FAP is an autosomal dominantly inherited syndrome of tumor predisposition due to a germline mutation in the tumor suppressor gene APC. APC is a key “gatekeeper” gene that controls β[beta] catenin degradation and so the activation status of multiple genes stimulating cell growth and differentiation. It is one of the first genes inactivated in the chromosomal instability mechanism leading to sporadic colorectal cancer and in FAP loss of APC from a germline mutation and a second sporadic “hit” leads to extensive tumor formation in multiple organs. The large bowel is primarily affected and multiple adenomas start to form, usually in the second decade of life. Untreated, colorectal cancer develops usually about age 39. The severity of the expression of the germline mutation varies from one patient and one family to another, with the locus of the mutation being one determinant. Extracolonic manifestations of FAP include gastroduodenal polyps and desmoid disease [9]. Desmoid disease is the second most common cause of death in patients with FAP. It is a proliferations of fibroblasts with a spectrum of presentations, either as tumors or sheets, often within the abdomen where they kink and distort bowel [10]. Desmoid disease sometimes affects operative strategy in FAP, in particular plans for the rectum.

MAP is an autosomal recessively inherited syndrome of colorectal cancer predisposition due to biallelic inheritance of mutations in MYH, a gene involved in DNA base excision repair. Loss of MYH means that oxidized DNA replicates falsely. Oxidized guanine will bond with thymine instead of cytosine, creating a G=C to T=A transversion in the next generation of cells. This transversion is a mutation that can alter the function of susceptible genes. Both APC and KRAS are susceptible genes, and adenomas as well as serrated polyps are part of the MAP phenotype. Clinically MAP most often presents as a sort of “mini” FAP. The family history is often different however, reflecting recessive inheritance, but MAP can mimic LS, classical FAP, sporadic colorectal cancer, young age of onset colorectal cancer and even serrated polyposis [11].

LS syndrome presents with a primary rectal cancer about 20 % of the time; slightly more often when there is a germline MSH6 mutation. A MSI-H rectal cancer is very likely to be associated with LS, as sporadic, hypermethylation MSI-H tumors are almost never found there [16]. Biopsy of a rectal cancer for microsatellite instability and immunohistochemistry is a good way of screening for LS, as long as it is done prior to neo-adjuvant chemoradiation.

One of the hallmarks of LS is a high incidence of both synchronous and metachronous colon neoplasia. It is essential that LS patients with a rectal cancer undergo high quality colonoscopy. Proximal neoplasms must be removed and if they are advanced, total proctocolectomy with ileal pouch-anal anastomosis or end ileostomy is indicated. If there is no synchronous proximal neoplasm, consideration turns to the chances of a metachronous neoplasm. There are few data addressing the risk of a metachronous colon cancer in a patient whose rectum has been removed for a primary cancer. Kalady et al. reported on 33 patients with HNPCC who underwent rectal resection for cancer [17]. Thirteen patients (39.4 %) developed a metachronous high-risk colonic adenoma and five patients (15.2 %) developed metachronous colonic cancer, three of them advanced. In all, 17 of 33 patients (51.5 %) developed high-risk adenoma or cancer, over a 6 year follow-up after proctectomy. Whether this risk is high enough to indicate routine proctocolectomy is questionable. These patients were an average of 61 years old, an age where pouch function may not be good [18]. The increased magnitude of the surgery and the need for a temporary stoma in patients with co-morbidities is also daunting and finally the use of neo-adjuvant radiation and chemotherapy is another cause for pause in taking up the radical option. If a standard anterior resection is done however, then prevention of metachronous neoplasia falls on colonoscopists’ shoulders.

Colonoscopic surveillance after anterior resection in a patient with LS must be meticulous and uncompromising. Stoffel et al. reported an adenoma miss rate in HNPCC of 55 % [19], and interval cancers can develop in a 1 year from a “negative” examination [20]. Good compliance with surveillance recommendations is essential and should be emphasized during the decision-making process at initial presentation.

Oncologic results after resection of rectal cancers in patients with LS are not well documented in the literature. Samowitz et al. reported on 990 rectal cancers and found that survival was significantly worse in MSI-H tumors [21]. This was surprising as sporadic MSI-H colorectal cancers and LS colon cancers have a better than expected prognosis. In the Samowitz et al. series there were 22 MSI-H rectal cancers, 1 with a BRAF mutation, 2 with MLH1 promoter methylation and 4 expressing CIMP. Most, therefore, were likely LS. Approximately half of their patients received neo-adjuvant therapy, which may have affected prognosis adversely, although the influence of 5 flouroacil-based chemotherapy on prognosis in MSI-H colorectal cancer is controversial. In the absence of firm data indicating that LS rectal cancers should be managed differently to sporadic MSI-H tumors or MSS tumors, standard approaches to staging, neo-adjuvant therapy and resection should be followed.

Patients with FAP are almost guaranteed to develop colorectal cancer if the colorectal polyps are not removed. In general there are too many adenomas to be managed endoscopically and so prophylactic colectomy has become routine. The issues are the timing of the surgery and the extent of the resection.

Timing generally revolves around the risk of cancer, which is determined by the number, size, histology (presence of high grade dysplasia) and rapidity of growth of the adenomas. Patients with symptoms attributable to the polyps are operated without delay, as are those with large, severely dysplastic or rapidly developing adenomas. In patients with small, infrequent and stable adenomas without high-grade dysplasia, surgery may be deferred until convenient.

The extent of surgery in patients with FAP comes down to a choice between colectomy and ileorectal anastomosis and proctocolectomy with ileostomy or ileal pouch-anal anastomosis. This is a choice between keeping the rectum or removing the rectum; keeping the organ of defecation with the associated risk of metachronous rectal cancer but a definite advantage in bowel function, or losing the organ of defecation and making do with a non-physiological replacement in the interest of minimizing cancer risk. Some centers recommend universal pouch anal anastomosis for all patients with FAP [22], while others triage patients according to rectal cancer risk. Data show quite conclusively that rectal cancer risk is determined by the colorectal polyp counts [23]. When there are <5 rectal adenomas and <1,000 colonic adenomas, proctectomy for rectal cancer or advanced neoplasia is extremely uncommon. With 5–20 rectal adenomas at colectomy, proctectomy may be required in about a third of patients but when there are >20 rectal adenomas, later proctectomy is likely in over half of cases. In many studies describing rectal cancer risk after IRA, data were at least partially derived from a time prior to 1983, when the ileal pouch anastomosis became widely adopted as an alternative to IRA and ileostomy in patients with FAP. In this “pre pouch” era, rectums severely affected by polyposis that would now be resected were retained, leading to artificially raised rectal cancer rates in subsequent years [24]. Current management triages patients into IRA or IPAA depending on the rectal polyp count. Such a policy has resulted in very low rates of proctectomy and cancer.