carcinoma

Paraproteins

• Detectable in either serum or urine in 98–99% of patients with myeloma.

• Valuable in the diagnosis of this condition

• Concentrations correlate well with tumour bulk

• A good indicator of the efficacy of treatment.

Prostate –Specific Antigen (PSA)

• A 33-kDa glycoprotein serine protease, which is normally secreted into the prostatic duct system, although small amounts diffuse into the plasma

• Plasma concentrations increase with both benign and malignant prostatic disease limiting its usefulness for diagnosis.

• The likelihood of cancer increases significantly at concentrations of >10 μg/L

• Newer approaches include: the development of age-related reference ranges, determining the rate of change of concentration with time (PSA velocity) and measuring free and bound PSA.

Hormones as Tumour Markers

• The measurement, for example, of catecholamines and metanephrines in phaeochromocytomas and of metabolites of serotonin in the diagnosis of carcinoid syndrome is discussed elsewhere .

• Calcitonin is a valuable marker, particularly for medullary cell carcinoma of the thyroid (eutopic secretion) and occasionally in carcinoma of the breast (ectopic secretion).

• Although basal plasma concentrations of calcitonin may occasionally be normal in affected patients, an excessive rise after provocation with intravenous calcium or pentagastrin is typical in patients with medullary carcinoma.

• The doubling time of plasma calcitonin concentrations after treatment is helpful to predict prognosis

Human Chorionic Gonadotrophin (hCG)

• hCG is a hormone produced by the normal placenta

• May also indicate the presence of abnormal trophoblastic tissue or a tumour secreting the hormone ectopically

• Assays for hCG as a tumour marker should measure both intact hCG and its free β-subunit (total β-hCG), because some tumours (e.g. seminomas) may produce a significant proportion β-hCG

• hCG is also secreted by ∼50% of testicular NSGCTs and should be measured together with AFP in the follow-up of patients after treatment of the tumour.

• hCG is an almost ideal tumour marker for choriocarcinoma , a malignant proliferation of chorionic villi that may develop from a hydatidiform mole, potentially malignant proliferation of placental tissue

• hCG is an extremely sensitive tumour marker

• All patients who have had hydatidiform moles must be followed up with regular checks of serum and urine hCG concentrations (monitoring)

• It can be used as an indicator of the response to treatment and in long- term follow-up thereafter.

Enzymes as Tumour Markers

• Tumour related effect of the tumour :secretion of an enzyme by the tumour.

• Alkaline phosphatase has several isoenzymes, and an increase in the plasma activity of the placental type occurs in many patients with testicular seminomas

• Lactate dehydrogenase is used as an additional marker in the monitoring of patients with some lymphomas, leukaemias and testicular tumours and reflects tumour bulk.

• Neuron-specific enolase (NSE) is an isoenzyme of enolase present in nerve and neuroendocrine cells. (Small cell carcinomas of bronchus). Raised NSE concentrations may also indicate metastatic spread of malignant melanomas of skin or ocular origin.

Other Tumour Markers

• Thyroglobulin is a sensitive marker of disease recurrence in patients with follicular or papillary thyroid cancer who are taking suppressive doses of thyroxine

• Faecal occult blood analysis : Faecal immunochemical tests

• New tumour markers are continually being developed :
  S-100 for melanoma, CA50 for gastrointestinal cancers, and cytokeratin fragments (CYFRA) 21-1 and squamous cell carcinoma antigen in bronchial carcinoma.

• The measurement of tumour-specific messenger RNA or DNA in plasma, urine or faeces may become a useful tool in the management of cancers in the future.

Summary of Tumour Markers

Conclusion

• Laboratory investigations should include a FBC with an electrolyte and metabolic panel, urinalysis, tumour markers

• Paraprotein analysis with serum and urine protein electrophoresis