tbl 4 clinical: colorectal cancer Flashcards
Features of colorectal cancer
- Patients with colorectal cancer presents in 3 ways:
o Suspicious symptoms – change in bowel habits: diarrhoea, constipation, _______________, per-rectal bleeding, abdominal pain, loss of appetite/weight, anaemia
o Emergency situation – intestinal obstruction, ________ and acute GI bleeding
o Asymptomatic – early stage disease, detected via routine screening program - Unusual presentations of colorectal cancer
o Fever of unknown origin
o Malignant fistula formation
o Streptococcus bovis, Clostridium septicum infection – can lead to sepsis - Symptoms of CRC are typically due to growth of tumor into the lumen or adjacent structures, and usually reflects a relatively advanced cancer
o Change in bowel habits is a more common presenting symptom for leftsided as compared with right-sided cancers
o _____________ is more likely with rectal than colon cancers, and __________ is more common with caecal and ascending colon cancers - The increasing uptake of colon cancer screening has led to more cases being diagnosed at an asymptomatic stage
o However, most cancers are still being diagnosed after the onset of symptoms, with a more advanced stage of disease at diagnosis – associated with a poorer outcome
o 1 in 5 patients with colorectal cancer presents with metastatic disease, most commonly to the lymph nodes, liver, lung or peritoneum
smaller stool calibre;
peritonitis;
Haematochezia; occult colonic bleeding
Risk factors for colorectal cancer
- Major factors that increase the risk of colon cancer and influence screening recommendations
o Age – typically starting at age 50
o Personal or family history of sporadic colorectal cancer (and possibly large or advanced adenomas)
o History of ____________________
o Hereditary form of colorectal cancer such as FAP (familial adenomatous polyposis – 100% risk of CRC)
o Affected by conditions that are associated with an increased risk of colorectal cancer such as ___________
- Modifiable risk factors that has been associated with an increased risk of colorectal cancer include – tobacco use, excessive consumption of alcohol, obesity, diabetes, lack of exercise and consumption of __________
- Increased age and positive family history
o Risk of developing CRC increases with age, starting at about age 40 and roughly doubling with each decade
o Most screening programs chose to start at age 50 as over 90% of colorectal cancers occurs after age 50
o Risk of colon cancer not only increases with age but is also higher in those with a family history of colon cancer – particularly when there is a first degree relative with colon cancer diagnosed at an early age
§ Risk is higher when multiple first-degree relatives are affected by colon cancer
abdominal irradiation;
inflammatory bowel disease;
processed meat;
Sporadic colorectal cancer – occurs at average age of 69 years with a lifetime risk of 1:18 in females and 1:17 in males
- Adenoma-carcinoma sequence accounts for about 80% of sporadic colorectal cancers
o Progressive genetic mutations involving inactivation of tumor suppressor genes (APC, DCC, p53) and activation of oncogenes (K-ras) are associated with the progression from normal colonic mucosa to localized colon epithelial proliferation
o Progresses to the formation of ____________ which gradually becomes bigger and more dysplastic and eventually progressing to invasive cancers - Evidence of importance of adenocarcinomas
o Early carcinomas are frequently seen within _________________, and areas of adenomatous change often found surrounding human colorectal cancers
o Adenomas and carcinomas are found in similar distributions throughout large bowel
o Adenomas are observed 10 to 15years prior to onset of cancer in both sporadic and familial cases
o In animal models – adenomas develop before carcinomas and carcinomas develop exclusively in adenomatous tissue
o (2004) National Polyp Study showed removal of colonic adenomas during colonoscopy prevented subsequent development of colorectal cancers
small adenomas;
large adenomatous polyps
Molecular Pathogenesis of colorectal cancer – there appear to be at least three molecular pathways leading to colorectal tumorigenesis
Chromosomal instability pathway:
- Results from gain of function mutations that results in activation of growth promoting pathways including oncogenes or diminished activity of tumor suppressor genes
- These tumours may be inherited (as with FAP) or sporadic, and they are characterized by gross chromosomal abnormalities including deletions, insertions, and _________________.
Mismatch repair pathway
- Implicated in the inherited condition Lynch syndrome as well as in a small proportion of sporadic CRCs
- The key element of this pathway is dysfunction of DNA mismatch repair (MMR) enzymes resulting from germline mutations in one of several different DNA mismatch repair genes, most commonly MLH1 or MSH2. Cells with deficient DNA repair capacity accumulate DNA errors throughout the genome, resulting in high levels of microsatellite instability (MSI-H), the biological footprint of __________________.
Serrated polyp pathway
- Activating mutations in the ___________ results in high frequency of methylation of some CpG islands and leading to hypermethylation of the promoter region of MMR enzymes such as MLH1, and silencing of gene expression
loss of heterozygosity;
MMR protein deficiency;
BRAF gene;
Diagnosis, staging and treatment of colorectal cancer
- Diagnosis of colorectal cancer requires luminal imaging and histological confirmation – _____________ of the suspected lesion is needed to arrive at a diagnosis
- In patients with newly diagnosed invasive colon cancer, preoperative chest, abdomen, and pelvis CT scans can demonstrate regional tumour extension, regional lymphatic and distant metastases, and tumour-related complications (e.g. obstruction, perforation, fistula formation), findings that can assist in selecting the best therapeutic approach
o If the tumour is located in the rectum, ________ can provide valuable information on the T and N staging of the disease - _________________ should be taken at the time of diagnosis, which is elevated in about 60% of cases
o Monitoring of CEA levels can be useful to assess effectiveness of surgery (persistent elevated CEA may imply residual disease) and to detect early recurrence in post-operative surveillance
o CEA can be falsely elevated in benign conditions like smoking, or polyps, or other pathologies e.g. lung pathologies, gastric cancer - Family history of colorectal and extracolonic tumours should be sought prior to surgery
o The surgical approach may be altered in a patient suspected or confirmed to have an inherited predisposition to colorectal cancer – subtotal or total colectomy in high risk individuals - Treatment –
o Surgical resection curative for localised cancer
o ____________ – alternative to surgery for early stage colorectal cancer arising from a polyp, without unfavourable features –
§ Invasion into deep submucosa, poorly differentiated histology,
lymphovascular invasion, residual cancer at resection margins
o Chemotherapy and/or radiotherapy can be used as neoadjuvant (preoperative) or adjuvant (post-operative) therapy, depending on the location (rectal vs colon) and stage of disease - For metastatic disease –
o Palliative chemotherapy recommended
o Selected patients with limited metastatic disease to liver/lung may still benefit for combined aggressive surgery/chemotherapy
colonoscopy with biopsies;
MRI rectum;
CEA (carcinoembryonic antigen) levels;
Endoscopic resection
Screening for colorectal cancer
- Screening – defined as application of tests or procedures for the early detection of disease in asymptomatic individual
- Rationale for screening for colorectal cancer is that most patients with colorectal cancer are diagnosed at an advanced stage when they present after the onset of symptoms
- Most colorectal cancers arise from adenomatous polyps that progresses from small (<8mm) to large (>8mm) polyps, then to ___________ and carcinoma – taking an estimated average of 10yrs
During this time, if these polyps sought for and removed, colon cancer can
be prevented
- Detection of early stage colon cancer is also beneficial as they are easier to treat and has a better prognosis
o Studies have shown that colorectal cancer screening has resulted in a decrease of colorectal cancer incidence and mortality rates
- Trends in colorectal cancer incidence and mortality reveal declined rates with – early detection and prevention through __________ and improved treatment, reduced exposure to risk factors
- Screening methods – stool tests, CT (computed tomography) colonography, _____________ and colonoscopy
o Risk stratification determines the age of onset of screening, screening test and screening interval
dysplasia;
polypectomy;
flexible sigmoidoscopy
- Stool tests – guaiac based faecal occult blood test, faecal immunochemical test and stool DNA test
Mechanism
- gFOBT Detects blood through _________ activity of heme to Hb. Needs 3 stool samples annually if negative
- FIT Detects __________ – constitutes human Hb along with heme. More specific for human blood – guaiac-based tests
- Stool DNA Detect known DNA alterations in the adenoma-carcinoma sequence of colorectal carcinogenesis. No single gene mutation in cells shed by every adenoma or cancer. Need _____________
[Pros and cons]
gFOBT
- Can be done in physician’s office/lab
- Has diet interaction – avoid aspirin, ____________, red meat (false positive), poultry, fish, some raw vegetables
- Guaiac based test react to peroxidase present in dietary constituents e.g. rare red meat, ___________ and some fruits
- Avoid vitamin C (>250mg) 3 days before testing – false negative as high dose vitamin C blocks the peroxidase reaction
FIT
- Done in clinical lab
- Globin is degraded by digestive enzymes in upper GI tract – more specific for ____________
- No dietary restriction
- 2 samples may be superior to 1
Stool DNA
- Need entire stool specimen (30g minimum) – transported in customized kit with designed ice pack
- Sensitivity based on panel of markers that identify majority of CRC (but not all)
- Unsure frequency to perform
Clinical relevance of positive test without identification of cause of abnormality
- Both FOBT and FIT tests for occult blood in the stools – FIT test has the following advantages compared to the guaiac based FOBT test
o More sensitive and more specific for human blood than guaiac based FOBT.
o FIT is more specific for lower GI Bleeding
o Dietary restrictions are not required, in contrast to the gFOBT, which may be falsely positive or negative due to interference from dietary constituents, such as red meat or vitamin C
- FIT test should be performed ______
- The stool DNA test is a noninvasive laboratory test that identifies DNA changes in the cells of a stool sample (new method to screen for colon cancer)
o Looks for abnormal DNA associated with colon cancer or colon polyps
o The test is performed __________ on one stool collection sample
pseudoperoxidase ;
human globin
multitarget DNA stool assay;
NSAIDs;
cruciferous vegetables;
lower GI bleeding;
annually; every three years
Flexible sigmoidoscopy
- Examines the left side of the colon – insertion to ≥40cm is required up till the ___________, can be performed without sedation
- Requires “limited bowel prep” – can be done with __________, however, may still have suboptimal view compared to using full bowel preparation with polyethylene glycol
o Studies have demonstrated a 60 to 80% reduction in colorectal cancer mortality for the area of the colon within its reach
- Limitations of flexible sigmoidoscopy
o The variation of depth of insertion between examiners
o Major limitation is that – ________ is not examined, hence there is a risk of missing colonic polyps and cancer in the right colon - While the prevalence of proximal neoplasia varies
with age, gender, ethnicity, if an adenoma (of any size) in the distal colon found – there is a 2x or higher increased risk of proximal advanced neoplasia
splenic flexure;
fleet enema;
proximal colon;
- Colonoscopy
- Allows direct mucosal inspection of the entire colon from the ____________ to dentate line and allows biopsy or definitive treatment of polyps by endoscopic resection e.g. polypectomy
o National Polyp Study reported incidence of colorectal cancer after clearing colonoscopy was reduced by 76 to 90%
o Screening average risk adults starts at age 50 years
- Limitations of colonoscopy include the need for bowel preparation, more invasive procedure compared to flexible sigmoidoscopy with potential complications, and it is also operator-skill dependent
- Potential complications of colonoscopy include e.g. ______________, perforation (1 in 1000), cardiopulmonary complications (usually sedation related)
appendix orifice;
post-polypectomy bleeding
- CT colonography or virtual colonoscopy – minimally invasive radiological examination of the entire colon and rectum
- Images are acquired with advanced 2D and 3D image display techniques, takes about 10 mins to complete and can be done without sedation
- It has a 97% sensitivity at detecting invasive colorectal cancer – more sensitive at detecting polyps >10mm than smaller polyps, with a sensitivity of up to 93%
- In addition to detecting colonic polyps and tumors, CT colonography has the added advantage of being able to detect ___________, especially if contrast used
- Limitations of CT colonoscopy
o Bowel preparation is still required for CT colonography
o The colon has to be adequately distended for this examination – a ______ is inserted for air insufflation
o Purely a diagnostic tool and a colonoscopy is still needed if an abnormality is found
o There is exposure to low dose radiation
o Perforation can still occur, with rates reported 0.03% to 0.06%
extracolonic lesions;
rectal tube
Risk stratification for colorectal cancer – determines the age of onset of screening, screening test and screening interval
Average – shared decision making with patient regarding options of screening test
- Aged _________
- No family history of CRC
- No personal history of adenoma, sessile serrated polyps, CRC, Inflammatory bowel disease (IBD)
Increased – colonoscopy recommended as screening modality
- Personal history of adenomatous polyps, sessile serrated polyps, CRC, IBD
- Family history – 1 first-degree relative (FDR) with CRC or advanced adenoma/__________ aged <60 years or 2 FDR with CRC or advanced adenoma at any age –
colonoscopy recommended every five years, beginning ________________ in the family or at 40 years of age at the latest
- 1 FDR with CRC or advanced adenoma/serrated aged ≥60 years or one second-degree relative diagnosed prior to 50 years of age – colonoscopy should begin at _______________.
- An FDR with advanced adenoma (high-grade dysplasia, lesions ≥ 1cm, villous elements) – should undergo colonoscopy at the relative’s age of
onset of adenoma, or by 50 years of age at the latest
- Advanced serrated lesion – _____________/traditional serrated adenoma>1cm, SSP with cytologic dysplasia
High Presence of high-risk syndromes e.g. hereditary nonpolyposis CRC and polyposis syndrome (e.g. familial adenomatous polyposis)
- Must be referred and co-managed by a gastroenterologist, colorectal surgeon and/or cancer geneticist for regular and active surveillance of CRC
≥ 50 years;
serrated lesion;
ten years prior to the earliest diagnosis;
50 years of age;
sessile serrated polyp (SSP);
Screening for an average-risk individual – screening for colon cancer begins at the age of 50
- While limited data suggests the benefit of screening at an earlier age of 45 years, this has not been universally accepted
- Recommended screening options include annual FIT tests for occult blood, CT colonography __________- and colonoscopy _____________.
- Other options include multi-targeted stool DNA test every 3 years and flexible sigmoidoscopy every 5 years
- Every positive CRC screening (other than colonoscopy) should be followed expeditiously by ___________
- When to stop screening
o Continue through to age of 75 years – stop if one is in good health, life expectancy 10 years
o Screening individualised for age 76 to 85 years – discourage continuing screening after age _______
Colorectal cancer screening in Singapore
- Citizens and permanent residents ≥50 years are invited to screen for CRC annually with free faecal immunochemical test (FIT) kits from Community Health Assist Scheme general practice clinics
- FIT kit also available for collection at Singapore Cancer Society and selected retail pharmacy outlets for free Colorectal cancer screening in increased-risk individual – enhanced screening
- For individuals with a family history of CRC, advanced adenoma or advanced serrated lesion, enhanced screening is suggested rather than average-risk screening
- Positive family history of CRC or an advanced adenoma in 2 FDRs at any age or 1 FDR at age <60 years
o Should undergo colonoscopy ____________, beginning 10 years before the age at diagnosis of the youngest affected individual or at age 40, whichever is earlier
- In those with a single FDR diagnosed at age of 60yrs and above, CRC screening should begin at the age of 40 years, with tests and screening intervals as recommended for average risk individuals
every 5 years; every 10 years;
colonoscopy;
> 85 years;
every 5 years;
Hereditary cancer syndromes
- 5 to 10% of all cancers are attributable to a hereditary cancer predisposition syndrome
- Approximately _______ of patients with colorectal cancer (CRC) have sporadic disease, but the remaining 20 to 30% have a familial/inherited component
Types of hereditary cancer syndromes
- Familial adenomatous polyposis (FAP) and ______________ (FAP with extracolonic manifestations)
- Haematomatous polyp syndromes – Peutz-Jeghers syndrome (PJS) and juvenile polyposis syndrome (JPS)
- Lynch syndrome – hereditary non polyposis colorectal cancer (HNPCC)
70 to 80%; Gardner’s syndrome
- Familial adenomatous polyposis (FAP) – characterized by the presence of multiple
colorectal adenomatous polyps (typically more than 100)
- Estimated prevalence of three cases per 100,000 individuals, affects both sexes equally and has a worldwide distribution
- FAP and its variants are caused by germline mutations in the tumour suppressor gene, Adenomatous Polyposis Coli (APC), located on chromosome ________
o Follows an autosomal dominant pattern of inheritance with nearly complete penetrance of colonic polyposis but variable penetrance of the extracolonic manifestations of the disease
- Diffuse polyposis typically develops in the 2nd and 3rd decade of life – without colectomy, colon cancer develops in all patients at an average age of ________
- Increased risk of extracolonic tumours e.g. thyroid cancer, pancreatic cancer, duodenal and ampullary cancer, gastric cancer - Attenuated FAP – milder form of FAP characterised by lesser colonic polyps (_____________), usually with adenomas numbering less than 100
- Average age of CRC reported at 49 years old and has an incidence of 1:9000
- Autosomal dominant condition and gene abnormality involved are APC in >90% cases
o Polyps in attenuated FAP has a more proximal distribution or __________ predominance
o Patients develop adenomas and colon cancer at a later age – while the risk of developing CRC is still high, it is lower than classic FAP - Gardner’s syndrome – FAP with extracolonic manifestations
- ____________, sebaceous/epidermoid cysts, lipomas, fibromas
- Osteomas, supernumerary teeth, juvenile nasopharyngeal angiofibromas
- Congenital hypertrophy of the __________ (CHRPE)
5q21-22; 39 years
oligopolyposis; right sided
Desmoid tumours; retinal pigment epithelium
- Harmatomatous polyp syndromes – Peutz-Jeghers syndrome (PJS)
- Characterised by multiple harmatomatous polyps in the GI tract, __________ and increased risk of GI and non-GI cancers (estimated risk of 2-20%) and extra-intestinal malignancies – prevalence rate of 10 to 30% e.g. pancreatic, breast and reproductive organ
(ovary, testis)
o Rare with an estimated prevalence of 1: 8000 to 200,000, affects males and females equally
- Autosomal dominant syndrome – most often caused by germline mutations in the ______ gene mapped to chromosome ________
o High penetrance (expressed in the phenotype), with 90% manifesting the disease, by age 30
o However, mutations in the STK11 gene accounts for only 50 to 80% of cases, suggesting there is a 2nd PJS gene locus
There are two main clinical manifestations of PJS – pigmented mucocutaneous macules and multiple gastrointestinal harmatomatous polyps.
o Characteristic mucocutaneous pigmentations (melanin spots) of PJS are present in more than 95 percent of patients, occurring most commonly on
the ___________ region, buccal mucosa, and on the palms of the hands, and soles of the feet
o Gastrointestinal hamartomatous polyps are present in most patients with PJS and can occur anywhere in the gastrointestinal tract, but most commonly in the __________
§ Polyps develop in the first decade of life and most patients become symptomatic between the age of 10 and 30 years
§ Number of polyps ranges from 1 to more than 20 per segment of bowel and can result in symptoms of iron deficiency anaemia and intussusception with bowel obstruction.- These patients have an increased risk of GI cancers (colorectal, stomach, small bowel and pancreas) and extraintestinal cancers (lung, breast, uterus, ovarian and testicular tumours)
mucocutaneous pigmentation;
STK11(LKB1); 19p13.3;
lips and perioral;
jejunum;
