Colorectal Adenocarcinoma
Common sites:
- 55% are in rectosigmoid colon
- MSI pathway carcinomas:
Gross features:
- R colon cancers tend to be polypoid, exophytic
masses
- L colon cancers tend to be annular, constrictive
lesions.
- Completeness of mesorectum
(rectal carcinomas)
- Predictive of local recurrence
- Incomplete:
- Little bulk to mesorectum
- Defects of mesorectum
down to muscularis propria
- Irregular circumferential margin after transverse sectioning
- Nearly complete:
- Moderate bulk to mesorectum
- Irregularity to mesorectum
with defects > 5 mm (none extending to muscularis
propria)
- Only the insertion site of levator
ani muscles is visible muscularis
propria
- Complete:
- Intact bulky mesorectum
with a smooth surface
- Only minor irregularities
- No surface defects > 5 mm
- No coning towards distal margin of specimen
- Circumferential margin appears smooth after
transverse sectioning
Histologic features:
- Cribriform arrangement of glands
- Invasion, which is accompanied by a strong desmoplastic
response
- Low-grade:
- Well-differentiated – more than 95% glandular
architecture
- Mod-differentiated – more than 50% glandular
architecture
- High-grade:
- Poorly-differentiated – less than 50% gland
architecture
- Undifferentiated – less than 5% gland
architecture
- Mucinous subtype
- more than 50% showing stromal mucin
- If mucinous areas are < 50% it is
categorized as having a mucinous component
- Many are MSI-H
- Behaves as high-grade carcinoma if it is MSS or
MSI-L (not MSI-H)
- Signet ring carcinoma
- > 50% signet ring cells
- < 50% is termed “with a signet-ring cell
component”
- Poor prognosis (if it lacks MSI-H)
- Medullary Carcinoma (favourable
prognosis)
- Sheets of malignant cells
- Vesicular nuclei
- Abundant eosinophilic cytoplasm
- Rare
- Almost invariably MSI-H
- Serrated adenocarcinoma
- Rare
- Sessile serrated polyp type architecture
- Glandular serration
- Mucinous, cribriform, lacy, and trabecular
areas maybe
- Low N:C ratio
- MSI-L or MSI-H maybe
- BRAF mutations maybe
- CpG
island hypermethylation maybe
- Cribriform comedo-type
adenocarcinoma:
- Rare
- Extensive large cribriform glands with central
necrosis
- Analogous to breast adenocarcinomas
- Usually MSS with CpG
island hypermethylation
- Micropapillary
adenocarcinoma
- Rare
- Small clusters of tumour
cells within stromal spaces mimicking vascular channels
- Same as described in breast and bladder cancer
- May be seen as a component in a conventional
CRC
- Characteristic MUC1 staining pattern by IHC
- Adenosquamous
carcinoma
- Either separate areas within the tumour, or admixed
- More than just occasional small foci of
squamous differentiation
- Pure squamous cell carcinoma is very rare
- Spindle cell carcinoma
- Biphasic with a spindle cell sarcomatoid component
- Spindle component is at least focally IHC+ for
keratins
- Undifferentiated carcinoma:
- Rare
- Lacking morphological, immunohistochemical,
and molecular biological evidence of differentiation beyond that of an
epithelial tumour
- Variable histologic features
- Some have MSI-H
- Small cell carcinoma
- Clue for metastases:
- Necrotic debris rimmed by a row of malignant
cells
- MSI carcinomas:
- Some hyperplastic polyps and many sessile
serrated adenomas show this pathway of carcinogenesis
- Medullary growth pattern
- Solid
- Nested
- Organoid
- trabecular
- Mucinous or signet ring cell differentiation
- Prominent lymphocytic response to tumour
- Tumour infiltrating lymphocytes ( >= 3 / HPF)
- Crohn-like extratumoural
lymphoid follicles
- Negative for immunohistochemical
neuroendocrine differentiation
- Lack of dirty necrosis
- Malignant Polyps (polyps with invasive adenoCA)
- Invasion through the muscularis
mucosa into the submucosa (pT1)
- (Invasion within lamina propria
or MM is reported as HGD)
- Report the following for malignant polyps (may
require colectomy with lymph node examination):
- Poorly differentiated component (presence or
absence, any amount)
- LVI (presence or absence)
- Distance to margin (1mm or less is considered
positive) (some do not agree with this criterium)
- Optional reporting elements:
- Tumour budding (not widely accepted)
- Haggitt level in pedunculated polyps
- Sessile polyp with invasion below the
background muscularis mucosa (not widely
accepted)
- Tumor budding (poor prognosis, but no uniformly
accepted criteria currently):
- Criteria of Ueno et al for ‘high-grade budding’
- >= 10 groups of < 5 cells in a 20x
objective field
- IHC may be used for cases with 5-10 definite
buds and some indefinite, but should not be used routinely
- Concentrate on invasive tumour
front
Immunophenotype:
Marker:
|
Sensitivity:
|
Specificity:
|
CEA
|
|
|
CK7 (–)
|
|
|
CK20 (+)
|
Some are CK20-
(tend to be
MSI-H)
|
|
CDX-2
|
Most
(not associated
with MSI status)
|
|
MLH1
|
Negative in
some MSI carcinomas
(sporadic or
HNPCC)
|
|
MSH2
|
Negative in
some MSI carcinomas (HNPCC)
|
|
MSH6
|
Negative in
some MSI carcinomas (HNPCC)
|
|
PMS2
|
Negative in
some MSI carcinomas (HNPCC)
|
|
- MMR protein testing by IHC (MLH1, PMS2, MSH2,
MSH6):
Molecular features:
- Sporadic:
- Chromosomal instability pathway (~75%):
- APC mutation (> 90%)
- Biallelic APC mutation
(early in development of conventional adenomas)
- APC normally facilitates the sequestration and
degradation of cytoplasmic beta-catenin, thereby regulating cell
proliferation
- also regulates microtubule function
- dysfunctional APC results in abnormal
chromosomal segregation during mitosis
- genetic instability
- LOH
- Wnt signaling pathway abnormalities
- KRAS mutation (50%) (prognostic
effect is controversial)
- [Draft recommendation] : RAS mutation testing should be performed for
patients who are being
considered for anti-EGFR therapy.
- Must include KRAS
and NRAS codons 12 and 13 of exon 2; 59 and 61 of exon 3; and 117 and
146 of exon 4 (« expanded » or
« extended » RAS)
- 20% of KRAS exon 2 non-mutated
tumours harboured
one of the extended RAS mutations
- [Draft expert
consensus opinion] :
- Labs should use molecular marker testing
methods that are
able to detect mutations in specimens with at least
5% mutant allele freqeuncy,
taking into account the analytical sensitivity of the assay
(level of dection
/ LOD) and tumour enrichment
(ex. microdissection). It is recommended that the operational
minimal neoplastic carcinoma
cell content tested
should be set at
least 2 times the assay’s LOD.
- BRAF mutation (?poor prognosis)
- Mutually exclusive with
KRAS
- [Draft recommendation ] : BRAF V600 mutational analysis in conjunction with dMMR/MSI testing must be performed in carcinoma tissue of patients with
metastatic colorectal carcinoma
for prognostic stratification
- [Draft no recommendation] : There is
insufficient evidence
to recommend BRAF V600 mutational
status as a predictive
molecular marker for response
to anti-EGFR inhibitors (53% agree, 16% disagree)
- PIK3CA mutation (25%) (late
event) (?poor prognosis)
- [Draft no recommendation] : There is
insufficient evidence
to recommend PIK3CA mutational
analysis for therapy
selection outside
of a clinical
trial.
- TP53 mutation (70%)
- PTEN loss :
- [Draft no recommendation ] : There is insufficient evidence to
recommend PTEN analysis
(IHC or FISH) for patients being considered for therapy selection outside of a clinical trial.
- FBXW7/CDC4 mutation (late
event)
- CHEK2 mutation (low frequency)
- BUB1 mutation (low frequency)
- Aneuploidy and structurally unbalanced
rearrrangements
- Increased nuclear DNA content
- Losses :
- 18q loss (?poor prognosis)
- Loss of SMADs
- Loss of p53
- Microsatellite instability pathway / serrated neoplastic
pathway (15% of sporadic, nearly 100% in HNPCC):
- Microsatelite instability caused by
hypermethylationof cytosine residues at CpG islands within promoter
region of MLH-1, MSH-2, MSH-6, MSH-3, PMS-2, or TACSTD1) (sporadic)
- MLH-1 mostly
- Usually associated with loss of expression of
the protein but not always
- This can be evaluated by looking at 5 loci by
PCR (compare to non-tumour tissues in same
patient)
- low-frequency (MSI-L) – 1 locus with allelic
shift (often grouped with MSI-stable tumours)
- high-frequency (MSI-H) – 2 or more loci with
allelic shift
- microsatellite –stable (MSS) – 0 loci with
allelic shift
- CpG island methylator phenotype (CIMP)
- Loss of O6-methylguanine-methyltransferase
(MGMT expression
- Mutations:
- BRAF mutations (50%) (present in sporadic MSI
but not Lynch syndrome)
- APC mutation
- RARELY:
- Frequent frameshift mutations:
- TGFBR2
- IGF2R
- BAX
- TCF7L2
- E2F4
- PTEN
- MSH6
- MSH3
- CASP5
- BMPR2
- Lynch Syndrome-associated:
- CTNNB1 mutation (alternative to APC)
-
- diploid usually
- LOH frequency is low, including 5q
- Associated clinicopathologic
characteristics:
- Right-sided
- Mucinous
- Medullary (occasionally)
- Crohn-like peritumoral
lymphocyte infiltrate
- Intratumoural lymphocyte
infiltrate
- Devoid of “dirty” necrosis
- Lower stage
- Expansile growth
- Better stage-specific prognosis
- less responsive to certain chemotherapies
(5-FU and oxaliplatin)
- better response to irinotecan maybe
- microsatellite-stable and chromosome-stable tumours (up to
15%)
- CpG
island methylator phenotype (CIMP) tumours:
- Widespread CpG
island methylation (type C methylation)
- Often MSI-H but > 50% are microsatellite
stable
- KRAS mutation and microsatellite stable
(CIMP2)
- BRAF mutation with MSI-H (CIMP1)
- TP53 mutation and microsatellite stable
(CIMP-negative
o MSI (PCR) testing (93% sensitivity for identifying
individuals with a germline MMR gene variant – Shia 2008) (range of 75-100% -
CCO evidence review)
§ Test tumour tissue and
normal tissue concurrently
§ Panel of 5 microsatellite markers (recommended BAT25,
BAT26, D2S123, D5S346, and D17S250)
· MSI-high: > 30 % of markers show instability
· MSI-low: < 30% of markers show instability
· MSI-stable: 0% of markers show instability
- Familial:
- FAP
- Hereditary non-polyposis colon cancer – HNPCC
- germline mutation of one of mismatch repair
genes (MLH-1, MSH-2, MSH-6, MSH-3, PMS-2)
Other features:
- histologic type can be prognostic (see above)
- perforation at tumour
is associated with poor prognosis
- Perforation proximal to tumour
also has a high mortality
- Treatment response pathologically is prognostically significant
- Minimal residual disease is better than gross
residual disease
- Acellular pools of mucin don’t count as
residual disease
- MMR deficient (MMR-D) / MSI positive sporadic
cancers:
- Better prognosis
- Lower recurrence risk in stage II and III
- Limited benefit from 5-FU-based chemotherapy in
stage II
- Mutations conferring resistance to anti-EGFR
monoclonal antibodies cetuximab and panitumumab:
- KRAS (note: G13D appears to be an exception)
- ?BRAF
- ?PIK3CA
- PTEN loss of expression
- EGFR amplification may predict favourable response to EGFR inhibitors
References:
- Robbins 2007
- WHO Classification of Tumours
of the Digestive System (2010)
- EGAPP Working Group, Genetics in Medicine, 2013,
PMID:23429431
- Mitrovic
B, Schaeffer DF, Riddell RH, Kirsch R.
Tumor budding in colorectal carcinoma: time to take notice. Modern Pathology (2012)
25:1315-1325.
- National Colorectal Cancer Screening Network Classification of Benign Polyps: Pathology Working Group Report
(June 2011)\
- [Draft ASCP/CAP/AMP/ASCO Guideline on the
Evaluation of Molecular Markers for Colorectal Cancer] – March
2016