Epidemiology

- 10% of cancer deaths worldwide
- Second-highest cancer deaths
- Peak age 60-70yo
- <20% of cases before age 50, but this is increasing

Risk factors

Modifiable

- - Obesity
  - Diabetes
  - Red and processed meat
  - Low intake insoluble fibre
  - High intake processed carbohydrates and fat
  - Smoking
  - Alcohol
  - Androgen deprivation therapy

Non-modifiable

- - Hereditary cancer syndromes (see separate topics under Oncology)
    - FAP - 100%
    - MUTYH-associated polyposis - 86% without screening
    - Lynch syndrome 70% men/40% women
    - Peutz-Jeghers syndrome - 39%
    - Serrated polyposis syndrome - 25% without screening
    - Li-Fraumeni 24%
    - Juvenile polyposis syndrome - 20%
  - Personal or family history of sporadic CRC or adenomatous polyp
  - IBD
  - Abdominopelvic radiation
  - CF
  - Age
  - Renal transplant
  - Bacterial/viral agents
    - Streptococcus bovis
      - Well-described - but likely a consequence of, rather than a risk factor for, CRC
    - H pylori
    - JC virus
    - HPV
    - Fusobacterium
    - Decreased diversity of gut microbiome

Protective factors

- Aspirin/NSAIDs

Pathophysiology

Gross appearance

- - Right sided tumours are usually polypoid
  - Left sided tumours often appear as circumferential apple-core lesions

Molecular pathways - two common pathways

- - Chromosomal instability pathway (APC/b-catenin pathway)
    - Responsible for 80% of sporadic cancers
    - Majority of cancers arise via a defined pathway over about a 10 year period, especially sporadic cancers. The pathway starts with adenomatous polyps that become dysplastic over time.
    - Stepwise series of mutations, some activations of oncogenes and some loss of tumour suppressor genes
      - APC (adenomatous polyposis coli - inactivated - tumour suppressor gene)
        Normally binds to and promotes degradation of b-catenin. If lost, b-catenin can accumulate and leads to proliferation of the cell.
        
        This is the FAP gene
        
        Both copies of the gene must be functionally inactivated - either mutation or epigenetic events
      - KRAS (activation - oncogene)
        Promotes growth, prevent apoptosis
      - SMAD2/SMAD4 - tumour suppressor genes which can be lost
      - TP53 (inactivation - tumour suppressor gene)
        Mutated in 70-80% of cancers
    - Chromosomal instability - changes in the number of chromosomes - is a hallmark of this pathway. Tumour suppressor genes can be removed by chromosomal deletions.
  - Microsatellite instability (MSI) pathway
    - Microsatellite instability mutator pathway
      - Mutation in genes that are responsible for repairing base mismatches, leading to progressive accumulation of mutations
      - Resulting cancers will be MSI-H - larger tumours, proximal colon, absence of metastatic disease, poor differentiation
      - With the genetic form (Lynch syndrome) it occurs in younger patients
      - When this happens sporadically, often occurs in elderly patients
    - CpG island methylator phenotype (hypermethylation phenotype)
      - MLH1 promoter region is typically hypermethylated, thereby reducing MLH1 expression and repair function
      - Most commonly initiated by a mutation of the BRAF gene, causing inhibition of normal colon cell apoptosis. Leads to hyperplastic polyps or SSAs.
        KRAS and TP53 are not typically activated
      - Results in microsatellite instable-high (MSI-H) cancers, which generally form from SSAs and are found in the right colon.
    - Both MSI pathways have slightly better prognosis

Molecular classification of colorectal carcinoma

Heredity	Chromosomal instability pathway	Mismatch repair pathway	Serrated/CIMP pathway		Hybrid pathway
	Hereditary and sporadic	Hereditary	Hereditary and sporadic		Sporadic
CIMP status	Negative	Negative	High	High	Low
MSI status	MSS	MSI-H	MSI-H	MSI-L	MSI-L or MSS
Chromosomal instability	Present (pMMR)	Absent (dMMR)	Absent (dMMR)	Absent (dMMR)	Present (pMMR)
KRAS mutation	+++	+/-	---	---	+++
BRAF mutation	---	---	+++	+++	---
MLH1 status	Normal	Mutation	Methylated	Partial methylation	Normal
MGMT methylation	---	---	+/-	+++	+++

Evidence for molecular pathways:

- - Epidemiological - colonoscopic removal of adenomas reduces CRC mortality
  - Histological - foci of CRC within adenomas
  - Molecular - CRCs match molecular 'signatures' of surrounding adenomatous tissue

Identifying CRC

- - Cytokeratin 20 (CK20)
  - Caudal-type homeobox 2 (CDX2)
  - Both quite sensitive and specific for CRC

Epithelial-mesenchymal transition

- - The process whereby cells need to lose their epithelial features and gain a mesenchymal phenotype to invade/metastasise
  - Epithelial cell loss of polarity, loss of cell-to-cell adhesion, gain of a migratory and invasive phenotype
  - Need to reverse back to epithelial phenotype at the metastatic destination

Consensus molecular subtypes

- - CMS1 - most MSI-H tumours - hypermutated, microsatellite unstable, and exhibit strong immune activation
  - CMS2 - high CIN - epithelial phenotype, and exhibit marked WNT and MYC signalling activation
  - CMS3 - epithelial phenotype and metabolic dysregulation
  - CMS4 - frequently CIMP-phenotype - mesenchymal phenotype, prominent transforming growth factor-beta activation, stromal invasion, and angiogenesis
  - This information may be used in the future for custom treatments

Grading

- - WHO classifies into either well-/moderately-differentiated (low-grade) and poorly-differentiated (high-grade)
  - Grade reflects the degree of gland formation
    - Grade 1 - well-differentiated (>95% gland formation)
    - Grade 2 - moderately differentiated (50-95% gland formation)
    - Grade 3 - poorly-differentiated (<50% gland formation)
    - Grade 4 - undifferentiated (no gland or mucin formation; no squamous or neuroendocrine differentiation)
  - Higher-grade tumours do not form glands, but instead have solid sheets or cords of infiltrating cells, with marked atypia and pleomorphism and a high mitotic rate

Molecular markers for treatment planning

- - KRAS
    - Independently associated with a worse prognosis
    - May provide a target for immunotherapy targeting EGFR - tumours that harbour activating mutations for KRAS or NRAS are resistant to EGFR inhibitors, whereas those that are wild-type can have them
  - BRAF
    - If a BRAF mutation is present, probably not HNPCC, despite MSI-H
    - BRAF mutations induce resistance to EGFR inhibitors
  - MSI
    - MSI-H: two or more of a set of five nucleotide repeats are affected by instability
    - MSI-L: one or none are affected by instability
    - MS-S (stable): no instability
  - MMR
    - Cells deficient in MMR will likely have high MSI - MMR is a surrogate marker for MSI
    - If MMR-deficient, immunotherapy will be given for advanced stage disease (see below)
    - MMR deficient makes HNPCC more likely
  - HER2
    - Allows use of immunotherapy for stage IV disease

Metastases

- - Direct
  - Lymphatic
  - Blood
    - Liver
    - Lung
    - Also ovary, adrenal, bone, brain, kidney

Morphological variants

- - Mucinous (11-17%)
    - Tumours producing extracellular mucin, which may aid in tissue plane dissection and penetration
    - Defined as >50% mucin within the tumour mass
  - Signet ring (1-2%)
    - >50% of tumour mass made up of cells with intracellular mucin pushing nucleus to the side
    - Strong association with HNPCC
    - Worse prognosis and much higher rate of stage III or IV disease at diagnosis
  - Medullary
    - Associated with dMMR tumours, via HNPCC or BRAF
    - Good prognosis
  - Micropapillary
  - Serrated
  - Cribriform
  - Comedo
  - Adenosquamous (0.2%)
    - Worse prognosis
  - Spindle cell
  - Undifferentiated
- Synoptic report
  - Clinical information
    - Perforation?
    - Obstruction?
    - Location
    - Pre-op radiotherapy
    - Residual cancer post-surgery
    - Involvement of adjacent organs
    - New primary or recurrence
  - Macroscopic
    - Tissue banking
    - Specimen images
    - Specimen length
    - Tumour site
    - Anterior peritoneal reflection
    - Perforation?
    - Intactness of mesorectum
    - Maximum tumour diameter
    - Peritoneum
    - Distance from margins - proximal, distal, circumferential
    - Lymph nodes
    - Polyps
    - Comments
    - Nature and site of blocks
  - Microscopic
    - Tumour type
    - Histological grade
    - Depth of invasion
    - Small vessel invasion
    - Intramural vein invasion
    - Extramural vein invasion
    - Perineural invasion
    - Margins - proximal, distal, circumferential
    - Lymph node involvement
    - Isolated extramural deposits
    - Apical node involvement
    - Distant metastases
    - Coexisting abnormalities
    - Response to treatment
    - Comment
  - Ancillary studies
    - IHC for MMR genes
  - Synthesis
    - Stage
    - Stage group
    - Residual tumour status

Presentation

- Generally, one of three patterns
  - Sporadic (70%) - most common >50yo, with dietary/environmental risk factors
  - Inherited (<10%) - defined cancer syndrome as above with a specific germline mutation
  - Familial (25%) - family history of CRC, but no defined genetic syndrome
- Mode of presentation:
  - Elective (80%)
  - Emergency (20%)
    - Obstruction (16%)
    - Perforation
    - Bleeding
- Most common
  - PR bleeding
  - Abdo pain
  - Anaemia
  - Constipation/diarrhoea
- Anal pain/tenesmus/incontinence are rare
- Location dictates type of symptoms
- 6-8% chance of synchronous lesion
- 20% have metastatic disease at diagnosis

Workup

- Colonoscopy
  - Tattoo or clip
  - Questionable whether you really need to tattoo the caecum - risk of perforation/bleeding
- Clinical staging
  - CT CAP
  - CEA - see 'tumour markers'
  - History and examination
  - MRI, PET and PET/CT are not generally used for initial staging, unless there are contrast allergies or equivocal cases

Staging

- Poor prognostic indicators not captured by TNM staging
  - High CEA
  - Tumour deposits within the lymph drainage area of a cancer
  - Lymphovascular and perineural invasion
  - Histologic grade
  - Mucinous and signet ring adenocarcinomas
- Pathological staging - Colorectal cancer TNM staging AJCC UICC 8th edition

Primary tumor (T)
T category	T criteria
TX	Primary tumor cannot be assessed
T0	No evidence of primary tumor
Tis	Carcinoma in situ, intramucosal carcinoma (involvement of lamina propria with no extension through muscularis mucosae)
T1	Tumor invades the submucosa (through the muscularis mucosa but not into the muscularis propria)
T2	Tumor invades the muscularis propria
T3	Tumor invades through the muscularis propria into pericolorectal tissues
T4	Tumor invades* the visceral peritoneum or invades or adheres¶ to adjacent organ or structure
T4a	Tumor invades* through the visceral peritoneum (including gross perforation of the bowel through tumor and continuous invasion of tumor through areas of inflammation to the surface of the visceral peritoneum)
T4b	Tumor directly invades* or adheres¶ to adjacent organs or structures
* Direct invasion in T4 includes invasion of other organs or other segments of the colorectum as a result of direct extension through the serosa, as confirmed on microscopic examination (for example, invasion of the sigmoid colon by a carcinoma of the cecum) or, for cancers in a retroperitoneal or subperitoneal location, direct invasion of other organs or structures by virtue of extension beyond the muscularis propria (ie, respectively, a tumor on the posterior wall of the descending colon invading the left kidney or lateral abdominal wall; or a mid or distal rectal cancer with invasion of prostate, seminal vesicles, cervix, or vagina). ¶ Tumor that is adherent to other organs or structures, grossly, is classified cT4b. However, if no tumor is present in the adhesion, microscopically, the classification should be pT1-4a depending on the anatomical depth of wall invasion. The V and L classification should be used to identify the presence or absence of vascular or lymphatic invasion whereas the PN prognostic factor should be used for perineural invasion.
Regional lymph nodes (N)
N category	N criteria
NX	Regional lymph nodes cannot be assessed
N0	No regional lymph node metastasis
N1	One to three regional lymph nodes are positive (tumor in lymph nodes measuring ≥0.2 mm), or any number of tumor deposits are present and all identifiable lymph nodes are negative
N1a	One regional lymph node is positive
N1b	Two or three regional lymph nodes are positive
N1c	No regional lymph nodes are positive, but there are tumor deposits in the: · Subserosa · Mesentery · Nonperitonealized pericolic, or perirectal/mesorectal tissues
N2	Four or more regional nodes are positive
N2a	Four to six regional lymph nodes are positive
N2b	Seven or more regional lymph nodes are positive
Distant metastasis (M)
M category	M criteria
M0	No distant metastasis by imaging, etc; no evidence of tumor in distant sites or organs. (This category is not assigned by pathologists.)
M1	Metastasis to one or more distant sites or organs or peritoneal metastasis is identified
M1a	Metastasis to one site or organ is identified without peritoneal metastasis
M1b	Metastasis to two or more sites or organs is identified without peritoneal metastasis
M1c	Metastasis to the peritoneal surface is identified alone or with other site or organ metastases
Prognostic stage groups
When T is...	And N is...	And M is...	Then the stage group is...
Tis	N0	M0	0
T1, T2	N0	M0	I
T3	N0	M0	IIA
T4a	N0	M0	IIB
T4b	N0	M0	IIC
T1-T2	N1/N1c	M0	IIIA
T1	N2a	M0	IIIA
T3-T4a	N1/N1c	M0	IIIB
T2-T3	N2a	M0	IIIB
T1-T2	N2b	M0	IIIB
T4a	N2a	M0	IIIC
T3-T4a	N2b	M0	IIIC
T4b	N1-N2	M0	IIIC
Any T	Any N	M1a	IVA
Any T	Any N	M1b	IVB
Any T	Any N	M1c	IVC

Management

Approach

- - Resectable non-metastatic cancers
    - Where the primary tumour can be resected with adequate free margins, en bloc with locoregional lymphadenectomy
  - Potentially resectable metastatic cancers
    - Neoadjuvant therapy followed by restaging and surgery
    - Consider up-front resection of everything
    - See separate topic under 'liver'
  - Unresectable metastatic cancers
    - Palliative chemotherapy vs best supportive care

Neoadjuvant therapy

- Indications
  - Locally advanced disease with compromised surgical margins/clinical T4b
  - Medically inoperable cancer
  - Consider with bulky nodal disease
- Benefits
  - Reduce micro-metastatic disease
  - Improve operability of the primary tumour
  - Improved compliance compared to adjuvant therapy

Surgery

- Principles
  - Gentle surgery, avoiding manipulation of the tumour
  - At least 12 nodes required, but generally around 20 are resected
  - Aim for a free margin of 5cm to minimise risk of recurrent cancer and capture perivisceral lymph nodes; however, if is more complex than that if we follow guidelines from JSCCR
    - If there is a clear main vessel, resect 5cm past it, or 10cm past the tumour in the opposite direction
    - If the tumour is between two main vessels, then 5cm past each main vessel is necessary
  - Tension-free anastomosis
  - Avoid injury to vascular supply of the colon, including marginal artery
  - Central venous ligation should be performed
  - Aim for D3 resection - there is a survival benefit, although it is small, and only relevant for more advanced disease. However, it is almost impossible to accurately stage these cancers pre-op, so best to perform D3 resection by default.
- Open vs laparoscopic
  - Favourable recovery with minimally invasive
  - Oncologic outcomes non-inferior, with similar disease-free survival and local recurrence rate
  - No clear advantages to robotics yet
- Right-sided cancers
  - Right hemicolectomy
  - Excise the lymphatic tissue around SMV en bloc for a complete lymphadenectomy
- Transverse colon cancers
  - Mostly extended right hemicolectomy - need to also divide middle colic vessels at the origin
- Splenic flexure cancers
  - Controversial - extended right hemicolectomy or left hemicolectomy (segmental) or extended left hemicolectomy or subtotal colectomy
    - Extended RHC would take both branches of middle colic and go round as far as upper descending colon, but is really only an option when you think lymphatic drainage will definitely be to the middle colic pedicle
    - Segmental left hemicolectomy would involve IMV ligation, left colic artery division at origin, sometimes the left branch of middle colic, and anastomosis between transverse colon and descending colon. Still usually gets enough nodes to stage.
    - Extended left hemicolectomy ligates left branch of middle colic with IMA at origin, then joins distal transverse to sigmoid. Not thought to be a good operation by some colorectal surgeons as it is non-anatomical.
    - Subtotal colectomy - perhaps the best oncological operation, given total resection of middle colic and IMA pedicles, but worst functional outcome
  - In one study, 96% of normal splenic flexure lymphatic drainage was to left colic/IMA pedicle, so argument for middle colic lymphadenectomy is probably not warranted
  - Key factors:
    - Younger patients can handle the longer operation and functional impairment of subtotal colectomy better
    - Older patients may opt for a segmental left hemicolectomy to preserve function
- Left-sided cancers
  - Left hemicolectomy - high ligation of IMA, IMV ligation, splenic flexure mobilisation, and anastomosis between left colon and proximal rectum with circular stapler

Adjuvant CTX

- Candidates:
  - Node-positive (stage III)
  - Node-negative (stage II) but high-risk
    - Consider adjuvant (poorly-differentiated, lymphovascular invasion, inadequate margins, T4 lesion, inadequate number of lymph nodes harvested, perforated or obstructed, MSI microsatellite instability)
    - However even in this group, the benefits are minimal
- Regimen:

- - Most commonly FOLFOX (folinic acid, 5-FU and oxaliplatin) for 6 months
  - Fluoropyrimidine alone can be used for more frail patients
  - Sometimes FOLFIRI is also used (folinic acid, 5-FU and irinotecan
  - Trials ongoing 3 months vs 6 months

Other systemic options

- EGFR inhibitors

- - Cetuximab or panitumumab
  - Indicated with metastatic disease and wild-type KRAS/NRAS and BRAF wild-type
  - If BRAF is mutated, EGFR inhibitors can be combined with a BRAF inhibitor (encorafenib)

- Immune checkpoint inhibitors

- - Given for patients with stage IV CRC and dMMR (MSI-H)
  - Nivolumab plus ipilimumab usually given instead of traditional chemotherapy for those patients

- HER2-targeted therapy

- - Used as second-line therapy for patients with HER2 overexpression

- VEGF inhibitors

- - Bevacizumab (Avastin)
  - Small benefit when added to cytotoxic chemotherapy in some situations
  - Risk of perforation

Adjuvant RTX

- Unlike rectal cancer, rarely used for colon cancer

Complications

- Obstructing cancers
  - Approach
    - Surgery
    - Stent (see below for left-sided cancers)
      - Bridge to surgery only
      - Reduces stoma rates from 69% to 45%
  - Timing of intervention
    - Expedited if caecal tenderness, signs of sepsis or caecal diameter >12cm
    - Otherwise prefer using experienced staff during daylight hours
  - Principles of surgery
    - Colonic decompression
      - Often done at start of case - use either a 19G needle on suction or a Foley
      - If no caecal injury, may allow left-sided segmental resection
    - Anastomosis?
      - If proximal bowel viable, segmental resection with primary anastomosis (unless there is a contraindication, in which case do Hartmann procedure)
      - Leak rates 2-8% (similar to elective surgery)
      - Consider diverting ileostomy, but does not decrease leak rates, just leaks requiring operation
      - Companion series suggests defunctioning in most cases
      - If unwell, just do a Hartmann's; and if seriously compromised physiology is present, just defunction
  - Choice of operation
    - Right-sided, up to and including splenic flexure
      - Oncological segmental resection - right hemicolectomy
      - Most cases can have primary anastomosis, but consider diversion for those at risk of failure
    - Left-sided
      - Options
        Resect (Hartmann's (wouldn't survive a leak, or too high risk for leak), or primary anastomosis +/- proximal diversion)
        Resectable tumour, curative intent
        
        Resectable tumour, not much metastatic disease and prospect of survival
        
        Divert
        Unresectable primary tumour
        
        Obstructing rectal cancer
        
        Widespread metastatic disease
        
        Major comorbidities precluding resection
        
        Stent
        May permit higher rates of primary anastomosis, decreased wound infections and a lower rate of conversion. Mainly in high-risk or unwell patients. Contraindicated in suspected ischaemic or perforated bowel. See separate topic.
- Perforation
  - Usually occurs in the caecum (Laplace), but can also be at the tumour or in a segment of diverticulitis proximal to the tumour
  - Contained perf: drain percutaneously followed by semi-elective surgery
  - Free perf: surgical emergency. Resection with proximal colostomy or ileostomy (Hartmann's). Can possibly MAYBE do primary anastomosis with covering loop ileostomy.

Prognosis

- Majority of recurrences occur within two years
- Stage IV
  - Chemotherapy median survival - 2 years
  - Best supportive care median survival - 6 months

Surveillance

- Normal CEA does not negate utility of tracking CEA later to detect recurrences
- Goals:
  - Identify recurrence a stage potentially resectable
  - Identify metachronous tumours
  - Identify mets (especially liver)
  - Reassures patient
- T1/T2 or patient doesn't want further treatment
  - ?Less than below, need local guidelines on specifics
  - In the engaged, well patient who would like surveillance, it is reasonable to offer the same protocol as for stage II/III disease
- T3 or greater:
  - 2 years of 3-monthly hx, exam, CEA. Then 3 years of 6-monthly hx, exam, CEA - then depending on risk
    - If concerns, colonoscopy and CT
  - Minimum annual CT CAP regardless though (needs to be 5mm slices, contrast-enhanced) for first three years, then depending on risk
- Colonoscopy at 1 year, then 4 or 5 years, then every 5 years until 75 or 80
  - Do the colonoscopy within 6 months if it could not be done pre-operatively (e.g. because of obstructing cancer)
  - If further adenomas found, keep doing yearly colonoscopy (i.e. at year 2, year 3, etc) until colon is clear (Sabiston)

Screening

- NBSCP
  - FOBT 2-yearly between 45 and 74
    - Two samples each time
    - iFOBT (now used for NBCSP): immunochemical test which identifies only human haemoglobin
    - gFOBT: The samples placed in a hydrogen peroxide solution. If haem is in the stool sample, there will be pseudoperoxidase activity, and oxygen will be released from the hydrogen peroxide in the ensuing reaction. A card containing guiac resin is placed in the solution, and if oxygen is present, the guiac will be oxidised to a different colour. Thus, the guiac changes colour if haem is present. False positives can occur with dietary red meat, vitamin C and anti-inflammatories for three days prior.
    - Can also be ok to use as screening tool in 50-74 year olds with abdo pain/weight loss/fe-defic anaemia
  - For pre-cancerous adenoma detection: 90.6% sp / 33.9% se
  - For early CRC: 89.8% sp / 84.6% se
  - Positive FOBT:
    - 58% normal colonoscopy
    - 39% polyp
    - 10% advanced adenoma >1cm
    - 3% CRC
  - Benefits:
    - 9% disease-specific mortality vs 24%
    - 2300-3200 deaths prevented each year in Australia
- If positive - should proceed to colonoscopy within 120 days