CHAPTER OUTLINE

Tumours may exert metabolic effects on the host via a wide range of mechanisms. Some of the metabolic derangements related to tumours are directly related to a hormone or other substance that the tumour secretes. Such hormone secretion can be appropriate to the cell line from which the tumour originates or may be inappropriate or ‘ectopic’. In the last decade, molecular genetic techniques have helped characterize tumours and explain how neoplastic tissues can secrete hormones that are not typically associated with them. Metabolic derangements can also arise non-specifically, in the absence of hormone secretion or immunological phenomena, for example owing to tumour burden compromising host metabolism or the effects on the host of rapid cell turnover. Autoimmune reactions evoked by tumour antigens may also give rise to systemic effects and are increasingly being implicated in the causation of various tumour-related or paraneoplastic, syndromes. The recognition and characterization of the antibodies to shared tumour and host antigens that play a prominent role in paraneoplastic syndromes have advanced their use in both diagnosis and treatment.

Scientific advances have rapidly opened up new possibilities for the management of tumours, even in their advanced stages, where formerly only observation and palliation was possible. Clinical biochemistry has a key role in both diagnosis and monitoring treatment.

Neuroendocrine cells can be identified by their production of a neurotransmitter, neuromodulator or neuropeptide hormone. Neuroendocrine tumours (NETs) are distinguished by their ability to secrete peptides causing characteristic endocrine syndromes. The gastroenteropancreatic system has diffuse neuroendocrine components and NETs most commonly arise from these tissues, more than 50% being carcinoid tumours.

Carcinoids are NETs that arise from enterochromaffin cells, principally in the intestine (~ 80% in the ileum), the main bronchi and, rarely, other tissues including the ovaries, thymus, pancreas and thyroid. Carcinoid tumours all show a similar pattern of neuroendocrine expression and may contain or secrete amines, peptides or prostaglandins. The carcinoid syndrome is the clinical result of systemic release of these substances, particularly serotonin.

The normal excretion of 5-HIAA is < 50 μmol/24 h. In patients with typical carcinoids, 99% of metabolized 5HT and 5HTP are excreted as 5HIAA. Urinary 5HIAA excretion is typically in the range 150–1500 μmol/24 h, generally exceeds 500 μmol/24 h and occasionally is as high as 3000 μmol/24 h. Carcinoid tumours of the colon and rectum do not contain the hydroxylase or decarboxylase enzymes and so do not form 5HTP or 5HT. A small number of patients have ‘atypical’ tumours. These patients excrete large amounts of 5HTP and 5HT in their urine. It is believed that these tumours, usually bronchial, are deficient in dopa decarboxylase and cannot convert 5HTP to 5HT so that the former is secreted into the bloodstream. Some of the 5HTP is converted to 5HT and subsequently to 5HIAA in extrarenal sites; some is decarboxylated in the kidneys and excreted into the urine as 5HT, and some escapes decarboxylation and is excreted directly into the urine. Thus, patients with atypical carcinoid tumours have a marked increase in 5HTP and 5HT excretion and only a moderate increase in 5HIAA excretion.

Even in those patients whose tumours produce predominantly 5HTP, urinary 5HIAA constitutes 50–60% of total urinary 5-hydroxyindoles and increased values are found in almost all patients.

Chromogranin A (CgA) is a 48 kDa protein distributed in dense core granules of neuroendocrine cells, the highest plasma concentrations being found in patients with carcinoid tumours. It has been reported to have a sensitivity of 75–85% and a specificity of 84–95% in the diagnosis of carcinoid syndrome. It is not dependent upon serotonin secretion and is therefore particularly useful in patients with non-secretory or atypical carcinoids and as its concentration reflects tumour burden, it can be used as a marker for assessing response to treatment. False positive results can be seen in hepatic and renal failure, atrophic gastritis, proton pump inhibitor therapy, and inflammatory bowel disease. Prostatic cancers, which may contain a significant neuroendocrine component, myeloma, exercise, trauma and hypertension may also increase CgA concentrations.

In isolated carcinoid tumours, where surgical excision is a management option, anatomical localization may be useful. Conventional imaging modalities include computed tomography (CT), magnetic resonance imaging (MRI) and positron emission spectroscopy (PET). A more specific option is the use of somatostatin receptor scintography, e.g. using ¹¹¹In-DTPA-pentetreotide (Octreoscan™), which binds to somatostatin receptors on the tumour.

Circumscribed tumours may be removable by surgical resection. For patients with significant hepatic metastatic disease, radiofrequency ablation or hepatic embolization, alone or in combination with intra-arterial chemotherapy (chemoembolization), while not curative, may provide significant palliation. Somatostatin analogues have been used effectively in the management of the symptoms of carcinoid syndrome.

Two distinct genetic defects contribute to tumourigenesis in MEN syndromes: in MEN1, inactivation (loss of function) of a tumour suppressor gene is thought to be responsible, while MEN2 is caused by overactivation (gain of function or overexpression) of a proto-oncogene. A tumour suppressor gene restrains cell proliferation and tumours are stimulated by inactivating mutations or deletions in such a gene, which render the gene product either absent or nonfunctional. In contrast, a proto-oncogene (the normal unmutated version of an oncogene) can be converted to an oncogene, which can cause cell proliferations or deregulated cell growth when overexpressed.

Multiple endocrine neoplasia type 1 (MEN1) typically becomes manifest after the first decade of life, with most men and women developing symptoms in the fourth and third decades, respectively. Typically, MEN1 tumours appear two decades earlier than isolated endocrine tumours.

Gastroenteropancreatic (GEP) neuroendocrine tumours are the second most common tumours in MEN1, with some 60% of patients being affected. They usually present between the second and fifth decades, unless diagnosed earlier by screening. Approximately half of the tumours are gastrinomas. The Zollinger–Ellison syndrome (ZES) is severe, intractable, multiple and recurrent peptic ulcer disease caused by a gastrin secreting tumour, which can be located in the duodenum or pancreas. The majority of gastrinomas associated with MEN1 are in the duodenum, where they are often small (< 0.5 cm in diameter) and multiple. Since gastrin secreting cells are not normally found in the duodenum or pancreas, gastrinomas in these sites should be regarded as ectopic and potentially malignant, irrespective of their histological grade. The clinical syndrome does not differ from that seen with non-MEN1 gastrinomas. The extreme hypersecretion of gastric acid may be associated with inactivation of pancreatic lipase, resulting in fat malabsorption and steatorrhoea. Hyperparathyroidism in MEN1 can exacerbate hypergastrinaemia. The diagnosis can be made by demonstrating increased gastric acid secretion with simultaneously elevated plasma gastrin concentrations. Secretin infusion (2 U/kg) may cause augmented gastrin production in those patients whose basal values are equivocal. Excellent treatments are now available for the medical management of peptic ulcer disease using histamine H₂ receptor antagonists or proton pump inhibitors.

The true prevalence of anterior pituitary tumours in MEN1 is unclear. Between 30% and 50% of patients with MEN1 develop anterior pituitary tumours. Whilst some are non-functional, approximately 60% secrete prolactin, 25% secrete growth hormone and 5% secrete ACTH. Occasionally, excess secretion of GH and cortisol in MEN1 is the result of ectopic secretion of GHRH and ACTH, respectively, e.g. by a pancreatic islet or carcinoid tumour. It is important to identify such patients in order to ensure appropriate therapy.

Carcinoid tumours occur more frequently with MEN1 than in the general population; some 10% of MEN1 patients are affected. In contrast to sporadic carcinoid tumours, which are predominantly derived from the midgut and hindgut, MEN1 carcinoid tumours are usually derived primarily from the foregut. Foregut carcinoids rarely secrete serotonin, peptide hormones or calcitonin and are usually considered as clinically non-functional.

Adrenal cortical lesions are common in MEN1: 20–40% of patients are affected, mostly with bilateral tumours. However, the majority are non-functional, clinically silent and rarely require treatment. Cushing and Conn syndromes are rare in MEN1.

MEN1 is the result of an inactivating mutation in the MEN-1 gene, a tumour suppressor gene located on chromosome 11q13. It consists of 10 exons and encodes a 610-amino acid nuclear protein termed menin. Menin interacts with diverse groups of transcription factors and coregulators, including JunD, suggesting a role in gene transcription, DNA replication and cell cycle control. Genetic mapping studies indicate somatic loss of heterozygosity in accord with the ‘two hit’ hypothesis. The first hit is a genetic mutation rendering the subject heterozygous for the MEN-1