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REVIEW ARTICLE
Year : 2015  |  Volume : 42  |  Issue : 3  |  Page : 132-137

Carcinoid tumors: Challenges and considerations during anesthetic management


1 Department of Anaesthesiology and Intensive Care, Gian Sagar Medical College and Hospital, Ramnagar, Banur, Punjab, India
2 Department of Anaesthesiology, AIIMS, Bhubaneshwar, Odisha, India

Date of Web Publication16-Sep-2015

Correspondence Address:
Dr. Sukhminder Jit Singh Bajwa
House No. 27-A, Ratan Nagar, Tripuri, Patiala - 147 001, Punjab
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0974-5009.165537

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  Abstract 

Carcinoid tumors are rare, slow-growing neoplasms of neuroendocrine tissues from enterochromaffin or kulchitsky cells, which have the potential to metastasize. The mediators released from these tumors when bypass the hepatic metabolism, can lead to the possible development of carcinoid syndrome. This is a life-threatening complication, which can lead to profound hemodynamic instability, especially in a peri-operative period, when the patient is exposed to various types of noxious stimuli. Off late, use of octreotide, a synthetic analog of somatostatin, has significantly reduced the peri-operative morbidity and mortality. The current review discusses the various anesthetic challenges and considerations during peri-operative management of carcinoid tumors.

Keywords: Carcinoid tumor, octreotide, somastatin, vasoactive mediators


How to cite this article:
Bajwa SJ, Panda A, Kaur G. Carcinoid tumors: Challenges and considerations during anesthetic management. J Sci Soc 2015;42:132-7

How to cite this URL:
Bajwa SJ, Panda A, Kaur G. Carcinoid tumors: Challenges and considerations during anesthetic management. J Sci Soc [serial online] 2015 [cited 2019 Mar 23];42:132-7. Available from: http://www.jscisociety.com/text.asp?2015/42/3/132/165537


  Introduction Top


Carcinoid tumors were first described by Lubarch in 1888, when he observed multiple tumors in the distal ileum during autopsy of two patients. In 1907, Oberndorfer coined the term Karzinoide tumor due to its similarities to carcinoma though they are apparently benign in nature. [1] Ransom first described the classic symptoms of a carcinoid tumor. [2] In 1914, Gosset and Masson described its relationship to endocrine tissue. [3] Carcinoid tumors are the most common type of neuroendocrine (NE) tumors. Leotlela et al. suggested that those NE tumors, which secrete serotonin and are of midgut embryonic origin, should be referred to as "carcinoids." In 2000, the World Health Organization developed a classical system, that recommended "NE tumor" instead of "carcinoid." According to this classification system, these tumors are of three classes based on malignant potential as assessed histologically:

  1. Well-differentiated NE tumor.
  2. Well-differentiated NE carcinoma.
  3. Poorly differentiated NE carcinoma.


But still the term carcinoid continues to be used widely by many clinicians and researchers. Carcinoid tumors are slow-growing, fairly benign, but capable of metastasis to distant organs. They secrete a wide variety of vasoactive substances according to their cell types. Electron microscopically, they contain membrane-bound granules, which contain these biogenic amines and hormones.


  Search Strategies Top


Research articles, systematic reviews and editorial comments in various international and national bibliographic indices were extensively searched with emphasis on key words "carcinoid tumor, octreotide, somastatin, vasoactive mediators." The various search engines included Entrez (including PubMed), WebMD.com, MedHelp.org, Search Medica, MD consult and google.com. A manual search was also carried out and various text books of anaesthesia, endocrinology and surgery were looked for the management of carcinoid syndrome.

Incidence

Carcinoid tumors are approximately 0.28/100,000 populations/year. [4] The highest incidence (67.5%) is seen in gastrointestinal tract (GIT), followed by the bronchopulmonary system (25.3%). In GIT, small intestine is the most common site (40%) involved, followed by rectum (27%) and stomach (10%). Prognosis depends on staging and metastasis at the time of diagnosis, irrespective of their site of origin. The most common site of metastasis is liver. These tumors are found either between 25 and 45 years of age or over 60 years. [5] It is found in children, most commonly in the appendix. [6] 5 years survival is 99% in carcinoid tumor of the appendix.


  Pathophysiologic Basis of Disease Top


Mostly carcinoid tumors are found incidentally during surgery for other purposes. Clinical course in the patient does not necessarily relate to the extent of the tumor. The patient may remain asymptomatic with the large tumor for years, whereas small ones may produce significant symptoms. [7],[8],[9],[10] These syndromes are mostly encountered, when the primary tumor does not drain into the portal system or with hepatic metastasis because hepatic metabolism is bypassed in these cases and their systemic effects are manifested? [5] The clinical presentation depends on the type of mediators released and their interactions. [11] The three most important mediators released are serotonin, histamine and kinins. [5] Serotonin is synthesized by hydroxylation and decarboxylation of tryptophan. [12] Serotonin released into circulation by adrenergic stimulation is metabolized by aldehyde dehydrogenase and monoamine oxidase to 5 hydroxy indole acetic acid (5-HIAA) [5],[12] which is excreted in the urine. So elevated levels of 5-HIAA in urine indicate excess serotonin production, thus the presence of a carcinoid tumor. [5] Exercise, alcohol, tyramine-rich foods (cheese, chocolate, etc.) causes an exaggeration of symptoms. Serotonin can produce both vasoconstriction and vasodilatation, thus resulting in hyper or hypotension. Serotonin does not have any effect on the heart at normal serum concentration, but it affects cardiac function at elevated levels. It has both chronotropic and inotropic response [12] due to the release of norepinephrine. [13] Increased serotonin also causes secretion of sodium, potassium, chloride, and water by the small intestine and increases gut motility. [12] Vomiting, bronchospasm, hyperglycemia, and drowsiness are also the effects of the increased levels of serotonin. Normal gastric mucosa contains histidine decarboxylase, so gastric and foregut carcinoids predominantly secrete histamine, [12],[14],[15] which is thought to be the cause of bronchospasm and flushing. [12] The sympathetic stimulation causes release of lysosomal kallikreins, which produce kinins by the action of proteolytic enzymes. These kinins, when produced in high quantity, escape metabolism and produce exaggerated and prolonged symptoms. [13] Severe hypotension caused by bradykinin is due to profound vasomotor relaxation. Bradykinin also causes flushing due to increased production of nitric oxide. Mostly right side heart is involved in carcinoid syndrome, causing fibrous tissue growth and thickening of endocardium. Right-sided valvular lesion is almost a universal finding due to retraction and fixation of valve leaflets. It is related to prolonged exposure to high concentration of 5-HT. Hence, tricuspid and pulmonary valvular diseases are well-known findings. [16],[17],[18],[19] Left-sided heart diseases are uncommon but may be associated with bronchial carcinoid or right to left intracardiac shunt. [12],[20],[21] Fibrous tissue growth may also interrupt conduction pathway leading to arrhythmias. [22] Treatment to decrease HIAA did not show any regression of the cardiac lesion. [17]


  Disease Symptomatology Top


Carcinoid tumors are usually slow growing, so remain asymptomatic or may produce vague abdominal pain, that is ignored or misdiagnosed as irritable bowel syndrome. Only 25% of tumors produce mediators, which produce symptoms of carcinoid syndrome. [12] The mediators produced are generally metabolized in liver, [17] but when the production exceeds the hepatic metabolism, then the syndrome results. [12],[18] These signs and symptoms indicate that these mediators are produced in those sites, which do not drain into portal circulation, thus bypassing hepatic metabolism, e.g., bronchial, ovarian and testicular tumors. [5],[23] Less than 10% of the patients develops classic carcinoid syndrome. [24] The clinical spectrum includes hypotension or hypertension, cutaneous flushing, bronchoconstriction, diarrhea and carcinoid heart diseases. [23] Episodic flushing of head and neck with a classic distribution over the upper chest, neck, face, upper arm and torso has been seen in about 94% of patients. [5],[12] In severe cases of flushing, blood pressure (BP) may become very labile but it may not coincide with flushing episode. Diarrhea is the most common GI symptom. [5] It varies from a mild change in bowel habits to severe diarrhea leading to dehydration, hyponatremia, hypokalemia, hypochloremia, abdominal pain and nausea. [12] A life-threatening form of carcinoid syndrome is known as carcinoid crisis, which may be precipitated by physical manipulation of the tumor (as bedside palpation etc.), chemical stimulation, tumor necrosis resulting from chemotherapy and hepatic artery ligation or embolization. [25] It may occur during induction of anesthesia or spontaneously. Clinical manifestation of carcinoid crisis include flushing with an associated dramatic change in BP, cardiac arrhythmias, bronchoconstriction and mental changes. [26]


  Diagnostic Modalities and Dilemmas Top


Due to the presence of nonspecific symptoms, diagnosis is often delayed, and metastasis is common at the time of diagnosis. [17] The clinical presentation depends on the function of the tumor. Functional tumors present with carcinoid syndrome due to secretion of mediators. Nonfunctional tumors usually present with GI bleed, pain and intestinal obstruction etc.

Various imaging techniques can be used in suspected cases such as endoscopy, endoscopic ultrasonography and video capsule endoscopy to locate the tumors. [24] Computed tomography (CT) scan, magnetic resonance imaging (MRI), abdominal ultrasonography, selective mesenteric angiography and barium small bowel radiography can be used to identify primary tumors and sometimes metastasis. [24] However, ultrasonography lacks sensitivity as well as specificity. MRI is helpful to evaluate lung and liver lesions. [27] Metastatic deposits appear as isodense, hypervascular lesions. Somatostatin receptor scintigraphy, using indium-111 labeled octreotide is used. [28] Measurement of serotonin metabolites such as 5-HIAA in 24 h urine collection is helpful both in the diagnosis and to monitor tumor activity. A positive result is 73% sensitive and 100% specific for carcinoid tumor. HIAA is normally <10 mg in 24 h and >25 mg is diagnostic, [5] but about 20% patients have normal levels. Serum chromograffinA measurement is also useful, which is a glycoprotein secreted by NE tumor, but it is 80% sensitive and 95% specific. The gold standard for locating functional NE tumor tissue is radiolabelled somatostatin analog scintigraphy. [19] Bone scintigraphy is used to detect bone metastasis. Radiolabelled pentetreotide and octreotide are used for this purpose. They bind to the same somatostatin receptors, subtype 2 and 5. [29] Hence, pentetreotide is an ideal compound for imaging tumors positive for somatostatin receptor 2 and 5. Radiolabelled metaiodobenzylguanidine, which is actively taken up by NE tumors, can also be used for diagnosis and as a part of therapy. [30],[31] Positron emission tomography may also be used to localize fast growing tumor. Penta gastrin challenge test is sometimes used for the diagnosis to monitor the disease progress and to assess the response to medical management. [5],[12] The definitive diagnosis of carcinoid cardiac disease is difficult and requires a high degree of suspicion.


  Therapeutic Strategies Top


Treatment depends on the type, location and stage of the tumor. Octreotide was introduced in late 1980s after which there has been a significant increase in survival rate. [32] Complete surgical excision of the tumor is the most effective treatment, which may be a partial bowel resection and mesenteric lymphadenectomy. [17],[25],[33] Some metastatic lesions can also be removed surgically. Octreotide can also be used to treat the symptoms produced by any residual tumor left after surgery. [33] Ideal time of surgery and efficacy of the surgical intervention is still controversial. Hepatic metastasis can be dealt with hepatic artery occlusion by ligation, embolization and transarterial chemoembolization (TACE). [24],[34] When chemotherapy is added to TACE, the tumor tissue size reduced in 78% of patients. [35] Chemotherapy is beneficial for poorly differentiated tumors and in those which are resistant to standard treatments. [24]

Goals of peri-operative management

The goal of peri-operative management is to avoid carcinoid crisis by preventing the release of bioactive mediators. Life-threatening complication with hemodynamic instability can occur in a peri-operative period when the patient is exposed to various types of noxious stimulus, which can lead to significant morbidity and motality. [4],[29]


  Preoperative Evaluation and Optimization Top


Preoperative assessment includes detailed history and physical examination for determining the presence and severity of any symptoms of carcinoid syndrome. Basic laboratory tests such as complete hemogram, liver function tests (LFTs), renal function tests (RFTs), serum electrolytes, blood glucose, and 24 h urinary 5-HIAA should be included. A complete cardiac evaluation should be done including electrocardiogram and Echocardiography cardiography. Presence of the metastatic tumor can be detected by CT scanning or MRI. As most of the tumors take up octreotide, radiolabeled octreotide can be used to locate the tumor by a scintillation detector preoperatively and postoperatively to confirm the complete removal of the tumor.

Preoperative optimization of patient's general condition and underlying pathology for surgery play a major role. Malnutrition, dehydration, anemia, electrolyte imbalance due to diarrhea and intestinal obstruction are common findings. Symptoms and signs of on-going uncontrolled hormonal activity may be present. Unpredictable, uncontrolled release of hormones precipitated by any stimulation like variation of hemodynamics, anesthetic agents or surgical stimulus can occur which may result in hypo or hypertensive crisis and hemodynamic collapse and this may be unresponsive to conventional drug therapy. So, it is very important to minimize the tumor activity before taking up the patient for surgery. Fluid and electrolyte abnormalities should be corrected. A wide variety of drugs are used to block the production, release, or action of mediators from the tumor. They are chlorpheniramine, ranitidine, aprotonin, ketanserin, steroid, methysergide, cyproheptidine, somatostatin and somatostatin analog. [18],[36],[37],[38] Octreotide is a synthetic somatostatin analog and is most commonly used. It has a longer half-life of 1-1.5 h when given subcutaneously and 50 min when given intravenously. [5],[24],[39] It acts by blocking the release of hormones and by inhibiting the action of circulating peptides through inhibition of either phophatidylinositol or adenylate cyclase. [18],[40] This drug has almost replaced all other drugs used for carcinoid patients. [41] No standard octreotide administration regimen is reliable, and various recommendations have been proposed. [14] Octreotide is given in various dose regimens. Ideally, it should be started at the dose of 100 mcg thrice daily and 100 mcg just before induction to suppress sudden release of mediators. [42] It should be given in infusion at 50 mcg/h for at least 12 h prior to surgery. [29] However, postoperatively it should be tapered off over 1-week. Different types of regimens are followed by different clinicians.

Premedication

All the medicines of the patients should be continued till the day of surgery. Benzodiazepines and antihistamines may be given to reduce anxiety and stress.

Anesthetic technique

Although most of the patients with carcinoid tumor are operated under general anesthesia in order to avoid sympathectomy by neuraxial anesthesia, but both spinal and epidural anesthesia have been used successfully. [14],[43] Preoperative use of octreotide, judicious fluid therapy, low dose local anesthetics with low dose opioids made neuraxial block possible. Moreover, epidural catheter can be used for postoperative analgesia. TIVA with propofol and remifentanil has been proved to be successful, particularly for abdominal surgery. Its major advantages are hemodynamic stability, significantly shorter times of emergence and the exceptional acceptance by the patients [44] and results in a clinically significant reduction of postoperative nausea and vomiting compared with isoflurane-nitrous oxide anesthesia. [45] For conventional general anesthesia also, the primary aim is to provide a stable and controlled condition. The keys for achieving this condition is adequate depth, good analgesia and avoiding stimulatory drugs for the release of mediators like morphine, atracurium and suxamethonium, etc. Remifentanil and fentanyl have been used for optimizing intubating condition, providing analgesia and intra-operative BP control. [41] Vecuronium or rocuronium should be used for providing muscle relaxation for their cardiovascular stability. Isofluorane and sevoflurane are the most commonly used inhalational agents. Endocrine anesthesia has made giant strides in the last few years, and many endocrine surgeries have been possible because of these advancements with an aim of patient safety and better prognosis. Anesthetic techniques are invariably influenced by the type of endocrinological disease pathology. [46],[47],[48],[49],[50],[51],[52],[53],[54]


  Peri-Operative Monitoring and Maintenance of Anaesthesia Top


In addition to all standard monitoring, measurement of urinary output, invasive BP and central venous pressure monitoring should be included with particular emphasis on peri-operative renal protection. [55] Any change in BP and volume status of the patient can be monitored and managed. Transoesophageal echocardiography is helpful in patients with coexisting cardiac diseases. [56] Onset of bronchospasm can be rapidly detected by airway pressure monitoring. Temperature monitoring is also necessary and warm fluids should be used to avoid hypothermia, which is a trigger for release of mediators. Bispectral index should be used whenever possible to ensure adequate depth of anesthesia. ABG monitoring can be used to assess the adequacy of ventilation. Elevated levels of serotonin can lead to hyperglycemia. So blood glucose level should be monitored and controlled with insulin infusion. Use of a balanced anesthetic technique is preferred. It includes an opioid, an inhalational anesthetic agent, a nondepolarizing neuromuscular blocking agent or TIVA. [12],[57],[58] All emergency drugs should be kept ready for any untoward event. Intravenous boluses of 20-25 mcg of octreotide can be used to treat the release of mediators intra-operatively. Vasopressin is an alternative for this. [59] Fluid loss should be dealt with warm fluids or blood. Labetalol infusion has been used to tackle prolonged hypertension. The peri-operative complication is more common in patients with heart diseases. [36] In patients having chronic right ventricular valvular lesions and right heart failure, factors which can lead to increase right ventricular workload like hypoxemia, hypercarbia, the lighter plane of anesthesia should be avoided. [60] Intra-operative hypertension can be handled by increasing the depth of anesthesia, use of beta blocker, 5HT2 receptor blockade with ketanserin and octreotide. [61],[62]


  Postoperative Care Top


These patients are very prone for delayed emergence from anesthesia due to high levels of serotonin. All standard monitoring used intra-operatively should be continued in postoperative period also and particular care to be exercised while managing morbidly obese patients. [63] The mediators may continue to exert their effects after removal of the tumor and some occult tumor may continue to produce mediators. [12] Hence, these patients need to be monitored in intensive care units or high dependency units. Octreotide therapy should be continued, which can slowly tapered off over 1-week according to patient's response. During surgery, there may be a large fluid shift and hence fluid and electrolytes should be monitored. [64] Good analgesia plays a major role to prevent any excess sympathetic activity and stress. It can be achieved by epidural analgesia or intravenous fentanyl infusion. [61] Dexmedetomidine is a newer agent in anesthesia practice, which can be effectively used for sedation and augmentation of postoperative analgesia. [65] Serotonin induced hyperglycemia should be monitored and controlled with insulin infusion. [12] Ideally, such patients should always be operated in tertiary care institutes with facilities for intensive care units as endocrine emergencies are easier to manage in these well-equipped setups. [66] Intensive monitoring, good analgesia and judicious fluid management are required to ensure safe recovery from surgery. [29]


  Conclusion Top


Carcinoid syndrome is a challenge for the anesthesiologist due to its unpredictable clinical manifestations and the peri-operative complications associated with it. Surgery in these patients and requires a thorough preoperative preparation and optimization of the patient with drugs like octreotide. Newer diagnostic and treatment modalities can be combined to achieve safe and better outcome. Anesthesiologist should be ready and plan for every event that can occur in peri-operative period and should be in a position to recognize and tackle the events. Severity of preoperative symptoms may not predict the severity of intra-operative complications. Urinary 5-HIAA levels also may not predict the response to intra-operative tumor manipulation. It can only be used to assess the disease progression. Newer treatment modalities for carcinoid tumor have prolonged and improved the quality of life in these patients. Good communication between an anesthesiologist, a surgeon and an endocrinologist is necessary for the preoperative optimization and successful anesthetic management and a good surgical outcome.

 
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