 Management
Carcinoid Tumours
Carcinoid of the Large and Small Bowel P.J.
McMurrick MBBS (Hons) FRACS H Nelson
MD FACS This paper is an abbreviated version of a book chapter written by Dr McMurrick and Dr Nelson, and pending publication in "Current Therapy in Colon and Rectal Surgery". Editors : VW Fazio, JM Church. Mosby-Year Book, Inc. (Accepted, in press). Introduction Carcinoid, or neuroendocrine tumours are derived from Kulchitskys cells: chromaffin cells at the base of the crypts of Lieberkühn. They are hence classified as APUDomas. The many and varied hormonal products of these tumours, particularly serotonin, are responsible for the well described syndrome of physiological disturbance referred to as malignant carcinoid syndrome. Carcinoid tumours of the gastrointestinal tract are typically indolent in behaviour. Whilst the specific site within the GI tract influences presentation and outcome, the treatment protocols for each site are remarkably similar, and determined largely by site, extent of disease and the ability to surgically excise the lesion with microscopic margins. Carcinoid syndrome is uncommonly seen, is associated with extensive hepatic metastases, or disease outside of the GI tract and portends a poor prognosis. Serotonin is not produced by tumours of hindgut origin, and hence carcinoid syndrome is not seen in rectal lesions. Whilst surgery is frequently curative in early lesions, prolongation of life may be achieved by a combination of aggressive surgical and medical therapy even in advanced metastatic cases. There is some evidence that histological growth patterns influence survival, however in the vast majority of cases, decision making in clinical therapy is independent of consideration of histological pattern. Diagnosis Diagnosis of these lesions may be difficult, and the indolent nature of their growth dictates that they are often asymptomatic until widespread. The measurement of elevated 24-hour urinary 5-hydroxyindolacetic acid (derived from serotonin) is characteristic, but will not diagnose the condition in a curable stage, and is not elevated in rectal carcinoid. As mentioned, classic carcinoid syndrome (paroxysmal wheeze, flushing, diarrhoea, cardiac valvular lesions, arthropathy and telangiectasia) is associated with advanced disease, and seen in less than 3% of patients. Hence, early diagnosis of a carcinoid lesion is an uncommon event. The majority of appendiceal lesions are found incidentally at operation. The are rarely anticipated prior to operation, and hence no approach to preoperative diagnosis need be formalised. Colonic carcinoid is usually diagnosed late, when complications of the disease or its metastases become clinically apparent. If suspected, it can usually be readily be diagnosed by endoscopic biopsy. Early rectal carcinoid may be diagnosed at screening endoscopy, however more established lesions may cause a variety of clinical manifestations, often mimicking adenocarcinoma. For rectal lesions larger than 1 cm in size, endorectal ultrasonography may yield valuable information for treatment decision, including the size and depth of penetration. Diagnosis of early small bowel carcinoid remains a challenge. Enteroclysis is frequently recommended, but yields a diagnostic return of approximately 40%. Angiography may also aid in diagnosis particularly in combination with enteroclysis. The lesions may also be visualised at laparoscopy. The early assessment of somatostatin receptor scintigraphy using 111-Indium-Pentetreotide has yielded encouraging results, but its availability is currently limited. Ultimately, the diagnosis may only be made at laparotomy. Diagnosis of advanced carcinoid lesions is achieved principally by 2 groups of investigations. i) Assessment of hormonal status Urinary 5-HIAA in excess of 9mg/24 hours in a patient without malabsorption is strongly suggestive of carcinoid syndrome. The pentagastrin stimulation test (induction of flushing and gastrointestinal symptoms) is usually positive in the patient with liver metastases. ii) Imaging modalities CT scanning has remained the mainstay of detection of advanced lesions, and will detect the majority of liver metastases. The characteristic spoke wheel appearance is produced by encasement of the bowel with mesenteric vessels, resulting from extensive mesenteric fibrosis. PET scanning may offer additional sensitivity in smaller lesions. Ultrasonosgraphy may be of value in guiding percutaneous biopsy. Localised Carcinoid of the Intestine This may be defined as disease which may be macroscopically resected with histologically clear margins. Surgery remains the mainstay of treatment of carcinoid tumours in this setting. In this setting, carcinoid is a highly curable disease with long term survival in the order of 90%. Despite marked variations in the frequency and presentation of disease at various sites in the small and large bowel, the recommended treatment algorithm remains similar. For lesions less than 1 cm in size, local excision with clear margins is appropriate. For lesions greater than 2 cm in size, segmental bowel resection, including resection of draining lymph node fields is indicated, and results in an excellent cure rate. For those lesions between 1 and 2 cm, consideration needs to be given to the general state of the patient, the anatomical site of the lesion, the consequences of definitive resection (e.g. loss of the anus) and the feasibility of post resection surveillance. Small Bowel Carcinoid Lesions in the small bowel characteristically present late. The diagnosis of a small, isolated carcinoid tumour in the small bowel is rare, and usually made as an incidental finding at laparotomy for some other indication. The presentation of established lesions may be one of obstruction, or of intestinal ischaemia. Occlusion of the mesenteric vessels results from a number of factors characteristic of these lesions, including a profound desmoplastic reaction, vascular elastosis and tumour secretion products. Lesions smaller than 1 cm may be treated by conservative local resection. For tumours greater than 1 cm, a segmental resection of small bowel is indicated, with wide local margins. Generally, a margin of around 10 cm on either side of the lesion is appropriate. Because of the high frequency of metachronous lesions in small bowel carcinoid (30 - 40%), a thorough exploratory laparotomy is mandatory, concentrating particularly on the rest of the small bowel; the most common site of metachronous tumours in this setting. In approximately the same percentage of patients, the lesion is associated with a second primary tumour. Those patients with lesions greater than 1 cm in size are at elevated risk of recurrence. Because of the difficulty in diagnosing asymptomatic small bowel carcinoid, no standard post resection surveillance program is currently recommended, although routine CT scanning may be of value. Any patient who develops suggestive symptoms after previous successful resection should be investigated. Appendiceal Carcinoid This is the most common site of origin of carcinoid tumour. These lesions tend to present at a younger age than in patients with carcinoid at other sites. They are frequently identified as an incidental finding at operation for other reasons, entirely accounting for the increased incidence in women. The overall risk of metastases is between 2 and 8 %. Those lesions smaller than 1 cm are almost universally associated with an excellent outcome, and should be treated with appendicectomy alone. The only exception to this rule is in the setting of invasion of the caecum, in which case right hemicolectomy is indicated. Invasion of the mesoappendix per se does not mandate hemicolectomy. Lesions of between 1 and 2 cms in size are associated with a 0 - 11% rate of metastases, and hence the management of these lesions should be tailored to the individual patient, giving consideration to such factors as age, general health, the presence of angiolymphatic invasion, and the presence of clinically involved nodes. Lesions larger than 2 cm should be treated with right hemicolectomy. When right hemicolectomy is performed, lymph nodes to the right side of the superior mesenteric artery should be removed with care. Multicentricity occurs in around 5% of cases, and hence thorough laparotomy should be performed in all cases. Overall, the 5 year survival for appendiceal carcinoid is 99%. Colonic Carcinoid Colonic carcinoid is most commonly found in the caecum: the incidence diminishes further along the colon. The finding of an early, resectable colonic carcinoid is a rare event. They are usually greater than 5 cm and symptomatic at presentation. The carcinoid syndrome is rare with colonic carcinoid, and occurs in only around 3%. The overall 5 year survival is approximately 20 - 50%. Colonic lesions should be treated by segmental resection, including a wedge of mesentery and draining lymph nodes. Unresectable tumours should be debulked provided that the projected surgical morbidity of such a procedure is minimal. Rectal Carcinoid These lesions are in many ways analogous to appendiceal carcinoids; often diagnosed incidentally, and associated with a good prognosis. The carcinoid syndrome is virtually unknown with rectal carcinoid. The majority are found in patients greater than 40 years of age. More than 99% are found between 4 and 13 cm above the dentate line, and hence are often palpable on digital rectal examination. For those lesions of less than 1 cm, treatment by either local resection or fulgaration is acceptable management. Again, cure rates of 100% can be anticipated. Local resection may be achieved by either transanal surgical excision, or by endoscopic techniques, depending on the size and site of the lesion. Lesions in the lower half of the rectum are usually best managed by transanal resection. Higher rectal lesions are best removed through an endoscope, either by snare cautery or by hot biopsy and ablation. Lesions larger than 2 cm in size require definitive rectal resection, usually either as an anterior resection, or as abdominoperineal resection. The management of lesions of intermediate size, from 1 to 2 cm, needs to be tailored to the individual patient. The frequency of metastases is this setting is approximately 11 %. Usually, local excision is adequate, but unfavourable factors, particularly invasion of the muscularis propria, may suggest the need for more extensive resection. Endorectal ultrasonograpy may be of value in determining the depth of invasion. Decision making should be tailored to the general condition of the patient Predicted survival in rectal carcinoid is dependant on stage. In the absence of metastases, the 5 year survival is 92%. If nodes are involved, the figure is 44%, falling to 7% if distant and unresectable metastases are present. A difficult scenario is the referral of a patient with incomplete removal of a rectal carcinoid, particularly after attempted endoscopic resection. Initial assessment should include accurate assessment of the size of the original lesion (if this is possible) followed by repeat endoscopy to macroscopically assess the site. Repeat biopsy of the base of site of excision may demonstrate residual tumour. In this case, ultrasonography, although difficult to interpret in this setting, may define the relationship of the lesion to the muscularis propria. If the lesion was reliably determined to have been less than 1 cm in size, cautery ablation of the base of the resection site may be all that is required. If the lesion is larger, or repeat biopsy positive, then formal resection of the bed will be required. If the lesion is small and confined to the superficial tissues, then transanal local excision will suffice. If the lesion was larger than 2 cm, or invaded the muscularis propria, then formal resection is preferable. Carcinoid of the Intestine With Regional Involvement Those lesions which extend from the bowel to include local structures, or in whom lymph node metastases are present, are still curable using aggressive surgical management. The aim of operation should be the resection of all macroscopic disease, including nodal and peritoneal disease with clear histopathological margins. If this goal can be achieved, then excellent cure rates are again attainable, with a 5 year survival in the region of 70%. The risk of local recurrence is increased in this setting, and a structured follow up program needs to be implemented Metastatic Intestinal Carcinoid It is important to remember that many advanced lesions tend to demonstrate indolent growth and a relatively benign clinical course. Survival to 2 years even in the presence of liver metastases is common. It the patient is asymptomatic at the time of presentation, observation may be the most appropriate course of action. The major aim of therapy in the presence of metastatic disease is palliation of symptoms, although enrolment of patients into clinical trials of non-surgical modalities, with a view to producing prolongation of survival, is entirely appropriate. Randomised controlled data pertaining to these techniques is difficult to produce given the rarity of these lesions.
i) Surgical management Specific complications of disease within the peritoneal cavity, that may be palliated by surgical resection include obstruction of small bowel, regional ischaemia and infarction. In patients with unresectable disease, bypass, debulking and stoma formation may all be appropriate measures. Metastatic involvement of the liver tends to be diffuse, and can rarely be resected with curative intent. There is a clear role for palliative hepatectomy or enucleation of liver mets in the presence of the carcinoid syndrome. Rarely, patients with otherwise good health, indolent carcinoid and cardiac valvular lesions may be candidates for valve replacement therapy. ii) Chemotherapy There exists no clear evidence to indicate that chemotherapy prolongs life in this setting. In general, its use is reserved for those patients with severe symptoms or those who develop poor prognostic signs. Approximately 30% will demonstrate some response, although the impact of this response on survival is arguable. Single agent regimens (adriamycin, 5-fluouracil, dacarbazine or alpha interferon) have produced objective response rates of approximately 20%. Combination therapy has produced response rates of 20 - 40%. The combination of streptozotocin and 5-fluorouracil, as trialed by the Eastern Co-operative Oncology Group and the Mayo Clinic demonstrated a 33% objective response rate, but at the cost of substantial morbidity. Various trials, particularly from northern Europe, have produced favourable response with the use of interferon, either alone or in combination with other therapy (including hepatic artery embolisation. A comparison of alpha interferon with combination chemotherapy demonstrated greatly superior survival for the interferon arm. These encouraging preliminary results support ongoing assessment of these interferon based therapies. iii) Chemoembolisation The most common approach is the use of fluoruracil or doxorubicin, in combination with embolisation of the hepatic artery with collagen fibres. This approximately halves the bulk of liver metastases in around 60% of patients, with limited morbidity. iv) Radiation therapy The use of radiation in carcinoid is restricted to symptomatic palliation, particularly of painful bony metastases. v) 1311-MIBG Iodine 131-labelled metaiodobenzylguanidine has been demonstrated to reduce symptoms in preliminary studies. In summary, there remains no uniform approach to the treatment of advanced carcinoid lesions. Minimally symptomatic patients may best be managed expectantly. Acute surgical management may be required in the setting of a specific complication. Patients with symptoms related to tumour bulk may benefit symptomatically from either debulking surgery, chemotherapy, chemoembolisation or immunomodulation with interferon, the specific treatment being tailored to the patient and to local expertise. Where possible, these patients should be entered into therapeutic trials. Management of the Carcinoid Syndrome Due to the high first pass extraction effect of the portal circulation, the syndrome is seen in association with gastrointestinal carcinoid only in the presence of bulky hepatic metastases, or extra intestinal metastases. Treatment of this condition associated with gastrointestinal carcinoid is twofold: i)
directed at debulking of hepatic metastases. For those patients in whom invasive techniques fail to control symptoms, the somatostatin analogue octreotide is highly effective. It reduces flushing suppressing serotonin levels, and has direct effects on gut motility, reducing diarrhoea. Alfa interferon preparations have been demonstrated to produce transient control of symptoms in carcinoid syndrome, and to produce short lived slowing of tumour growth. The combination of alpha interferon and fluoruracil has been demonstrated to produce anti tumour activity, and may provide useful palliation. Symptomatic patients should be considered for chemotherapy combinations in a trial setting. Monoamine oxidase inhibitors are contraindicated in carcinoid syndrome, as they will exacerbate the inhibition of serotonin degradation. The administration of general anaesthesia is prone to produce carcinoid crisis in predisposed individuals. This may best be prevented by the preoperative administration of 50 mg of somatostatin analogue prior to induction. Further boluses may be necessary should breakthrough symptoms develop. Authorised:
Mr PJ McMurrick |
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