Surgical Treatment of Malignant Carcinoid Tumours of the Appendix

M. E. O'Donnell; J. Carson; W. I. H. Garstin

Disclosures

Int J Clin Pract. 2007;61(3):431-437. 

In This Article

Discussion

The pathophysiology of malignant CCT and GCCT with particular emphasis on current management strategies for each particular type will be discussed, with reference to our own experience over the last 10 years.

Epidemiology. Gut carcinoid tumours were described as early as 1867,[11] and in more detail by Lubarsch[12] in 1888. However, the term karzinoide was not used until 1907 by Oberndorfer[13] to distinguish carcinoid tumours, which he believed to be benign, from malignant adenocarcinomata.

CCTs of the appendix have a prevalence of 0.3%−0.9% in patients undergoing routine appendicectomy and account for 32%−85% of all appendiceal neoplasms.[4,9,10] We report a prevalence of 0.23% with five cases of primary CCT identified from 2154 patients with acute appendicitis who underwent emergency appendicectomy during the study period. There is a slightly higher incidence among female patients.[10,14,15] It was initially thought that a lower threshold for appendicectomy in women, combined with an increase in the utilisation of laparoscopic procedures, resulted in an increase in the diagnosis of these incidental lesions.[16] However, this female predominance is independent of appendicectomy rate and is therefore a true epidemiological factor.[14,17,18] The reported peak incidence of 20-29 years and 15-19 years, for male[15] and female[17] patients, respectively, appears to be skewed towards the young, as these patients are more likely to undergo routine appendicectomy. Larger epidemiological studies, however, demonstrate an average age of 49 years for males and 38 years of age for females.[10,14,19] In this series, we demonstrated a lower mean age in males of 28, compared with 54 in females. In the male group, all but one of the CCTs was diagnosed incidentally at appendicectomy for acute appendicitis, of which there is a lower peak age of incidence in the population. In our female group, although the CCT were incidental findings, three of the older patients were undergoing a different therapeutic modality (hemicolectomy, oophorectomy) rather than simple appendicectomy.

Symptomatology. Clinical presentation is indistinguishable from acute appendicitis in over 50% of patients.[18,20,21] Chronic right lower quadrant pain may occur due to the tumour causing intermittent partial obstruction. However, histopathological analysis confirms an obstructing factor in only 25% of cases. CCT can also be identified from incidental appendiceal resections during laparotomy for other conditions.[22]

The symptoms of carcinoid syndrome are rare but may be indicative of liver metastases.[23,24] Haematological, biochemical, urinary investigations are then required to complement computerised tomography, or magnetic resonance imaging and radionucleotide scintigraphy to confirm carcinoid syndrome.[25,26] An increase in urinary excretion of 5-hydroxy-indoleacetic acid (5-HIAA) combined with raised urinary and platelet serotonin concentrations can be used to monitor disease progression.[25]

Pathology. CCT originate from neuroendocrine tissue found along the primitive gastrointestinal tract (Figure 1). The appendix is most commonly involved as a single site with the ileum second.[19] When confined to the appendix, they rarely cause metastatic disease, but when present, the primary mode of spread is through the lymphatic system.

Carcinoid tumour appendix demonstrating typical classical carcinoid tumour invading muscle wall (Haematoxylin and Eosin stain ×200). The tumour is composed of islands of uniform tumour cells with round nuclei and granular cytoplasm and lies in a hyalinised stroma.

Although there have been attempts to classify CCTs according to their histopathological behaviour,[27,28,29,30] the size of the tumour still remains the most important prognostic indicator of metastatic potential.[17,31] Eighty percent of appendiceal carcinoids measure less than 1 cm in diameter, with 14% measuring between 1 and 2 cm, and 6% greater than 2 cm in diameter. The tip of the appendix is involved in 75% of tumours, with 15% occurring in the mid-appendix and 10% at the base. CCTs are more aggressive in children, as there is an increased frequency of serosal and fat involvement (20% and 10% in adults vs. 40% and 30% in children).[7] Despite this increase in periappendicular involvement, metastatic spread is still rare. However, when present, meso appendiceal extension correlates well with nodal metastases and tumour size.[32]

The use of tumour proliferation markers to predict metastatic potential has already been well established in pancreatic and gastric (foregut) neuroendocrine tumours,[33] and further evidence that a high proliferation index correlates with more aggressive biological behaviour has also been shown in mid- and hind-gut tumours.[30] Although there is little evidence to support this correlation in appendiceal tumours, Goede et al.[34] state that appendiceal carcinoids with high mitotic and Ki67 positivity (tumour proliferation marker) indices should be regarded as potentially aggressive tumours, as is the case for other gastrointestinal carcinoids. However, they only regard these immunohistochemical markers as a complementary tool in prognostic decision making.

Treatment. Localised treatment such as simple appendicectomy is appropriate for tumours less than 2 cm in size, with a low proliferative index, towards the tip of the appendix, with no angiolymphatic, nor mesoappendiceal invasion.[32,34] For tumours greater than 2 cm in diameter, or with histological evidence of mesoappendiceal extension, or tumours at the base of the appendix with caecal extension, a right hemicolectomy is indicated, even though only 20% of resected specimens will show any residual or lymphatic disease following appendicectomy.[34] In our study, CCTs following appendicectomy or other procedures were less than 1 cm in diameter and present at the tip of the appendix. Thus, no further operative intervention was deemed necessary.

Prognosis. The prognosis for CCT is good, with a 90%−100% 5-year survival rate.[35,36] There is some suggestion that patients with appendiceal carcinoid have higher incidences of metachronous and synchronous lesions, and that gastrointestinal screening should be implemented. In this series, patient 9 died in the postoperative period from a perforated duodenal ulcer. All other patients have been reviewed on a regular basis and remain well. We have not yet instigated a formal colonic screening policy for these patients, as most of the lesions were incidental findings, less than 2 cm, with no evidence of mesoappendiceal or lymphatic involvement. We do, however, remain vigilant for the presence of carcinoid syndrome, and patient 3 currently attends the regional neuroendocrine unit for hormonal manipulation (lanreotide). Intra-operative findings confirmed the presence of liver metastases during a right hemicolectomy for a large caecal carcinoid tumour. She developed symptoms 9 months after surgery. The administration of a somatostatin analogue in these patients has been shown to produce a symptomatic improvement in 85% of patients, with a reduction in urinary 5-HIAA in 60%.[37,38,39,40,41] Disease stabilisation occurs in 50%, whereas 15% develop advanced disease. Patients with progressive or unresponsive carcinoid syndrome symptomatology may also benefit from the addition of a-interferon,[42] or combined surgical intervention (hepatic artery occlusion) with adjuvant chemotherapy.[43]

Epidemiology. GCCT of the appendix was first recognised as a distinct entity in 1969 and remains a rare variant of appendiceal carcinoid.[44] Peak age is between 53[45] and 58[46] years with a female predominance of 4 to 1. We identified two female patients with GCCT aged 46 and 76, presenting with acute appendicitis and a caecal mass, respectively. We report a prevalence of 0.05% with one case of primary GCCT identified from 2154 patients with acute appendicitis who underwent emergency appendicectomy during the study period.

Symptomatology. Clinical presentation is invariably indistinguishable from acute appendicitis in over 50% of patients[18,20,21] as described previously for CCT.

Pathology. GCCT has been described as adenocarcinoid, or crypt cell carcinoma, implying a duel differentiation from a pluripotent cell, into both mucinous and neuroendocrine cells, that have an aggressive and unpredictable natural history.[47] The biological and histological features are intermediate between both classical appendiceal carcinoid and colonic signet ring cell adenocarcinoma[48,49] (Figure 2). Metastases to intra-abdominal organs, especially the ovaries in female patients, and peritoneum are seen in 20% of cases[50] compared with CCT where the metastatic potential is restricted to rare lesions greater than 2 cm in dimension.[5] Gross tumour size is a poor indicator of biological potential in the case of GCCTs, because they are usually diffusely infiltrative and do not form discrete masses. Often, the tumours are very small and are represented only by the stenosis of the appendiceal lumen or by an area of induration in the wall of the appendix. Histologically, even small tumours may have already spread beyond the serosa and may already have metastasised. Warkel et al.[51] describe a high mortality rate for the 20% of GCCTs that metastasised. In female patients, 90% of these metastases involve the ovaries which may then serve as a source for further tumour dissemination.[50,51,52]

Goblet cell carcinoid appendix demonstrating the typical appearances of goblet-cell carcinoid tumour (Haematoxylin and Eosin stain ×400). The tumour is composed of the typical nests of vacuolated mucin-secreting cells mixed with cells which have a more carcinoid morphology.

Treatment. Ramnani et al.[49] completed the first molecular study of the mutations in the K-ras oncogene and the p53 tumour suppressor genes in GCCTs. They concluded that GCCT are variants of CCT rather than adenocarcinomas, due to a low incidence of metastases, lack of significant cytologic atypia, and that K-ras mutations seen in colorectal adenocarcinomas were not detected. These findings lend support to the recommendation that the therapeutic guidelines applied to appendiceal carcinoids should hold true for GCCT. Thus, GCCT tumours less than 2 cm in diameter, without serosal or lymphatic involvement, would be treated by appendicectomy alone, with a right hemicolectomy reserved for more advanced lesions. However, most studies recommend more extensive resections, such as a right hemicolectomy, regardless of pathological status, due to the unpredictable biological behaviour of the tumour, which includes delayed local recurrences and lung metastases.[47] Irrespective of stage, we feel that a right hemicolectomy is mandatory given the aggressive nature of these tumours.

In this series, two out of the 11 patients diagnosed with carcinoid tumours were found to have signet ring morphology in keeping with malignant GCCT. Patient 5 underwent routine appendicectomy for acute appendicitis. Histopathology demonstrated a 1.5-cm GCCT with evidence of serosal involvement and mesoappendiceal invasion. She proceeded to an elective right hemicolectomy, 1 month after initial surgery. Histopathology demonstrated no residual carcinoid. No adjuvant therapy was administered. She remains well. Patient 7 underwent emergency laparotomy for SBO. Intra-operative findings confirmed an obstructing caecal lesion. A right hemicolectomy was performed for a widely infiltrating GCCT. She was readmitted 8 months after her initial surgery with SBO secondary to tumour recurrence. She was treated palliatively. Shelater developed an anastomotic leak and unfortunately died 1 month later from bronchopneumonia.

Prognosis. Malignant GCCT are more aggressive than CCT and are associated with a poorer prognosis. The 5-year survival rate ranges from 73%[51] to 83%,[48] and the 10-year survival rate is 60%.[51] This higher mortality rate is thought to be associated with the higher rate of local recurrences and metastatic disease. We routinely refer all patients with GCCT to our oncology department for clinical assessment and follow-up.

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