Carcinoid tumour, though relatively rare, can provide the anaesthetist with a challenging task perioperatively. This review will outline carcinoid tumour and syndrome, its prevalence, pathophysiology, clinical features and management followed by an overview of anaesthetic implications and evidence for management during the perioperative period.
Carcinoid tumours are derived from enterochromaffin or Kulchitsky cells. They can be found in any tissue originating from endoderm, including the gastrointestinal tract, bronchi and genitourinary tract, though the gastrointestinal tract is by far the commonest site (1).
Carcinoid syndrome is defined as a constellation of symptoms mediated by various vasoactive substances released by the carcinoid tumour and characterised by intermittent episodes of flushing, diarrhoea, rhinorrhoea and lacrimation (2).
Carcinoid tumour is the most common gastrointestinal neuroendocrine tumour. Moreover, its incidence is much greater than previously recognised. Post mortem studies have identified carcinoid tumours incidentally in up to 8% (1). The incidence rates derived from a series of 13,715 carcinoids, has been reported to be 2.47 and 2.58 per 100,000 per year in Caucasian men and women over the decade 1990 to 1999, while they were marginally higher for black men and women (4.48 and 3.98 per 100,000 population per year) (3).
No clear risk factors have been identified to date, however there is a suggestion that the risk is increased in association with a family history of carcinoid tumour in a first-degree relative, a well educated social background and birth in a large city. This was derived by regression analysis of a Swedish database that included 5,184 patients with carcinoid tumours (4). Furthermore, the higher incidence seen in certain racial groups together with the increased risk associated with a family history may well be indicative of a genetic component to their development.
As stated previously, the gastrointestinal tract and the bronchopulmonary system are the predominant locations for the primary carcinoid tumour. Within the gastrointestinal tract, the locations in descending order of frequency are ileum, rectum, appendix, colon and stomach (2).
Carcinoid tumours are traditionally classified according to their embryonic site of origin as follows:
They can be sub classified according to histological characteristics as ‘typical’ and ‘atypical’. Typical tumours are well differentiated and have small regular cells with rounded nuclei. In contrast, atypical tumours exhibit greater nuclear atypia, more mitotic activity and show areas of necrosis (5). The difference between benign and malignant carcinoid tumour is based upon presence or absence of metastases rather than histology alone. Size and site of the primary tumour best predicts its metastatic potential (see table 1) (6).
Table 1: Incidence of metastases related to the size of the primary carcinoid tumour. (J. Surg Oncol 2005;89:151).
Carcinoid tumours contain neurosecretory granules composed of a large variety of vasoactive mediators that are released into the circulation. These mediators are ultimately responsible for the symptoms and signs exhibited when carcinoid syndrome occurs. As many as 40 different vasoactive products have been identified in carcinoid tumours (7). The most well known ones include serotonin, histamine, tachykinins, kallikrein and prostaglandins. The exact mechanisms by which these mediators produce the features of carcinoid syndrome are yet to be unravelled.
Table 2: Products of carcinoid tumours.
Most patients with carcinoid tumours are asymptomatic, their disease being diagnosed incidentally at surgery, endoscopy or autopsy. If symptoms are present, they are usually vague and nonspecific or related to effects of the tumour at its location. This vague symptomatology partly explains the long lag between symptom onset and diagnosis in many cases (8).
Carcinoid syndrome itself is infrequent, occurring in approximately 10% of patients with carcinoid tumour in general (2). This infrequency is mainly explained by the fact that the vasoactive mediators released by carcinoid tumours must gain access to the systemic circulation in order to produce symptoms. Because the liver inactivates the bioactive products as they pass through, carcinoid syndrome only occurs in the presence of liver metastases or a primary carcinoid tumour whose venous drainage is not via the portal vein (1, 7), as is the case in primary bronchial or ovarian carcinoid.
Carcinoid syndrome is typically intermittent. Episodes can be associated with exercise, alcohol, emotional events, stress and ingestion of tyramine rich food (such as chocolate). They are characterised by flushing, diarrhoea, rhinorrhoea, lacrimation and bronchospasm. A carcinoid crisis is an extreme form of the syndrome with haemodynamic instability, tachycardia, severe flushing and bronchospasm (2). These crises can be triggered by surgical, radiological and anaesthetic interventions.
Up to two thirds of patients with carcinoid syndrome exhibit symptoms and signs of right-sided heart disease. These may range from valvular heart lesions to right sided heart failure. Left-sided heart disease is very uncommon, usually only occurring in the presence of bronchial carcinoid or a right to left shunt (7, 1, 11).
Characteristics of carcinoid tumour vary according to their site. Foregut tumours predominantly encompass those of the stomach and the lung. There are three distinct types of gastric carcinoid tumours with different biologic behaviour and prognoses. Type 1 accounts for 70-80% of all gastric carcinoids (9, 10). This type is associated with chronic atrophic gastritis and often with pernicious anaemia (9). They tend to consist of small, multiple lesions, are commoner among women and usually diagnosed in the 7th or 8th decade (9). Metastases occur in fewer than 10% of tumours less than 2 cm in size. Type 2 accounts for 5% of gastric carcinoids. It occurs in association with gastrinomas (Zollinger-Ellison syndrome) or multiple endocrine neoplasia (MEN) type 1. Finally, type 3 accounts for 20% of gastric carcinoids. They are called ‘sporadic’ as they occur in the absence of atrophic gastritis or the Zollinger-Ellison and MEN1 syndromes and are the most aggressive type. In contrast to the former two types who are more likely to produce serotonin, type 3 gastric carcinoids often produce 5-hydroxytryptophan.
Bronchial carcinoids are one of several types of pulmonary neuroendocrine tumours. They account for only 2% of all primary lung tumours (2). Bronchial carcinoids tend to present in a similar way to other lung tumours with recurrent pneumonia, cough and haemoptysis. They may occasionally secrete ACTH or GH. Their prognosis is much better than with other lung tumours, with reports of survival rates of 92% at ten years (1).
Midgut tumours include those of the small intestine and appendix. Small intestinal carcinoid tumours account for around one third of small intestinal neoplasms (12). They arise from intraepithelial endocrine cells as opposed to appendiceal carcinoids that arise from subepithelial endocrine cells (5). The most common location is in the ileum within 60cm of the ileocecal valve (3). Unfortunately, these tumours are frequently malignant and diagnosed late (7th or 8th decade). They typically present with vague abdominal pain and have metastasized at diagnosis. Multiple tumours may be present in up to 30% of patients.
Carcinoid tumour is an incidental finding at appendicectomy in 1 in 300 cases (13). They are commoner among women and tend to be diagnosed in the 4th or 5th decade. The majority arise from the distal one third of the appendix, therefore only few cause obstructive symptoms. The size of the tumour is a good prognostic predictor (cf. table 1), with metastases being unusual in tumours up to 2cm. Occasionally, total resection is impossible but surgical debulking and radiofrequency ablation will reduce systemic effects of carcinoid and delay progression of the disease.
Hindgut tumours are commonly nonsecretory and present with symptoms similar to bowel adenocarcinoma, such as a change in bowel habit, obstruction and bleeding per rectum. Hindgut tumours include carcinoid tumours of the colon, rectum and rarely the genitourinary tract.
Colon carcinoid tumour typically presents in the 8th decade of life (14). Features of carcinoid syndrome are rare as the majority are nonsecretory. Metastases are present in two thirds of patients at presentation due to late diagnosis. The prognosis depends on patient’s age, tumour size, depth of invasion, lymph node involvement and presence of distant metastasis (15).
Rectal carcinoid tumours are found incidentally predominantly in the 7th decade of life. Again the size of the tumour correlates with likelihood of metastases.
Carcinoid tumours do arise from the genitourinary system. The ovary is interesting as, like bronchial carcinoids, they can produce the carcinoid syndrome without hepatic metastases due to their direct drainage into the inferior vena cava.
As stated previously, carcinoid tumours are frequently an incidental finding. If carcinoid tumours are suspected the following tests should be performed (2):
Management of patients with proven carcinoid tumour includes localisation of the tumour and possible metastases by CT scan and somatostatin receptor scintigraphy. In the absence of metastatic disease, the primary carcinoid tumour is surgically resected if possible. In the presence of metastatic disease or unresectable primary tumour, the symptoms are medically managed with or without surgical debulking of the tumour.
Patients with carcinoid disease present to the anaesthetist in a number of different ways: they may undergo surgical resection of the primary with or without resection of any liver metastases or cardiac surgery for carcinoid heart disease or surgery unrelated to their carcinoid.
The main concerns for the anaesthetist include carcinoid crises with severe haemodynamic instability and bronchospasm, carcinoid heart disease and an exaggerated or unpredictable response to vasoconstrictors. Considerations should therefore include prevention of mediator release, avoidance of triggering factors and preparation for the management of perioperative carcinoid crises (18, 19).
As pointed out before, carcinoid tumours are associated with a wide spectrum of symptomatology, ranging from mild, vague symptoms to full-blown carcinoid syndrome. It is worth emphasizing that even patients with minimal symptomatology may experience life threatening carcinoid crises intraoperatively (2).
General anaesthesia in patients with carcinoid tumour thus requires thorough planning preoperatively, including close collaboration between anaesthetist, surgeon and intensivist; meticulous intraoperative management and postoperative monitoring in a high dependency unit (1, 2).
1. History & examination.
In addition to the usual anaesthetic history, it is essential to elicit symptoms and signs of anaemia, malnutrition or electrolyte imbalance (1, 2, 19). Furthermore, a thorough cardiovascular history and examination must be taken to identify any carcinoid heart disease, looking for signs and/or symptoms of right ventricular or biventricular failure or valvular heart disease. Coronary spasm may occur due to the effects of vasoactive mediator release; therefore it is important to enquire about chest pain and their association with episodes of carcinoid syndrome.
As for any major surgical case these should include baseline bloods and a 12 lead ECG. Blood tests consist of a full blood count to detect anaemia or widespread marrow infiltration; urea, electrolytes and creatinine to detect electrolyte abnormalities possibly associated with malnutrition, dehydration and diarrhoea; liver profile, especially in the presence of liver metastases; coagulation profile, which is unlikely to be abnormal unless a significant derangement of liver function tests is present and finally, blood glucose which may be high associated with mediator release. A group and hold and/or crossmatch should be performed depending on the type of surgery.
On the 12 lead ECG one should aim to identify signs of ischaemia or right sided heart disease.
A chest x-ray is not warranted as any information gained from the chest x-ray should have been identified from the preoperative CT and/or somatostatin receptor scintigraphy as part of the work up for patients with carcinoid tumours.
In addition to these basic investigations, it is worthwhile repeating a urinary 5-HIAA test as it is a good biological marker of carcinoid tumour activity and a high value is predictive of increased likelihood of perioperative morbidity (20). An echocardiogram must be performed in all patients who exhibit symptoms of carcinoid syndrome as up to two thirds of patients with carcinoid syndrome have carcinoid cardiac disease (1, 2, 21, 22). Where carcinoid valvular heart disease is detected, the cardiothoracics team should be consulted with a view to assessing the need to address the valvular lesion(s) prior to any abdominal disease. Much carcinoid surgery involves removal of liver metastases. Therefore, the detection on echo of significant right-sided heart disease with high right-sided pressures may preclude resection of liver metastases due to the massive blood loss that would ensue.
Octreotide has revolutionised perioperative management of patients with carcinoid tumour &/or syndrome. It has been shown to improve the perioperative course of patients with carcinoid (20). Prior to the discovery of octreotide, drugs that inhibit serotonin synthesis (methyldopa), prevent serotonin release (phenoxybenzamine) and antagonise serotonin receptors (methysergide, ketanserin, and cyproheptadine) were used with varying efficacy (1, 19). The pharmacological action of octreotide is similar to the natural hormone, somatostatin, however, it is more potent at inhibiting growth hormone, glucagon and insulin. Octreotide also inhibits the LH response to GnRH, reduces splanchnic blood flow, and inhibits release of serotonin, gastrin, VIP, secretin, motilin and pancreatic polypeptide. Peak plasma concentrations occur 30-60 minutes after subcutaneous administration and 4 minutes after intravenous administration (19).
Octreotide’s side effect profile includes QT prolongation, bradycardia, conduction defects, nausea and vomiting, abdominal cramping, hyperglycaemia and rarely thrombocytopenia (1, 2).
Preoperative management must include the administration of octreotide. Past recommendations included the preoperative administration of 100micrograms octreotide subcutaneously and another 100 micrograms intravenously just prior to induction (1, 19). More recent recommendations are to commence an octreotide intravenous infusion at 50mcg/hour at least 12 hours prior to surgery (2, 17). This should occur even if patients lack symptoms or exhibit symptomatic control, as the stimulus for mediator release during surgery and anaesthesia is much higher than in everyday life (2). Anaesthetic factors (response to intubation, inadequate analgesia and use of drugs that release histamine), surgical stimuli or any haemodynamic variation may all prompt uncontrolled hormone release causing hypo- or hypertensive crises and difficulty ventilating/oxygenating lungs due to bronchospasm. This is not dissimilar to an anaphylactic crisis, however it does not respond to conventional inotrope and pressor therapy.
As mentioned previously, the main aims are to be prepared for managing a perioperative carcinoid crisis and to provide stable haemodynamics by avoidance of triggering factor for mediator release. Most likely this will be by using the anaesthetic technique the individual anaesthetist is most comfortable with provided risks of each technique are born in mind.
1. Lines and monitoring.
Large bore intravenous access is imperative in case of rapid volume loss. Central venous access should be established for liver resections and/or in patients with difficult intravenous access or if warranted by patient’s other comorbidities. As with any long case, temperature control is important, therefore, a fluid warmer, mattress warmer, convection blanket and temperature probe should all be used. As standard with any anaesthetic, continuous monitoring of SpO2 should be in place throughout the case as per ANZCA guidelines (23). Generally, a 3-lead ECG should suffice, however, a 5-lead ECG should be available and used if there is any history of ischaemic heart disease or chest pain associated with vasoactive mediator release (23).
An arterial line for measuring invasive blood pressures must be in use for all cases as haemodynamic changes may occur very quickly and need a prompt response (1, 2, 19). It will also allow for serial arterial blood gases both intraoperatively and postoperatively to monitor haemoglobin, sugar and electrolytes and acid base status.
Transoesophageal echo, pulmonary artery catheter is recommended if there is any evidence of cardiac carcinoid involvement and may be useful to guide fluid therapy (1, 2, 19).
It is also vital to monitor patient’s fluid status, as this may give a clue to correct management of intraoperative hypotension.
2. Induction and maintenance.
Preoperative anxiolysis is recommended with a benzodiazepine to avoid anxiety induced mediator release. A stable induction with adequate depth of anaesthesia prior to intubation is advised. Maintenance of anaesthesia can be achieved with total intravenous or inhalational anaesthesia (2). Remifentanil is an appealing choice for ablating response to intubation, easily titratable analgesia and blood pressure control though one must be aware of the risk of hypotension and bradycardia. In the one case report of its use in a patient with carcinoid tumour, it was found that an infusion at a rate of 0.15-0.2 micrograms/kg/min did not produce any adverse effects on haemodynamics (18). Drugs to avoid throughout the case are those associated with histamine release (e.g. morphine, atracurium, cisatracur.
The patient must be monitored in a high dependency environment to continue the provision of stable cardiorespiratory conditions and adequate analgesia. Ongoing control of hormone release by octreotide administration is important as postoperative crises do occur and the surgery may have only been a debulking. Therefore, 48 hours of invasive monitoring, analgesia and fluid management together with intravenous and subsequently subcutaneous octreotide is recommended (1, 2, 19).
Though carcinoid tumours and syndrome are rare, providing anaesthesia for these patients carries significant risks and should not be taken lightly. It is important that thorough preoperative planning and patient optimisation occurs involving close cooperation between anaesthetist, surgeon and intensivist. The risk of intraoperative release of mediators should not be underestimated even in seemingly asymptomatic patients. Octreotide must be readily available in the operating room and the cause of any intraoperative haemodynamic instability should be actively sought and treated appropriately. Finally, the patient should be monitored in a high dependency environment postoperatively as carcinoid crises do occur postoperatively.
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