Introduction
Colorectal cancer (CRC) is the most common gastrointestinal tract (GIT) malignancy
globally, being the third most common malignancy and second most common cause of cancer-related
death. In India, CRC is the fifth most common malignancy and seventh most common cause
of cancer-related death. CRC incidence and mortality rates vary by up to 10-fold not
just around the world but also across India, with the highest incidence in the world
being in Europe, Australia, and New Zealand and the lowest being in Western Africa
and Southcentral Asia. In India, the highest incidence is seen in Northeast and South
India, while the lowest incidence is observed in Central and East India. The incidence
and mortality are considerably greater in males compared to females.[1] This wide variation in incidence may be attributable to lifestyle, environmental,
and genetic factors.
CRC based on pathogenesis is classified as sporadic (70%), familial (20%), and inherited/hereditary
syndromes (10%). Sporadic CRC has no family history and is attributable to lifestyle
and environmental factors. Familial CRC have a family history of CRC, but is not consistent
with any of the hereditary syndromes. Hereditary CRC have an inherited genetic mutation,
which predisposes the affected individuals to develop CRC.
Hereditary CRC is divided into hereditary nonpolyposis colorectal cancer (HNPCC) and
hereditary polyposis colorectal cancer (HPCC). HNPCC is an autosomal dominant syndrome
(1.7 to 4.2% of all CRC) consisting of Lynch syndrome, Sporadic colorectal carcinomas
(MLH1-/PMS2-deficient), Muir-Torre syndrome and Turcot syndrome type I. Among these,
Lynch's syndrome is the most common hereditary CRC syndrome. It results from a defect
in DNA mismatch repair due to germline mutation in one of the mismatch repair genes,
that is, MLH1, MSH2, MSH6, PMS2, or deletion in the EPCAM gene. It is associated with
increased risk of CRC and endometrial cancer, gastric, ovary, small intestine, hepatopancreatobiliary,
ureter, renal pelvis, brain (glioblastoma), skin (sebaceous), prostate, and breast
cancers. Screening for Lynch's syndrome is usually done based on the Amsterdam II
Criteria and Revised Bethesda Guidelines. Prophylactic surgery is recommended (hysterectomy + bilateral
salpingo-oophorectomy, colectomy).[2]
HPCC (3–5% of all CRCs) consists of familial adenomatous polyposis (FAP), adenomatous
polyposis syndromes (adenomatous polyposis coli [APC] and MUTYH), juvenile polyposis
coli (BMPR1A and SMAD4), Peutz–Jeghers syndrome (STK11/LKB1), PTEN hamartoma tumor
syndrome (PHTS; PTEN), Cowden's syndrome (PTEN), Turcot's syndrome type II (APC),
and Gardner's syndrome (APC). FAP is the most common HPCC syndrome and the second
most common hereditary CRC.[2] In this article, we shall review the FAP in brief.
FAP is a syndrome charactered by the presence of multiple (>100) colorectal adenomas.
It occurs approximately 1 in 10,000 live births and both genders are equally affected.
FAP is associated with less than 1% of all cases of CRC. It is an autosomal dominant
hereditary CRC syndrome, caused by germline mutation in the APC gene, which is located
on the long arm of chromosome 5q21-q22. APC is the gatekeeper gene and usually follows
complete penetrance for colonic polyposis and variable penetrance for extracolonic
manifestations. Up to 25% of FAP cases result from de novo APC mutations.
Mutation resulting in inactivation of both the APC alleles (one inherited mutation
and another somatic mutation or deletion of allele) is required for developing adenomas
in FAP. Inactivation of both the APC alleles leads to the absence of functional APC
protein and abnormal accumulation of beta-catenin, leading to activation of wingless-type
(Wnt) signaling pathway, which plays an important role in controlling cell growth
and is implicated in carcinogenesis of various tumors including FAP.[3]
The location of mutation in the APC gene is an important factor in the management
of FAP as it is associated with risk of cancer, its age of onset, its severity, associated
survival, and presence of extracolonic manifestations. Mutations between codons 1250
and 1464 are associated with severe FAP; mutations between codons 158 and 1595 (except
that between codons 312 to 412 as well as between 1250 and 1464) are associated with
intermediate FAP; and mutations at the 3 prime end, 5 prime end and/or exon 9 (i.e.,
codon between 312 to 412) are associated with attenuated FAP. Mutations between codon
463 and 1,444 are associated with congenital hypertrophy of the retinal pigment epithelium,
mutations between codons 1,445 and 1,578 are associated with desmoid tumors, mutations
between codons 279 and 1,309 are associated with duodenal polyposis, mutations between
codons 686 and 1,217 are associated with medulloblastoma, and mutations in the promoter
region of APC are associated with gastric adenocarcinoma and proximal polyposis of
the stomach.[4]
Immune Microenvironmental
With increasing knowledge about microenvironment and the development of personalized
medicine with definitive therapy, apart from colectomy, which is associated with its
own set of complications, various studies are being conducted to understand the immune
microenvironment of FAP, mainly in murine models with heterozygous mutations in the
APC gene. The studies have shown that immune cells, that is, CD4 cells were decreased
in mesenteric lymph nodes and Peyer patches, CD8 T cells were decreased, CD4 T cells
were increased, regulator T cells were increased, tumor-associated macrophage subtype
M2 was increased, NK cells were decreased, B cells were decreased, mast cells were
increased, and tumor-associated neutrophil subtype N2 was increased. Cytokines, that
is, interleukin-6 (IL-6), IL-8, transforming growth factor-β (TGF-β), and IL-33 were
also shown to be increased. Use of this information for therapeutic purpose is still
in the research stage.[3]
Clinical Manifestations
The hallmark clinical manifestation of FAP is the presence of multiple colorectal
adenomas. Sixteen years is the average age of adenoma development, with 29 years being
the average age of diagnosis of a new patient and 39 years being the average age of
diagnosis of CRC.
They are usually asymptomatic until they develop signs and symptoms of CRC.
Extracolonic Manifestations
-
Gardner's syndrome: It is a subtype of FAP characterized by the presence of extracolonic
manifestations:
-
- Benign extraintestinal lesions like osteomas, dental abnormalities, cutaneous lesions,
desmoid tumors, congenital hypertrophy of the retinal pigment epithelium, adrenal
adenomas, and nasal angiofibromas.
-
- Extra-colonic malignancies like duodenal and periampullary adenomas and adenocarcinomas,
thyroid (papillary) and pancreatic adenocarcinoma, gastric fundic gland polyps and
adenomas and adenocarcinomas, central nervous system medulloblastoma, hepatoblastoma,
adenomas and adenocarcinomas of the small bowel distal to the duodenum, and adrenal
adenomas and adenocarcinomas.[5]
-
Turcot's syndrome: It is a subtype of FAP characterized by the presence of only central
nervous system tumors, that is, medulloblastomas and gliomas along with FAP.[6]
[7]
Diagnosis
FAP may be diagnosed genetically or clinically. The most common method used to screen
APC mutation is APC gene testing by protein truncation. Genetic testing reveals APC
germline mutation in approximately 80% of the cases. About 25% of the patients have
de novo mutation and thus have no family history. The indications for genetic testing
and counselling include the following:
The genes analyzed in a patient with colorectal polyps are APC, MUTYH, POLE, POLD1,
and GREM1. Colorectal screening should be done on all individuals with genetically
diagnosed FAP and persons with first-degree relatives with FAP. Screening colonoscopy
should start at the age of 10 to 15 years. If no polyps are found, repeat every year
and earlier if there are symptoms (till the age of 24 years, if no polyps are detected;
screening frequency is reduced once in every 2 years till the age of 34 years, then
every 3 years till the age of 44 years, and then every 3–5 years for the rest of their
lives). If polyps are seen, biopsy of multiple polyps is indicated.
Management
The most common cause of death in a patient with FAP is CRC. One hundred percent of
the patients with FAP develop CRC, with 39 years being the average age of diagnosis
of CRC. However, in AFAP, 70% of the patients develop CRC, with 58 years being the
average age of diagnosis of CRC. The most effective way to prevent CRC is colectomy.
Chemoprevention
No chemo-preventive drug is still found to be completely effective in FAP and thus
is not a routinely favored option. Sulindac (nonsteroidal anti-inflammatory drug with
cyclooxygenase-1 and cyclooxygenase-2 inhibitors) is the most commonly studied and
used chemo-preventive drug in FAP. It is used as an acceptable option in FAP patients
with pouch polyposis (as pouch removal can lead to end ileostomy), at a dose of 150
to 200 mg twice a day. Dyspepsia, GI bleeding, and renal impairment are its common
side effects.[8] Other drugs studied and used are celecoxib, rofecoxib, aspirin, and difluoromethylornithine.
In duodenal adenomas, erlotinib (epidermal growth factor inhibitor) in combination
with sulindac has shown promising results.[9]
Colectomy
Surgical options for FAP patients include total colectomy (TC) with ileorectal anastomosis
(IRA), total proctocolectomy (TPC) with ileal pouch anal anastomosis (IPAA), and TPC
with EI. Preferred surgical technique depends on age of patient, severity and distribution
(rectal) of polyps, risk of developing desmoids, comorbidities, and location of APC
mutation. The extent of resection should be discussed with the patient in detail including
its risks and follow-up surveillance including quality of life (preventive benefit
should never outweigh quality of life). Risk of rectal cancer is three times higher
in patients with mutations in the FAP gene after codon 1,250; thus, TC with IRA can
be done to minimize the risk of bleeding and infertility with TPC with IPAA in patients
with mutations in the FAP gene proximal to codon 1,250, and proctoscopy reveals few
or no polyps in rectum.
TC with IRA should be considered in patients with less than 1,000 colonic adenomas
with less than 10 rectal adenomas, all of which can be managed endoscopically (preoperatively
all rectal polyps ≥5 mm should be removed and confirmed for the absence of carcinoma)
and contraindicated in rectal carcinoma. TPC with IPAA should be considered in patients
with greater than 10 rectal adenomas or rectal carcinomas (not low rectal carcinoma)
and contraindicated in patients with high risk of desmoid and lack of surgical expertise.
TPC with EI should be considered in patients with low rectal carcinoma, in whom IPAA
is not possible, and those with poor sphincter function.[10] The differences between IRA and IPAA include the loss of rectum, the need for deep
pelvic dissection in IPAA, and distinct physiology of the ileal pouch.
TPC with mucosectomy up to the dentate line (S pouch is preferred in such a scenario)
is done in patients with rectal dysplasia, rectal carcinoma, and anal transitional
zone (ATZ) and/or low rectum having multiple adenomas. ATZ is a hot spot for adenomas.
Adenomas are twice as common after stapled IPAA in comparison to handsewn IPAA. These
are managed by snaring.
Urgent colectomy should be offered in patients diagnosed with colorectal carcinoma
or those with adenoma having high-grade dysplasia. Early colectomy should be considered
in a symptomatic patient (e.g., GI bleed), those with multiple (6- to 10-mm) polyps
that cannot be managed endoscopically, and those with a marked rise in the number
of polyps on consecutive colonoscopy. Elective colectomy can be deferred in asymptomatic
FAP patients with less than 10 or small (<5 mm) adenomas to the late teens or early
20s until they reach their physical and emotional maturity. The indications for delayed
surgery in an asymptomatic FAP patient are (1) a female who wishes to have a child
and wants to avoid the risk of infertility following proctectomy; (2) a morbidly obese
patient who wishes to make restorative proctocolectomy (RPC) with IPAA feasible by
losing weight; and (3) family history of desmoid as most of the desmoids develop following
surgery. Endoscopic surveillance of the rectum or ileal pouch including at least 15 cm
of terminal ileum above the IRA or pouch should be performed every 6 to 12 months
and yearly in EI. The risks of developing an adenoma and adenocarcinoma in the pouch
are around 45 and 1%, respectively.[11]
[12]
