Outcome
In 2002 the number of deaths from small bowel cancer in the UK was recorded as 5 per million 12 . Taking the annual incidence as 12 per million the overall prognosis remains poor. Reported series are inevitably hindered by the length of time needed to acquire adequate numbers from which to draw meaningful conclusions. Furthermore, new and current treatments that may influence response rates and survival will not be reflected in such figures. The most accurate evaluation of overall survival in current practice emanates from the BSG registry that reported survival at 30 months as 78% for carcinoid, 58% for adenocarcinoma, and 45% for lymphoma 13 . Unfortunately, because of the rarity of these tumors and the indolent and diverse mode of presentation, patients may be treated by non-specialist groups and denied access to state of the art treatments. It is hoped that with current imaging and less invasive meth-ods of diagnosis as well as earlier referral to specialist units will allow structured treatment with better outcomes in future.
APPENDICEAL TUMORS
The past 10 years have seen a major shift in our knowledge and understanding regarding the origin and treatments for appendiceal tumors. Whilst the commonest tumor arising at this site is the neuroendocrine carcinoid, the major-ity of which are diagnosed incidentally and do not metas-tasize, epithelial adenomatous tumors are now known to be more pervasive, associated with the development of dif-fuse peritoneal neoplasia. When the tumor is mucinous in nature the features are best described as Pseudomyxoma peritonei (PMP). The incidence of epithelial tumors that go on to generate the PMP syndrome is estimated as 1–2 per million of the population.
Epidemiology
Tumors of the appendix are rare accounting for 0.5% of GIT tumors. The principle tumor types are carcinoids, ade-nomas, adenocarciade-nomas, and rarer pathologies include GISTs, mesechymal tumors, metastatic carcinomas of colorectal origin, and rarely melanomas. On analysis of appendicectomy specimens, removed largely for the pre-sentation of appendicitis, < 1% are found to have tumors and only one-tenth of these are primary malignant tumors 25 . Overall, 30–55% of tumors prove to be carcinoid, 15%
adenomas, 10% primary adenocarcinomas and 15%
secondary malignancy half of which were adenocar-cinomas in patients with colorectal cancer. It is notable that in patients with appendiceal tumors of all histologi-cal types there is a high incidence of synchronous and
metachronous colorectal cancer: carcinoids 10%, adeno-mas 33%, secondary malignancy 55% 26 . Further support for an association between epithelial appendiceal tumors and colorectal cancer is provided from an observation of a 5% incidence of such tumors in appendices removed elec-tively in patients undergoing rectal and colonic cancer surgery 27 .
Clinical presentation, investigation and diagnosis For most patients an appendiceal tumor is diagnosed fol-lowing removal for presumed appendicitis. At operation the appendix may appear swollen and bulbous ( Figure 15.3 ) but the majority of tumors are diagnosed coincidentally by the histopathologist. If extra-appendiceal mucus or other peritoneal disease is noted at operation this must be considered when planning further treatment (see section on Outcome below). Carcinoid tumors are generally indo-lent, rarely perforate or metastasize, although the risk of progression increases with increasing size above 2 cm and with adenocarcinoid cellular differentiation 20 . Appendiceal carcinoids are often diagnosed at an early age: 15–19 years in females and 20–29 years in males; and family history in first-degree relatives increases the risk threefold 17 . Rarely patients present with a full blown secretory carcinoid syn-drome due to the systemic effects of 5-hydroxytryptamine (5HT): flushing, fever, diarrhea, bronchospasm, and car-diac dysfunction. Perforation of the appendix does occur with benign epithelial mucinous tumors and adenocarci-nomas both of which tend to reseal having disseminated cells into the peritoneal cavity ( Figure 15.4 ). Adenoma-tous lesions of the appendix tend to generate mucinous PMP which is relatively indolent, whilst peritoneal carcinomatosis will follow perforated adenocarcinoma and progress rapidly with signs of multifocal intestinal involvement.
Figure 15.3 Macroscopic appearance of a distended swollen appendix containing tumor confined to the lumen.
Carcinoid tumors
Patients with diagnosed carcinoids should be investigated for 5HT secretion using urinary 5HIAA analysis. CT scan of the thorax, abdomen and pelvis is required as synchro-nous primaries and metastatic disease needs to be deter-mined. The majority of appendiceal carcinoids do not metastasize. Debate remains regarding long-term follow-up as there are recorded cases of presentation with metastatic liver disease > 10 years following excision of the primary.
Metastatic carcinoid may be diagnosed following identifi-cation of liver lesions on CT scan or occult lesions may be found using octreotide radionucleotide scanning. Recently more aggressive surgical excision and ablation has been adopted for control of systemic symptoms and the use of adjuvant chemotherapy and pharmacological manipulation with somatostatin helps palliate the disease 20 . Adenocarci-noid tumors run a more aggressive course in some cases progressing with peritoneal deposits requiring treatment similar to PMP 28 .
Epithelial tumors and Pseudomyxoma peritonei In 2000 the pioneering work of Professor Sugarbaker from Washington DC was explored in a conference at the Royal College of Surgeons, London. At that time few sur-geons and oncologists understood the pathophysiology of PMP and many patients were erroneously treated: women commonly for ovarian cancer and men misdiagnosed as gastric cancer or unknown GIT primaries. Although it is true that some mucin-producing tumors will mimic a PMP picture and produce a PMP syndrome (character-ized by abundant production of mucinous ascites, gross abdominal distension, loss of peripheral lean body mass
secondary to limited nutritional intake, and GIT compres-sion), it is now accepted that true PMP develops second-ary to an epithelial adenomatous tumor of the appendix 29 . The spectrum of disease ranges from abundant production of mucin with very scant epithelial cell proliferation (dif-fuse peritoneal adenomucinosis) through peritoneal muci-nous carcinoma of intermediate/discordant type (PMCA I/D) to peritoneal mucinous carcinomatosis (PMCA).
The unique feature of PMP is the ability to develop surface peritoneal implants without progressing to intra-organal or lymph node metastases. Recent evaluation of adhesion molecules in PMP and colorectal cancer has demonstrated a distinct profile that may explain the pattern of disease and offer potential for molecular targeting to prevent invasion 30 .
Many patients with PMP present to non-specialist centers and are misdiagnosed as having ovarian pathology 31 . Some are treated with repeated laparotomies, debulking of the tumor and/or removing mucin, while others receive systemic chemotherapy with minimal response. In men incidental presentation of peritoneal nodules or mucin in a hernial sac whilst undergoing hernia repair is often the case 31 , 32 . It is now recognized that repeat laparotomy is unlikely to achieve cure and the recommended treatment is an attempt at complete cytoreduction and administra-tion of heated intraoperative intraperitoneal chemother-apy 33 . In the UK there are now two centers designated for the treatment of tumors of appendiceal origin: North Hampshire Hospital, Basingstoke and the Christie Hos-pital, Manchester. This approach is supported by the UK National Institute of Clinical Excellence (NICE) whose recommendations for PMP treatment in designated centers were published in 2004 34 . The concentration of patients to these treatment centers has allowed the teams to adopt techniques and gain experience in the radical approach of cytoreductive surgery and intraperitoneal chemotherapy.
Although this approach is associated with significant mor-bidity, with experience this can be minimized and satis-factory outcomes achieved 35 .
Investigations include CT scanning that often demon-strates classical features of disease in the right and left upper quadrants, porta hepatus, omentum, right iliac fossa, and pouch of Douglas ( Figure 15.5 ). Tumor markers (CEA and CA19.9) are helpful in determining disease activity, response to treatment and relapse during follow-up 36 .
Unfortunately some patients have severely advanced disease at presentation such that the more radical treatment cannot be offered. Palliative debulking has a place in these patients and a recent pilot study at the Christie Hospital, Manchester, UK using systemic mitomycin and oral capecitabine has achieved tumor response and clinical benefit in one-third of 40 patients treated to date (paper submitted for publication BJC 2007).
Figure 15.4 Appendix (A) with an extramural mucocele (M) following perforation. Classical appearance of very early localized Pseudomyxoma peritonei.
Outcome
The prognosis for patients diagnosed with tumors of the appendix is determined principally by the histological type but also by whether the disease is confined to the appendix. Benign carcinoid tumors are removed without
long-term sequelae and overall appendicular carcinoids have an 80–90% 5-year survival. For epithelial tumors the prognosis is dependent upon the ability to achieve complete cytoreduction which is influenced by the histo-logical variant and the distribution of the disease 37 . Debate continues regarding the need for right hemicolectomy for tumors confined to the appendix but in the presence of peritoneal disease more extensive resection does not incur a survival advantage unless required for complete macro-scopic cytoreduction 38 . The overall outlook for PMP patients is a 50–70% 5-year survival following cytoreduction and intraoperative chemotherapy 39 . The influence of histo-logical type is also important as patients with intermediate/
discordant features and PMCA do less well with 30% and 10% 3-year survival, respectively 40 . In all reported series the single most important factor that influences outcome is whether the surgeon can achieve complete macroscopic eradication of disease.
Advice regarding follow-up for patients with appendi-ceal tumors is difficult particularly when the tumor has been fully removed and confined to a non-perforated appendix. There are, however, reports of patients present-ing with metastatic disease decades later hence a healthy respect must be shown for early reinvestigation of occult symptoms in patients with a history of tumors of the appendix.
SUMMARY
Tumors of the small intestine and appendix are rare but can have devastating effects on individual patients as diag-nosis is difficult and often delayed. The outcome for patients is influenced by their ability to access specialist teams that can offer multimodality treatment where appropriate. It is hoped that with increased knowledge and education about new treatment options patients will benefit from advances in both surgical and non-surgical treatments.
Figure 15.5 (a) Computed tomography (CT) scan demonstrating classical appearance of advanced Pseudomyxoma peritonei: scalloping of liver (L) and involvement of spleen (S). (b) large appendiceal mucocele (M) and appendix (A).
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RELEVANT WEBSITES
www.christie.nhs.uk/profinfo/departments/Pseudomyxoma www.surgicaloncology.com
www.augis.org/news/articles/gist
CANCER OF THE COLON AND RECTUM Epidemiology and etiology
Worldwide, colorectal cancers (CRC) occur in approximately 8.1 million people and cause 5.2 million deaths each year. Nearly 150 000 new cases of colon and rectal cancer are diagnosed each year in the US, and it is the second leading cause of cancer death in this country 1 . These include approximately 106 000 colon cancers with the remainder being rectal cancers. Of sporadic CRC 90% occur in people after their fifth decade and it is uncommon before the age of 40. There has been an over-all decrease in the incidence rates over the past 20 years which is attributed to increased screening and prevention with the more widespread use of colonoscopy. During this time, however, the incidence of right-sided colon cancers has been increasing in the US and Europe. The overall incidence is higher in patients who have an inherited predisposition to CRC. This occurs in fewer than 10% of patients with CRC and these cases are subdivided according to whether or not colonic polyps are a major disease manifestation.
It is now understood that development of sporadic colon cancer is a multistep process of genetic mutations which drives the transformation from normal colonic epithelium to an invasive cancer. Pioneering work by Fearon and Vogelstein first identified the basic sequence of these events with mutations in the tumor suppressor adenomatous polyposis coli (APC) gene occurring early in the process, while others, such as mutations of the p53 suppressor gene, generally occur late in the process.
Chromosomal instability and many other important genetic and epigenetic events play important roles in colon cancer pathogenesis, including alterations in β -catenin and the wnt signaling pathway, DNA mismatch repair genes, and transforming growth factor (TGF)- β / SMAD pathways (adenoma-carcinoma sequence, see Figure 16.1 ).
Two inherited disorders are associated with the greatest risk of developing colon cancer: familial adeno-matous polyposis (FAP) and hereditary non-polyposis colorectal cancer (HNPCC) 3 , 4 . FAP is characterized by the development of hundreds to thousands of colon and rectal polyps which generally develop during the second to third decade of life, have an early and high incidence of development of CRC, and account for less than 1% of all CRC. There are three variants of FAP:
(1) Gardner's syndrome, which is associated with extraintestinal tumors including desmoid tumors, sebaceous or epidermoid cysts, lipomas, osteomas (especially of the mandible), and polyps of the proximal gastrointestinal tract (stomach and duodenum);
(2) Turcot's syndrome is associated with brain tumors, primarily medulloblastomas;
(3) Attenuated familial adenomatous polyposis, having fewer number of colonic polyps (generally < 100) and a delayed onset of CRC formation than the other variants.
These disorders are autosomal dominant diseases caused by mutations in the APC gene, located on chromosome 5q21-q22.
HNPCC is more common than FAP, accounting for about 2–3% of all CRC and results from mutations in one of several DNA mismatch repair genes resulting in microsatellite instability (MSI) 4. Traditionally, this disorder was classified as Lynch I and Lynch II syndromes.
These patients developed early onset, predominantly right-sided colon cancers that tend to develop from flat, villous polyps rather than tubular adenomas compared with patients with sporadic CRC. Lynch II patients were additionally characterized by having a high risk of developing extracolonic tumors including endometrial, gastric, small bowel, ovarian, pancreatic, hepatobiliary, or renal cancers. However, as more families are studied and