Editing Colon cancer (section)

== '''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'''
{| class="wikitable"
|'''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
|<nowiki>+++</nowiki>
|<nowiki>+/-</nowiki>
|<nowiki>---</nowiki>
|<nowiki>---</nowiki>
|<nowiki>+++</nowiki>
|-
|''BRAF'' mutation
|<nowiki>---</nowiki>
|<nowiki>---</nowiki>
|<nowiki>+++</nowiki>
|<nowiki>+++</nowiki>
|<nowiki>---</nowiki>
|-
|MLH1 status
|Normal
|Mutation
|Methylated
|Partial methylation
|Normal
|-
|MGMT methylation
|<nowiki>---</nowiki>
|<nowiki>---</nowiki>
|<nowiki>+/-</nowiki>
|<nowiki>+++</nowiki>
|<nowiki>+++</nowiki>
|}

=== '''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