Colorectal cancer Flashcards
What may be seen in colorectal cancer
Raised rolled edges, central ulcerated area
Summarise colorectal cancer
Major Cancer in ‘developed’ countries
4th most common cancer overall
2 leading cause of cancer death overall, behind lung cancer
Environmental (diet) and genetic factors in aetiology
Describe the basic anatomy of the colon
Front of colon lined by peritoneum
Back of colon- most lined by mesentery- with blood vessels
Rectum – completely covered by fatty tissue – no peritoneum
What type of carcinoma are most colon cancers
Adenocarcinoma
Describe the functions of the colon
What does the colon do? Extraction of water from faeces (electrolyte balance) Faecal reservoir (evolutionary advantage) Bacterial digestion for vitamins (e.g. B and K)
Faceal reservioir- don’t want to be defacating all the time- also prevents predators from tracing you
Describe the histology of colon
Epithelial layer and lamina propria-mucosa Muscularis mucosa Sub-mucosa Muscularis propria- thicker Fat and blood vessels- mesentery
Describe colonic anatomy
The colon is divided into:
the caecum which includes the ileocaecal valve and appendix
ascending (“right”) colon
the transverse colon
descending (left) colon
sigmoid colon and
rectum
The hepatic flexure is at the junction of the ascending and transverse colon while the splenic flexure is at the junction of transverse and descending colon. The rectum is below the level of the peritoneum surface ranging between 8-15 cm. in length.
Describe the importance of colon anatomy
The anatomy is important as the blood supply to these areas differs and also that colon cancers present in different ways when they arise in different parts of the colon. There is also evidence that there are some differences in molecular genetic abnormalities and behaviours in tumours arising in right side versus left side of the colon.
What are the crypts of liberkuhn
The colonic mucosal epithelium, from which carcinomas arise, consists of tubular crypts (of Lieberkuhn) lined by predominantly mucin secreting cells with intervening surface cells which are mainly absorptive cells. The absorptive cells have basally located nuclei and do not secret mucin, whereas in the crypts goblet cells synthesise and secrete mucin. Each crypt has 5-10 enteroendocrine cells (neuroendocrine cells) and a few stem cells. Occasional Paneth cells are seen in the base of the crypts of the caecum and ascending colon.
Describe the organisation of the colorectal mucosa
Columnar epithelial cells- basal nucleus- polarity occasional goblet cells stem cells at the bottom differentiate as they go up proliferate upwards endocrine cells mesenchyme cells
Red granules- endocrine cells
Describe the important of mucin production
Mucins involved in lubrication of the GI tract, frontline innate host defense
Goblet cells- mucin- increase lubrication to allow transit, immunological role too
Support cells- mesenchymal cells
Describe turnover of colon cells
2-5 million cells die per minute in the colon!
Proliferation renders cells vulnerable
APC mutation prevents cell loss mutation
Normally we have protective mechanisms to eliminate genetically defective cells by;
Natural loss
DNA monitors
Repair enzymes
Describe the significance of the high turnover rate of the colorectal mucosa
APC regulates a number of cellular functions including mitosis, migration and maintenance of genome stability.
High turnover- more likely for mutations to occur
Loss of cells – protects against cancer, DNA checkoiints and repair genes also play a role
Turnover:
o 2-5m cells per minute die in the colon high proliferation rate (cells are vulnerable to mutation).
o APC mutation PREVENTS cell loss and causes cell proliferation.
Normal protective mechanisms include – natural loss, DNA monitors & repair enzymes
What is the difference between polyps and adenomas
A polyp is any projection from a mucosal surface into a hollow viscus, and may be hyperplastic, neoplastic, inflammatory, hamartomatous, etc
An adenoma is a benign neoplasm of the mucosal epithelial cells
Describe the colonic polyp types
Metaplastic/Hyperplastic Adenomas Juvenile Peutz Jeghers Lipomas Others (essentially any circumscribed intramucosal lesions)
Peutz jehgers- mucosal hyperpigmentation- higher risk of polyps
Describe hyper plastic polyps
Very common <0.5 cm 90% of all LI polyps Often multiple No malignant potential 15% have k-ras mutation
Describe the histological appearance of hyper plastic polyps
Fig. 11.202 Microscopic appearance of hyperplastic polyp. The individual glands show a typical serration of their mid portion.
Serrated appearance- due to hyperplastic overgrowth
Describe the different types of colonic adenomas
Tubular (>75% tubular) 90% Tubulovillous (25- 50% villous) 10% Villous ( > 50% villous) (Flat) (Serrated) The more villous, the worse.
Summarise adenomas
Colonic adenomas are very common lesions and increase with age. Most adenomas present in the 30-60 year age group and may be incidental findings at colonoscopy or cause symptoms by bleeding. They range in size from very tiny to large masses which can obstruct the colon.
Sometimes gastroenterologists see colonic lesions and describe them as polyps, but the term polyp is just applied to a mass lesion in the bowel which may or may not have a stalk. There are many different types of polyp, most of which are benign, and most are not adenomas. The majority of small colonic polyps are benign so called hyperplastic polyps. A minority are adenomas which are true neoplasms with genetic abnormalities.
Up to the age of 60 almost half of the population may be harbouring a small adenomatous polyp. There is a greater risk of developing polyps if you have first-degree relatives with colorectal carcinoma or adenomas, particularly if they are multiple.
Describe the anatomy of adenomas
Figure 3-20. Diagrammatic representation of carcinoma within a polyp. Black wedges represent foci of carcinoma. A wedges indicate carcinoma in situ; malignant cells do not traverse the muscularis mucosae. B wedges indicate invasive carcinoma; malignant cells have breached the muscularis mucosae.
Anatomy of the adenoma:
o Adenomas on a stalk – pedunculated.
o Flat and raised adenoma – sessile.
Can both be tubular, villous, etc.
Describe the microscopic structure of tubular adenomas
Tubular
Columnar cells with nuclear enlargement, elongation, multilayering and loss of polarity
Increased proliferative activity
Reduced differentiation
Complexity/disorganisation of architecture
Purple- more nuclear material- also look larger
Nuceli lose paolarit- migrate to apical side
Describe the microscopic structure of villous adenomas
Villous
Mucinous cells with nuclear enlargement, elongation, multilayering and loss of polarity
Exophytic, frond-like extensions
Rarely may have hypersecretory function and result in excess mucus discharge and hypokalemia
Hypokalaemia due to mucin production- lose potassium into G.I tracts
Elongated nucleis
Increased nuclear:cutoplasmic ratio
What is an important difference between tubular and villous adenomas
The important features are that tubular adenomas are often well defined and pedundulated and whereas villous adenomas are often larger, more diffuse (‘carpet papillomas’) and difficult to sample in the centre where carcinomas develop. Some very large villous adenomas more than 5 cm in diameter have a high risk of harbouring a cancer (more likely than not).
Describe dysplasia
Literal meaning ‘bad growth’ Abnormal growth of cells with some features of cancer C.f. atypia Subjective analysis Indefinite, low grade and high grade
Poorly differentiated
Cribiform architecture- massive nuclei
High grade
Summarise villous carcinomas
Fig. 11.199 Large villous adenoma with an ulcerated adenocarcinoma in its center. (Courtesy of Dr. Facchetti, Brescia, Italy).
Ulceratec core- adenocarcinoma
Describe adenomatous polyposis coli (APC/FAP)
5q21 gene mutation
Site of mutation determines clinical variants (classic, attenuated, Gardner, Turcot etc)*
Many patients have prophylactic colectomy<30
Gardner’s- bone lesions and tumours in skin
Turcot- brain tumours too- glioblastomas and medulloblastomas
Describe the key figures associated with colonic adenoma
25% of adults have adenomas at age 50
5% of these become cancers if left
Large polyps have higher risk than small ones (so 5% > 1 cm 50-60, 15% at 75)
Lead time 10years?
Cancers stay at a curable stage c. 2 years
Lead time- development of adenoma to development to adenocarcinoma
Screening programme- need to know antural history well
Describe the link between adenomas and adenocarcinomas
Most CRCs arise from adenomas
Residual adenoma in ~ 10-30% of CRCs
Adenomas and Ca similar distribution
Adenomas usually precede cancer by 15 years
Endoscopic removal of polyps decreases the incidence of subsequent CRC
Summarise the genetic pathways involved in colorectal cancer progression
Adenoma carcinoma sequence
APC, K ras, Smads, p53, telomerase activation
Microsatellite instability
Microsatellites are repeat sequences prone to misalignment. Some microsatellites are in coding sequences of genes which inhibit growth or apoptosis e.g.TGFbR11
Mismatch repair genes (MSH2, MLH1 + 4 others). Recessive genes requiring 2 hits.
HNPCC- germline mutation in these genes
Repeat nature- prone to mutations
So defective DNA reapair enzymes- microsatellite instability- genes in which control cellular proliferation, apoptosis etc
Hereditary non polyposis colit- a.k.a lynch syndrome
Outline the adenoma-carcinoma sequence
Normal colon: gremlin or sporadic mutations of TSGs (first hit) - APC, MSH2 at 2p22
Mucosa at risk:
Methylation abnormalities, inactivation of normal alleles (second hit)- APC, Beta-cantenin, MSH2
Adenomas:
Protooncogene activation- K-ras at 12p12
Homozygous loss of additional TSGs (p53 AT 17P13 and LOH 18Q21)
Carcinoma:
Additional mutations, gross chromosomal alterations
Many genes
Metastasis
Summarise the genetic predisposition to colorectal cancers
2 main pathways:
FAP - inactivation of APC tumour suppressor genes
HNPCC - microsatellite instability
Why is APC particularly important in colorectal cancer
APC: holds beta-catenin in the cytoplasm; if APC not present then beta-catenin moves to nucleus to increase proliferation
Beta centanin- increase gene transcription and cell proliferation- targeted by Wnt signalling pathway
Want this in the stem cells
But turn off at top
mutation- progenitor like phenotype- site of future poly formation
want to switch beta-cantenin off at top- to arrest cells once they have differentiated- so they stop proliferating
Describe the role of p53 in adenoma progression
P53- usually expressed low levels- bkock positive/ diffisue poisitive p53- not working correctly- cell trying to express it- acumulates
Summarise the epidemiology of colonic carcinoma
35K cases p.a. in UK 10% of cancer related deaths (16K p.a.) Ages range 50-80. Sporadic rare < 30 High in US, Eastern Europe, Australia Low in Japan, Mexico, Africa Dietary Factors; High Fat, Low Fibre, High Red meat, Refined carbohydrates
Describe the correlation between colon cancer and consumption of fat
igure 3-6. Correlation between age-adjusted mortality from colon cancer and consumption of fat. Total dietary fat intake parallels the colon cancer-associated death rate. Potential mechanisms by which high fat intake may promote carcinogenesis in the colon are outlined in Figure 3-5. (From Reddy et al. [4]; with permission.)
Summarise the role of food in cancer risk
Food Contains 5-10K Bioactive Chemicals
Food contains Carcinogens
It also contains AntiCancer Agents!
Heat modifies chemicals further
Bacteria modify food residues
Describe heterocyclic amines
Dietary factors that predispose to colonic carcinoma – high fat, low fibre, high red meat, refined carbohydrates.
o High temperature cooking can modify chemicals further in food and induce mutagenic chemicals.
Heterocyclic Amines (HCAs) include PhIP.
o PhIP (is oxidised) N-OH-PhIP + deoxyguanosine mutagenesis.
red meat (L-pheynylalanine and creatine)
Describe the role of dietary deficicnies in colorectal cancer
Folates and colorectal cancer
Co enzyme for nucleotide synthesis and DNA methylation
MTHFR
Deficiency leads to disruption in DNA synthesis causing DNA instability (strand breaks and uracil incorporation)
Mutations
Decreased methionine synthesis leads to genomic hypomethylation and focal hypermethylation
Gene activation and silencing
Describe some anti-cancer food elements
Vitamin C - ROS scavenger Vitamin E - ROS scavenger Isothiocyanates (cruciferous veg) Polyphenols (green tea, fruit juice) Activate MAPK
Regulates Phase2 detoxifying enzymes as well as other genes (e.g.glut-S transferase) and reduce DNA oxidation
Describe some health foods
Other mechanisms –
Garlic associated apoptosis
(Ajoene, allicin)
Green tea
EGCG-induced telomerase activity!
Describe the relationship between colorectal cancer incidence and age
Figure 3-3. A and B, Colorectal cancer incidence by age in the United States. The percent of colorectal cancers by age at diagnosis is shown. The majority of colon cancer in the general population occurs after the age of 50. (Data from The Surveillance, Epidemiology and End Results (SEER) Program.)
Describe a typical presentation of colorectal cancer
Change in bowel habit
Bleeding PR
Unexplained Iron deficiency anaemia
Mucus PR
Bloating
Cramps (‘colic’)
Constitutional (weight loss, fatigue)
Patients rationalise these symptoms as ‘getting old, piles or irritable bowel’
And so do doctors!
Describe the macroscopic features of colorectal carcinomas
Small carcinomas may be present within larger polypoid adenomas, pedunculated or sessile
Describe the different distribution of colorectal cancers in the different parts of the G.I tract
Caecum/Ascending Colon 22%
Transverse Colon 11%
Descending Colon 6%
Rectosigmoid 55%
WILL PRESENT DIFFERENTLY
CAECUM- LARGE- SO CAN GROW AND AGROW BUT NOT OBSTRUCT LUMEN
Summarise the microscopic features of carcinomas
Adenocarcinomas Grade 1-3 (almost all)-Glands
Desmoplastic inflammatory reaction
Mucinous carcinomas- Mucinous carcinoma- worse prognosis
Signet ring cell
Neuroendocrine
Describe the grading of colorectal cancers
proportion of gland differentiation relative to solid areas or nests and cords of cells without lumina
~ 10% well differentiated
~ 70% moderately differentiated
~ 20% poorly differentiated
Describe Duke’s classification
Dukes A - growth limited to mucosa/submucosa
- nodes negative
Dukes B - growth into or beyond musc propria
- nodes negative
Dukes C1 - nodes positive
- apical LN negative
Dukes C2 - apical LN positive
Apical lymph nodes – highest lymph node to have been removed. If +ve, chance of spread to lymph.
The scale has a worse prognosis as you go down AC2.
Describe the clinical features that effect prognosis
Diagnosis of asymptomatic patients +ve
Rectal bleeding as presenting symptom +ve
Bowel obstruction -ve
Tumour location ±ve (colon better than rectum, left better than right- closer to rectum- may be picked up earlier)
Age <30 -ve
Preoperative serum CEA (high) -ve
Distant metastasis -ve
Describe the pathological features that effect prognosis
Decreased bowel wall penetration +ve Decreased regional LN involvement +ve Poor differentiation -ve Mucinous/signed ring cell type -ve Venous invasion -ve Lymphatic invasion -ve Peri-neural invasion -ve Local inflammation and +ve immunologic reaction
What is CEA
CEA–carcinoembryonic antigen.
Describe the different treatment options based on staging
I: surgery
II: surgery + 5FU
III: surgery + 5FU/leucovorin
IV: surgery + chemo + RT, metastectomy
Who is at high risk of colon cancers
Previous adenoma
1st Degree relative affected by colorectal cancer before the age of 45
2 affected first degree relatives
evidence of dominant familial cancer trait including colorectal, uterine, and other cancers
UC and Crohn’s disease
Hereditable cancer families (include other sites)
Uterine carcinomas in lynch sundromes
Define screening
Working definition
Screening is the practice of investigating apparently healthy individuals with the object of detecting unrecognised disease or people with an exceptionally high risk of developing disease, and of intervening in ways that will prevent the occurrence of disease or improve the prognosis when it develops.
Describe the Wilso criteria fro a good screening test
Criteria for screening programme.
Importance of the disease:- condition should be important in respect to the seriousness and/or frequency
The natural history of the disease must be known in order to:1. To identify where screening can take place2. To enable the effects of any intervention to be assessed
Test characteristicssimple and acceptable to the patientsensitive and selective
The screening population should have equal access to the screening procedure.
Cost effectiveness
Describe the screening test for colon cancer
FOB/FIT kit
Positives referred for: 60-75 years colonoscopy 55-60 years sigmoidoscopy
o They look for FOB – Faecal Occult Blood.
A 76 year old man presents with new onset rectal bleeding to the GP:
D/ Colorectal malignancy must be excluded in the first instance
What else may be found in the crypts
• Paneth cells are also found in the crypts (important antimicrobial function)
Define dysplasia
Dysplasia is a term often used by pathologists and literally means “bad moulding”. In the context of neoplasia, it indicates cells show features associated with precancerous change, such as enlarged nuclei with more heavily staining chromatin (hyper chromasia) and a coarser chromatin pattern, often accompanied by large nucleoli.
In the tubular adenomas nuclei are often enlarged and elongated (cigar shaped). In higher grades of dysplasia the nuclei enlarge to an irregular ovoid pattern with thick, irregular nuclear membranes and increased numbers of mitotic figures. Along with this the glandular structure tends to become more complicated with buds and branches and a greater degree of irregularity in the architecture. The changes are accompanied by an increasing number of genetic abnormalities. It is the excess and irregularly distributed chromosomes and DNA that gives the cells their features.
Pathologists often divide adenomas into low-grade and high-grade dysplasia and there is a much greater risk of invasive cancer developing with the high-grade dysplasia
Describe invasion
The essential difference between an adenoma and a carcinoma is an absence or presence of invasion, which in most circumstances implies that the malignant epithelial cells have acquired 3 abilities:
Extracellular (stromal) matrix degradation (especially basement membranes)
Adhesion to degraded or new extracellular matrix (ECM)
Ability to move into the newly degraded ECM
The hallmark of invasion in adenomas is penetration of the thin layer of muscle (the muscularis mucosae) that separates the epithelial containing compartment (lamina propria) from the underlying submucosa which lies above the thicker muscle layer, the muscularis propria.
Once the tumour cells have got beyond the muscularis mucosae they then have access to the vascular system (lymphatic and capillaries) and thus potentially can spread further.
What is important to remember about the relationships between adenomas and carcinomas
The distinction between and adenoma and carcinoma is very difficult using radiology and endoscopy, but generally speaking the larger the lesion the higher the risk that malignancy has developed.
On rare occasions there may be small early carcinomas encountered without any obvious adenoma. Generally speaking most cancers will develop in a setting of an adenoma.
Describe the key mutations in adenocarcinoma progression
The main genes affected are listed in table 3 but include APC, mismatch repair genes, P53, K-RAS, DCC (deleted in colorectal cancer), SMAD (loss) and E cadherin mutation.
Summarise the molecular pathogenesis of colorectal cancers
In the classical FAP syndrome, patients may have up to 2500 adenomas over the whole colon although predominantly in the left colon. If left unmanaged, almost all patients will develop cancer by the age of 30 years. There are some mutation variants where the risk is less and patients have relatively few polyps. Generally speaking if a patient has more than adenomatous polyps in their colon they are almost certain to have an hereditary syndrome. Always think of possible hereditable tendencies when people<30 develop cancers that usually affect older generations.
Hereditary Nonpolyposis Colorectal Cancer (HNPCC) Syndrome is a different autosomal dominant familial syndrome where there are fewer numbers of adenomas, usually on the right side of the colon. Here the mutation lies in DNA repair genes leading to micro satellite instability.
There are a few other familial syndromes which may predispose to colorectal cancer but these are far less common (Multiple Juvenile Polyposis, Peutz-Jeghers syndrome and Cowden’s syndrome).
Describe the key clinical features of colon cancers
Most colorectal cancers occur sporadically and the risk increases with age.
The patients usually present with:
altered bowel habit (constipation or diarrhoea or a mixture of the two) rectal bleeding (fresh blood or altered blood) discharge of mucus intermittent (colickly) abdominal pain intermittent obstruction leading to swelling of the abdomen tiredness and malaise due to an unexplained iron deficiency anaemia There is often a considerable delay in the diagnosis of colorectal cancer and General Practitioners have to be alert to the possibility of colorectal cancer in any middle aged to elderly patient who presents with vague abdominal symptoms and especially rectal bleeding. Occasionally patients will present with acute intestinal obstruction or with due to the blockage of the lumen of the colon by an advanced cancer, or with peritonitis due to perforation of the centre of an ulcerated carcinoma and rarely with bowel fistula’s due to the carcinoma invading other organs such as bladder or small bowel.
Where do most colon cancers occur
Half of all cancers will occur in the rectosigmoid area, the remainder are distributed throughout the colon. Minority of patients (5%) will have more than one carcinoma developing. It should also be remembered that patients who have been treated for colonic carcinoma are at risk of developing others.
Describe the diagnosis of colon cancers
Tumours occurring in the caecum and right colon often present later and with vaguer symptoms, partly due to the capacity of the caecum to expand before getting blocked, and also they more often mucinous and soft in nature so obstruction occurs later.
Diagnosis is usually by a combination of radiology (plain abdominal x-ray, barium enema and CT scan, but particularly endoscopy using a sigmotoscope or colonoscope.) As yet, there are no reliable markers of colorectal cancer than can be measured in the blood although carcinoembryonic antigen has been used as a response marker in advanced colorectal carcinoma. However it is elevated in many other conditions.
What are the different types of colorectal cancer
Pathologists usually assess colorectal carcinomas by their resemblance to the normal cells in the crypts and how abnormal the glands and cells are arranged, and describe this as differentiation.
Usually carcinomas are assessed as well, moderately or poorly differentiated but this is a relatively subjective assessment. In addition, some cancers may secrete a large amount of mucin (so called mucoid/colloid carcinomas). Others may rarely have a high content of endocrine cells and there are very rare pure endocrine carcinomas (carcinoids and high grade neuroendocrine cancers).
Describe spread and metastasis
Colorectal carcinomas go to the regional lymph nodes and liver in the first instance and subsequently may spread to the lungs and elsewhere. Most surgeons aim to clear the local lymph nodes in order to stage the tumours. The Dukes’ system was also adapted to try and assess whether lymph nodes near the tumour were involved (C1) or more distant nodes at the point of the mesenteric blood vessel ligature which represented more distant spread (C2). These seem to have some prognostic value.
In the past, involvement of the liver was very difficult to treat, but with modern surgical techniques including so called bloodless surgery with radio frequency ablation or laser techniques, it is possible to resect colorectal cancer metastases and allow the liver to regenerate hopefully to affect a cure or allow a greater window for chemotherapeutic effect.
On occasion colorectal cancers will spread across the abdominal cavity to the small bowel or the ovaries/uterus, particularly if they are of the mucinous type.
Describe the sex and age differences in prognosis
Age extremes – some very young patients (20-30 years old) present with colorectal carcinoma although it is extremely rare. In a few of these this is in a background of a pre-malignant condition such as ulcerative colitis or Crohn’s disease and many of these tumours are aggressive mucinous types. Added to this is the difficulty in making the diagnosis in such a young patient with what is effectively a rare tumour in that age group. Similarly in the very elderly patient, the vagueness of the presenting symptoms means the tumours often present at an extremely advanced or untreatable stage.
Sex – the prognosis is better for females than males. There is a slight female preponderance of the less common right-sided colorectal carcinomas which paradoxically have a worse prognosis. There is a good correlation between tumour size and extent which is reflected in the staging and outcome
Summarise advancements in screening for colorectal cancer
There is a new screening programme using the Fecal Occult Blood Test. The disadvantage is that this is relatively insensitive and produces some false positives but in pilot studies it has been shown to produce some benefit in picking up asymptomatic cancers. Many other molecular genetic tests have been proposed including screening for mutations by PCR-based techniques on fecal samples but many of these mutations are encountered in other carcinomas and may occasionally occur in the absence of a cancer. So, a completely robust technique has not yet been developed. Screening by sigmoidoscopy or colonoscopy is usually reserved for those with a significant family history (usually in a first degree relative) and obviously for those with known hereditary bowel cancer in the family.
1 APC gene (5q) 2 DNA hypomethylation 3 K-RAS mutation 4 Deleted in DCC (18q loss) 5 P53 (17p) 6 Mismatch repair (HMSH2) 7 TGF beta (receptor 2 mut.) 8 Beta catenin mutation (3p)
