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10 GENOMICS, HISTOPATHOLOGY, AND MOLECULAR PATHOLOGY OF SPORADIC AND HEREDITARY COLORECTAL CANCER 155
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Table 2 Histological features of serrated lesions/polyps.
Hyperplastic polyps Small polyps in distal bowel with normal architecture and proliferation. GCHP has mature
• Goblet cell-rich type (GCHP)
• Microvesicular type (MVHP)
Sessile serrated lesions (SSL) Different from hyperplastic polyps, SSLs show abnormal architectural features such as
Traditional serrated adenoma (TSA) Characterized by overall protuberant growth pattern with villiform projections,
Mixed serrated polyp Contains components from the above categories.
goblet cells in the upper crypt and harbor KRAS mutations in 50%. MVHP have enlarged
micro-vacuolated columnar cells in upper crypt and harbor BRAF mutations in 70–80%.
branching of crypts, dilation of crypt base and growth of crypts parallel to muscularis
mucosa.
BRAF mutations are detected in up to 90% of SSLs.
Low grade dysplasia relates to a loss of mismatch repair protein function and can be
detected immunohistochemically.
characteristic ectopic crypt foci that develop orthogonally to the crypt axis and tall
columnar cells with pencillate nuclei and eosinophilic cytoplasm.
and Whitehall 2010). A classification system was proposed by
Snover and colleagues, shown in Table2 (Snover etal. 2005).
While sporadic hyperplastic polyps are common and benign,
sessile serrated polyposis (SSP) is a rare condition characterized by multiple serrated polyps, some of which can be >1cm in
diameter (Winawer etal. 1997). Several studies have confirmed
an increased risk of CRC in patients with SSP (35–50%), suggesting that serrated lesions have pre-malignant potential
(Chow etal. 2006; Hyman etal. 2004).
Clinical criteria were proposed by the World Health
Organisation in 2019 for the diagnosis of serrated polyposis.
These are in Table3:
WHO criteria for the diagnosis of sessile serrated polyposis.
Table 3
Criterion 1: > 5 serrated lesions proximal to the rectum, all being ≥
5 mm in size, with ≥ 2 being 10 mm in size
Criterion 2: > 20 serrated lesions of any size distributed throughout the
large bowel, with ≥ 5 being proximal to the rectum
Note that any histological subtype of serrated lesion is included in the
final polyp count. The polyp count is cumulative over multiple
colonoscopies.
Additionally, sessile serrated lesions (SSLs) have been shown
to be precursors to tumors with MSI (C. Richard Boland and
Goel 2010). In the sporadic setting, conventional adenomas
rarely show MSI whereas serrated polyps sometimes have MSI
and loss of MLH1 expression (Iino etal. 1999).
Toyota and colleagues identified a subset of sporadic CRCs
that showed high levels of CpG island methylation (both in
MLH1 and in other cancer-specific genes), a group called CpG
island methylator phenotype (CIMP +) (Toyota et al. 1999).
Yang and colleagues detected CIMP, in increasing order of frequency, in MVHP (47%), SSL (75%) and TSA (80%), indicating
the sequence of events in the progression from precursor to
dysplastic lesion (Yang etal. 2004). As well as being present in
serrated polyps, CIMP has been identified in histologically
normal mucosal biopsies, supporting the importance of a colorectal field in the development of serrated neoplasia (Worthley
etal. 2010).
In addition to CIMP, BRAF mutations have been implicated
in the vast majority of sessile serrated adenomas but almost
never in conventional adenomas (Kambara etal. 2004). BRAF
mutations are not prevalent in Lynch syndrome, strengthening
its association with the serrated pathway rather than MSI (Yang
etal. 2004). An activating mutation in BRAF (typically V600E)
leads to constitutive activation of the mitogen-activated protein
kinase pathway, leading to cell proliferation and survival
independent of EGFR activation. BRAF appears to be mutated
early in the serrated pathway as 70–76% of MVHP are BRAFmutant, and BRAF mutations are found in aberrant crypt foci,
which are the earliest histologically evident lesions in the serrated pathway (O’Brien etal. 2006; Rosenberg etal. 2007). More
recently, a role for mutations in RNF43 in the serrated pathway
has been proposed. Yan and colleagues found that 85% of
MSI-H tumors with MLH1 promoter methylation had a mutation in RNF43, compared to only 33% of tumors without MLH1
promoter methylation (Yan etal. 2017).
Rarer Inherited Colorectal Cancer
Syndromes
With the widespread use of NGS on colorectal tumors, more
pathogenic variants are being associated with susceptibility to
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Summary of rare inherited colorectal cancer predisposition syndromes.
Table 4
Syndrome Genetic defect Features
Polyposis MUTYH (or MYH)-associated
polyposis (MAP)
Polymerase proofreading-
associated polyposis (PPAP)
Hamartomatous Peutz-Jehgers Syndrome (PJS) LKB1 (also called
Juvenile Polyposis Syndrome (JPS) SMAD4, BMPR1A Mucocutaneous telangiectasias, congenital cardiopulmonary defects.
Cowden disease PTEN Macrocephaly, oral, and skin papillomas. Increased risk of breast and
MYH <100 colorectal adenomas by the third decade of life.
POLE, POLD1 Multiple colorectal adenomas. Increased risk of endometrial, brain,
STK11)
CRC. While these contribute very little to the worldwide
burden of CRC, these syndromes help shed more light on the
molecular mechanisms that underpin colorectal tumorigenesis. These syndromes, summarized in Table 4, are broadly
classified as polyposis (including FAP or attenuated FAP, as discussed before), non-polyposis (Lynch syndrome) and hamartomatous syndromes.
Colitis Associated Cancer
An alternative route for CRC development relies on the
presence of chronic inflammation. Indeed, a wealth of evidence
has demonstrated that the prevalence of CRC in patients with
inflammatory bowel disease (IBD) (ulcerative colitis or Crohn’s
disease) is significantly increased relative to the healthy
population (Ekbom etal. 1990; Winther etal. 2004). In addition
to long disease duration, the severity of inflammation is a risk
factor for the development of CRC in inflammatory bowel disease (Gillen etal. 1994).
The underlying mechanism that promotes tumorigenesis in
the context of chronic inflammation remains to be elucidated
but is likely to be multifactorial. Pro-inflammatory pathways
such as the NF-kB, IL-6/STAT3, COX2/PGE2 and IL-23/Th17
are likely to be involved by regulating the expression of certain
inflammatory mediators and promoting a tumor-supporting
environment (O’Connor etal. 2010). In contrast to sporadic
CRC, the sequence of events in colitis-associated CRC appears
to be different. In particular, TP53 mutations (Figure6) appear
to be an early event as they are detected not only in precancerous lesions, but also in non-neoplastic mucosa in the context of chronic inflammation (Galandiuk etal. 2012; Yin etal.
1993). Furthermore, APC and KRAS mutations are less prevalent in colitis-associated CRC, arguing the case for the selection
of certain cancer-associated mutations by chronic inflammation (Burmer etal. 1990; Tannin etal. 1995).
breast, ovarian, and pancreatic cancers.
GI hamartomatous polyps, mucocutaneous pigmentation. Increased risk
of pancreatic, stomach, breast, ovarian, lung, and endometrial cancer.
Increased risk of pancreas, stomach, and small bowel cancers.
thyroid cancers.
Endoscopic surveillance in patients with IBD is crucial and
has been shown to reduce the incidence of colitis-associated
colorectal cancer (Castaño-Milla et al. 2014). In the UK, the
British Society of Gastroenterology (BSG) and Association of
Coloproctology for Great Britain and Ireland (ACPGBI) have
issued guidelines for CRC screening in patients with IBD
(Table5) (Cairns etal. 2010; Lamb etal. 2019). All patients with
ulcerative colitis or Crohn’s colitis are recommended to have a
screening colonoscopy approximately 10 years after the onset of
colitic symptoms. The frequency of subsequent colonoscopic
surveillance is then determined by stratifying patients into low,
Table 5 Summary of BSG/ACPGBI guidelines for colonoscopic
surveillance for CRC in IBD.
Low risk (offer colonoscopy at five years)
• Extensive but quiescent ulcerative colitis or
• Extensive but quiescent Crohn’s disease or
• Left-sided ulcerative colitis (but not proctitis alone) or Crohn’s colitis
of a similar extent.
Intermediate risk (offer colonoscopy at three years)
• Extensive ulcerative or Crohn’s colitis with mild active inflammation
that has been confirmed endoscopically or histologically or
• Post-inflammatory polyps or
• Family history of colorectal cancer in a first-degree relative aged 50
years or over.
High risk (offer colonoscopy at one year)
• Extensive ulcerative or Crohn’s colitis with moderate or severe active
inflammation that has been confirmed endoscopically or histologically or
• Primary sclerosing cholangitis (including after liver transplant) or
• Colonic stricture in the past five years or
• Any grade of dysplasia in the past five years or
• Family history of colorectal cancer in a first-degree relative aged
under 50 years.
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Figure6 Case of inflammatory bowel disease with high grade dysplasia characterized by nuclear atypia and loss of maturation in crypt epithelium
(A). The same crypt is seen in panel B (arrow) showing abnormal loss of TP53 expression contrasting with positive nuclei in the background inflammatory
cell infiltrate.
intermediate and high-risk groups based on their disease burden,
family history of CRC, presence of primary sclerosing cholangitis and endoscopic appearance at the index colonoscopy.
Transcriptomic Classification of
Colorectal Cancer
The heterogeneous nature of CRC has meant that stratification
of patients into clinically actionable groups has been difficult.
In an effort to integrate molecular characteristics into
classification, the consensus molecular subtypes (CMS) were
introduced in 2015 (Guinney etal. 2015). By making use of differences in tumor biology rather than clinical outcomes, the
CMS classification attempted to capture the intrinsic molecular
heterogeneity of CRC.
Four subtypes were identified (CMS1-4) based on differential
gene expression of the tumor tissue (comprising both the epithelium and stroma). CMS1 is enriched for MSI tumors and
BRAF mutations, and displays high immunogenicity. CMS2
tumors have marked Wnt and Myc activation, and these tumors
display high levels of chromosomal instability. CMS3 tumors
are enriched for KRAS mutations and have features of metabolic dysregulation. CMS4 tumors on the other hand are mesenchymal and show activation of the TGFB pathway, with
stromal invasion, angiogenesis and an immunosuppressive
phenotype (Becht etal. 2016).
The CMS classification has been shown to be of prognostic significance. Primary CMS4 tumors have been associated with worse overall survival compared with CMS1 and
CMS2 cancers (ten Hoorn etal. 2021). Similarly, adjuvant
chemotherapy has been shown to be more effective in CMS2
and CMS3 tumors. However, a criticism of the CMS
classification has been that it allocates a significant weight to
the stromal content of the tumor, thereby masking low abundance epithelial transcripts. The five CRC intrinsic subtypes
(CRIS) have been developed to address this (Isella et al.
2017). Increasingly, molecular profiling and patient
classification into molecular subtypes are being used for
treatment allocation in oncological trials. It remains to be
shown whether this approach will increase the treatment
effect by reducing the number of patients who do not
respond to treatment.
Histopathology
Careful and accurate pathology reporting of CRC is vital because
pathology reports are used not only to confirm the diagnosis, but
also to provide prognostic and predictive information allowing
clinicians to deliver a high standard of care for patients and
appropriate management for specific clinical circumstances. The
report also provides valuable audit data on the accuracy of other
clinical services such as radiology, surgery, oncology and screening programs. Systematic review of all original colorectal
pathology reports, macroscopic images/descriptions and slides
also acts to audit the quality and consistency of reporting within
the pathology department and to collect accurate data for cancer
registration and epidemiology, facilitate high quality research,
provide education, and plan service delivery (Loughrey et al.
2018). Pathologists are therefore well placed to help establish and
maintain high standards of clinical care for patients with CRC as
part of a multidisciplinary team.
The specimens examined by the pathologists will be considered separately, starting from the initial assessment of diagnostic biopsies and progressing through local excisions to
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resections. This approach broadly corresponds to the order in
which surgical specimens are examined as patients’ progress
along the colorectal cancer pathway.
Biopsy Diagnosis of Large Bowel
Adenocarcinoma
Frequently, the pathologist is required to interpret biopsies
taken from polypoid, ulcerated or flat lesions which are endoscopically suspicious of malignancy. The aim is to confirm the
diagnosis of malignancy, classify the type of malignancy
(including primary versus secondary) and assess tumor grade.
Less frequently, biopsies taken from sites other than the colon
and rectum may contain deposits of colorectal adenocarcinoma. In such cases, the pathologist is strongly aided by
detailed clinical information, including appropriate radiologic
imaging and may require the use of immunohistochemical
stains. Depending on the biopsy appearance, a report of metastatic adenocarcinoma may be suggestive of primary colorectal
malignancy.
Endoscopic biopsy confirmation of colorectal adenocarcinoma depends upon the identification of unequivocal evidence of invasion by tumor cells through the muscularis
mucosae into the submucosa. A desmoplastic stromal reaction may provide a clue to the diagnosis. Biopsies entirely
composed of superficial fragments of “dysplastic” epithelium
with no relation to muscularis mucosae or containing only
necrotic tissue are deemed inadequate and the pathologist is
unable to independently verify the diagnosis of malignancy.
Small biopsies from invasive tumors may also fail to accurately represent the true tumor grade, while areas of ulceration and associated inflammation from superficial parts of
the tumor may lead to the mistaken interpretation of a poorly
differentiated tumor.
It has been widely recommended that all CRCs should be
tested for MMR status with the purpose of detecting Lynch
syndrome at the time of diagnosis. As will be discussed in
more detail further on in this chapter, it is also important for
clinical management and prognosis. The initial test can be
MSI or MMR immunohistochemistry, depending on local
circumstances. The recommendation is that MMR immunohistochemistry should be performed on the endoscopic
biopsy, assuming this contains diagnostic material, and the
main reasons for this are:
• better fixation facilitates interpretation.
• the result is available clinically in a more timely fashion,
which is essential in the neoadjuvant pathway.
• avoids radiotherapy-induced artefacts that can affect
interpretation.
• patients who do not undergo surgery are tested.
Endoscopists should be encouraged to take more and larger
biopsy samples from all tumors, to allow confident diagnosis
and provide adequate tumor tissue for any required downstream testing for example, for Lynch syndrome (Loughrey
etal. 2018).
Local Excision Specimens
A biopsy diagnosis of adenocarcinoma may be followed by
planned local excision, which may be undertaken as a curative
procedure for some patients with early rectal cancer or as a palliative procedure in patients unsuitable for resectional surgery.
Lesions may be removed by endoscopically (endoscopic mucosal
resection or endoscopic submucosal dissection) or, in the case of
some rectal tumors, via transanal minimally invasive surgery.
As the majority of large bowel adenocarcinomas arise from
pre-existing adenomas and sessile serrated lesions, screening
colonoscopy and therapeutic polypectomy has a potential to
reduce CRC burden by early detection and removal of benign
polyps, thus decreasing CRC incidence and mortality (Lin etal.
2021). Careful assessment and reporting of these premalignant
lesions requires a standardized approach and the use of consistent terminology amongst pathologists, gastroenterologists,
and colorectal surgeons.
Conventional colorectal adenomas are subtyped according
to their histological pattern. Tubular adenomas, which are the
most common subtype, show normal crypt architecture
(Figure7) whereas villous adenomas are composed mainly of
leaf- or finger-like projections. Tubulovillous adenomas show a
mixture of both patterns (Figure 8). The grading of the dysplasia is based mainly on the degree of architectural complexity
Figure7 Tubular adenoma (left) showing similar architecture as adjacent
non-dysplastic mucosa (right).
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Figure8 Tubulovillous adenoma (A). Figure(B) is a higher magnification of the encircled area showing villiform projections.
Figure9 Tubular adenoma with low grade dysplasia (A, thin arrow) and high-grade dysplasia (A, thick arrow). Encircled area (B) shows nuclear crowding
with reduced stroma between glands, nuclear crowing, frequent mitotic figures (green arrows) and intraluminal necrosis (green star).
supplemented by cytological atypia. The use of a two-tier stratification of the adenomatous dysplasia into low grade and high
grade is recommended as this provides a uniform system for
integrating global histopathology grading data (Figure 9).
Although used in the Japanese literature, in order to avoid
overtreatment of lesions considered to have negligible risk of
metastatic spread, the terms carcinoma in situ and intramucosal carcinoma are not used in Europe and the USA.
The term “advanced adenoma” encompasses a group of ade-
nomas larger than 10
mm, tubulovillous or villous architecture,
and/or high-grade dysplasia. These are associated with a high
risk of synchronous or metachronous adenomas, the former
indicating the need for a full colonoscopy and the latter more
stringent surveillance (WHO 2019).
As mentioned before, serrated lesions (SLs) and polyps are
characterized by a sawtooth or stellate architecture of the epithelium. They are named according to their morphological
appearance as hyperplastic polyp (HP) (Figure10), sessile
serrated lesion (SSL), sessile serrated lesion with dysplasia,
traditional serrated adenoma (TSA) and mixed lesions (Table
2) (Bateman and Shepherd 2015). The distribution of SLs
varies with the type: HPs and TSAs are usually found in the
left colon, while SSLs occur more often in the proximal colon
(Carr etal. 2009; Lash etal. 2010; Qazi etal. 2014). SSLs are
commonly 10 mm or more, particularly the ones with dysplasia, and show an overall distortion of the normal crypt
architecture, probably resulting from alterations of the proliferative zone (Figure11) (Yang etal. 2015). Tiny distal HPs
do not appear to be associated with significant risk of CRC
development, while larger lesions with features of SSLs can
be associated with the development of dysplasia and adenocarcinoma (East etal. 2017). SSLs can show dysplasia that
can be low or high grade in nature and it is believed that dysplastic lesions are associated with faster progression to
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Figure10 (A) Microvesicular hyperplastic polyp with serrated appearance of the crypts. (B) Goblet cell-rich hyperplastic polyp.
Figure11 (A) Sessile serrated lesion with dilation extending to the base of crypts and crypt distortion. (B) Same lesion with an area of high-grade dysplasia.
adenocarcinoma than “classical” adenomas. TSAs can present as large polyps in the left colon and rectum or as flat
lesions predominantly in the proximal colon. They are characterized by the presence of dysplasia, almost always show
areas of conventional adenomas and seem to have a more
rapid malignant potential.
The principles of reporting an adenocarcinoma that has developed within an adenomatous lesion and has been removed by
local excision are the same as in major resections. However, a
number of features require special attention in local excisions of
(presumed) early cancers with curative intent because they are
used to determine the necessity for more radical surgery. In
addition to the assessment of completeness of excision, these
include the recording of parameters that predict the presence of
lymph node metastatic disease in early tumors, namely tumor size,
poor differentiation, the depth of invasion into the submucosa, the
presence of submucosal lymphatic or venous invasion and margin
involvement (Beaton etal. 2013; Ueno etal. 2004).
Tumors that invade the muscularis propria usually require
further surgery. For many years the Haggitt (1985) and
Kikuchi (1995) classifications (Figure12) have been used to
sub-stage the colorectal adenocarcinomas in relation to depth
of invasion into submucosa in pedunculated and sessile
tumors respectively. Haggitt and colleagues found that “level
4” invasion, in which the tumor extended beyond the stalk of
the polyp into the submucosa but did not invade the muscularis propria, was an adverse factor. Neither system is always
easy to use in practice, especially if there is fragmentation or
suboptimal orientation of the tissue. The Kikuchi level system
requires division of the submucosa into thirds and this is not
possible to do accurately unless muscularis propria is included
in the specimen.
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Figure12 Substaging of T1 cancer. (a) Haggitt staging of pedunculated adenocarcinoma. (b) Kikuchi staging in sessile T1 adenocarcinoma.
More recently, Ueno et al. (2004) have proposed that the
absolute thickness of the invasive tumor (depth of invasion
beyond the muscularis mucosae) and the width of tumor
invasion provide more objective measures of potential risk of
lymph node metastatic disease. At the moment, a firm recommendation cannot be made based on current evidence for
one method of assessing local invasion over another and
whenever possible, all three approaches should be mentioned
in the pathologist report to facilitate data collection for
further research and for local multidisciplinary teams to
select which they consider to be most appropriate to
management decisions.
Intact polypectomy specimens require assessment of both
the peripheral (mucosal) and deep margins. Involvement of a
peripheral margin may indicate the need for repeat endoscopy
and further local excision if feasible. Involvement of the deep
resection margin by invasive tumor has traditionally been an
indication for considering surgical intervention.
Another emerging feature, particularly for local excision
specimens, is the presence of tumor budding (single tumor
cells or cell clusters of up to four tumor cells). Until recently,
however, the application of this biomarker in clinical practice
was limited by the lack of a standardized assessment and
reporting methodology. In the context of CRC, tumor budding can be assessed according to the method agreed at the
International Tumor Budding Consensus Conference
(ITBCC) in 2016. Using the ITBCC scoring system, tumor
budding is an independent predictor of lymph node metastasis in patients with pT1 CRC and an adverse prognostic
factor that should warrant consideration of adjuvant
chemotherapy in patients with stage II colon cancer (Lugli
etal. 2021). The most recent WHO classification of tumors
(2019) has included this feature as an additional prognostic
factor for CRC.
Tumor budding can not only be observed at the invasive
tumor front (Figure 13), but also within the tumor bulk,
referred to as intra-tumoral budding. Tumor budding can be
observed in endoscopic biopsy specimens and their presence
has been shown to be associated with advanced tumor stage
assessed quantitatively (Lugli etal. 2021).
In an effort to combine the effect of depth of invasion with
other prognostic factors, the ACPGBI issued a position statement in 2013, highlighting the role of the resection margin,
degree of differentiation, tumor budding, lympho-vascular
invasion, and mucinous differentiation in conferring a risk of
residual disease following resection of a malignant polyp
(Williams etal. 2013).
Resection Specimens
Colorectal resection specimens require careful handling and
assessment if key prognostic data are to be determined reliably
and accurately. The critical role of a skilled surgical technique
and its effect on patient outcome (morbidity and mortality) is
well established for anterior resection (AR) and abdominoperineal excision of the rectum resection (APER) procedures
in the treatment of rectal cancer. Audit of the adequacy of the
surgical technique is regarded as a valuable source of feedback
to colorectal surgeons, including an assessment of the resection margin (R) status.
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Figure13 Tumor budding, single or small clusters of neoplastic cells infiltrating the desmoplastic stroma, seen on H&E (A) and highlighted with
immunohistochemistry for Cytokeratin in (B).
Ideally, specimens should be received fresh and unopened as
soon as possible after surgical resection. The colorectal
specimen should be photographed and carefully examined. In
rectal specimens, particular attention should be given to the
macroscopic assessment of the mesorectum which should be
intact, with no defect deeper than 5 mm and no coning toward
the distal margin. A three-tier scoring system has been proposed: complete, which shows an intact mesorectum; nearly
complete or intra-mesorectal; and incomplete when there is
exposure of muscularis propria (Nagtegaal et al. 2002). This
information predicts not only margin involvement but also
local recurrence and survival. The plane of resection can also
be used as a marker of the quality of surgery and continual
feedback to multidisciplinary teams has led to improved quality
of surgery and clinical outcomes with time (Nagtegaal et al.
2002; Quirke etal. 2009).
In addition to detailed macroscopic description which should
mention tumor location and diameter, the pathology report
should include information relating to the tumor type and
differentiation; extent of local tumor invasion (pT stage) specifying if invasion in other organs or tumor perforation; resection
margins; lymph node (LN) status (number present and number
involved); presence of tumor deposits; intra and/or extramural
venous invasion; lymphatic invasion and perineural invasion.
All of the lymph nodes that can be found in a specimen should
be examined histologically as the number of lymph nodes identified in resection specimens from patients with stage II and
stage III colon cancer has been positively correlated with survival
(Chang etal. 2007). This positive correlation is supported by the
results of a recent analysis by Lal etal. (2022) using cases from
The Cancer Genome Atlas (TCGA) which shows that a high LN
yield predicts overall and disease-free survival. In addition, they
found no association of higher LN yield and increasing nodal
positivity; and a high LN yield was strongly linked to an activated
immune response in tumors. Their data suggest that LN yield
may be driven by an enhanced immune response in the primary
tumor making nodes easier to identify ex vivo rather than
intrinsic surgical or pathologist-specific factors.
Additional prognostic factors are tumor budding, and the
inflammatory infiltrate (Loughrey etal. 2018; Lugli etal. 2021).
In relation to inflammatory infiltrate, the presence of intratumoral lymphocytes and Crohn-like reaction are associated
with improved outcome (Rozek et al. 2016). Tumor deposits
(satellites) are an established adverse prognostic factor in colorectal cancer (Nagtegaal etal. 2016) and according to TNM 8,
they are defined as "discrete macroscopic or microscopic nodules of cancer in the pericolorectal adipose tissue’s lymph
drainage area of a primary carcinoma that are discontinuous
from the primary tumor and without histological evidence of
residual lymph node or identifiable vascular or neural structures". In the absence of lymph node metastasis in regional
lymph nodes, the presence of a satellite deposits changes the
tumor status to pN1c.
Regular audit of resection specimen reports should ensure
that all of the relevant data is consistently and accurately
recorded.
Preoperative Chemoradiotherapy-Related
Changes in Surgical Specimens
Following neoadjuvant chemoradiotherapy, rectal tumors may
show evidence of extensive regression with widespread necrosis
and stromal fibrosis. Alterations in the appearance of the
advancing front of tumor cells and a reduced lymphocytic
response is also frequently seen. In some circumstances the
tumor may be entirely absent from the specimen despite extensive sampling. Alternatively, small foci of residual tumor cells
may appear isolated within the rectal wall. Lymph nodes, critical for accurate pathologic staging, may be small, difficult to
find and display features of necrosis.
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Table 6 Most commonly used system for assessing tumor regression grade (TRG) (Adapted from Langer and Becker 2018).
Grade Mandard AJCC 2010
TRG 0 – No residual tumor cells (complete response)
TRG 1 Absence of residual cancer cells Single cells or small groups of cancer cells (near complete response)
TRG 2 Rare residual cancer cells scattered through the fibrosis Residual cancer cell with desmosplastic response (partial response)
TRG 3 An increased in number of residual cells, but fibrosis still predominates Minimal evidence of tumor response (poor or no response)
TRG 4 Residual cancer outgrowing fibrosis
TRG 5 Absence of regressive changes
The response of rectal cancers to preoperative chemoradiotherapy is highly variable ranging from complete pathological response to no detectable effects. There is evidence
that patients with completely excised rectal carcinomas, who
have received neoadjuvant treatment that has resulted in
complete or marked regression, have a better prognosis than
those without significant regression (Hermanek etal. 2013;
Maas etal. 2010). In order to allow meaningful comparisons
of resected rectal tumors and to establish the prognostic
value of histologic chemoradiotherapeutic change, various
classification systems to assess tumor regression grade (TRG)
have been proposed (Table 6). Pathologists should be encouraged to document the TRG in all patients receiving neoadjuvant chemoradiotherapy.
The Emerging Role of Molecular
Diagnostics in Colorectal Cancer
As outlined throughout this chapter, molecular tumor characterization has become an integral part of the multidisciplinary
approach in the management of patients with CRC over the
past decade. Molecular diagnostics is of dual significance. First,
it allows accurate classification of the underlying pathology,
which itself guides treatment options that are becoming
increasingly personalized. Secondly, it may inform on the
presence of underlying hereditary tumor syndromes as outlined above, guiding surveillance and screening of relevant
family members. The technological progress in molecular
tumor characterization and access to large panel sequencing
provide information on prognostic tumor factors and lead to
the identification of targetable pathways and allow patients to
access clinical trials.
MSI and mutations in BRAF and RAS are established predictive biomarkers in CRC (WHO classification of tumors 2019)
and can be tested either by immunohistochemistry (MMR and
V600E
BRAF
In the UK, NICE recommends algorithmic testing for Lynch
syndrome (NICE 2017) (Figure 14). MSI CRCs should have
BRAF mutation testing and/or MLH1 promoter methylation
testing to distinguish between sporadic dMMR cancers and
Lynch syndrome. Absence of BRAF
) or sequencing.
V600E
mutation and/or
absent MLH1 promoter hypermethylation should prompt a recommendation of referral to clinical genetics for appropriate
counselling and screening of the relevant MMR genes, as should
loss of PMS2, MSH2, and/or MSH6 immunohistochemical
expression (Loughrey etal. 2022). BRAF-wildtype cases with
MSI have a good prognosis, and regardless of BRAF status,
dMMR tumors have a poorer response to 5-fluorouracil-based
chemotherapy but respond to immune checkpoint blockade (Le
et al. 2017). More recently, Cercek and colleagues described
complete clinical responses in all cases (n = 12) of dMMR stage
II or stage III locally advanced rectal cancer treated with dostarlimab, an anti-PD-1 monoclonal antibody, without the need for
chemoradiotherapy or surgery (Cercek etal. 2022).
Mutations in KRAS and NRAS also have therapeutic significance. Testing for KRAS and NRAS mutations in codons 12, 13,
59, 61, 117, and 146 in CRC with metastatic disease is recommended as it correlates with resistance to anti-epidermal
growth factor (anti-EGFR) therapy (such as cetuximab and
panitumumab) (Van Cutsem E, Lenz HJ, Köhne etal. 2015).
Early-stage clinical trials have shown promising results with
the KRAS
G12C
specific covalent inhibitor sotorasib in KRAS
G12C
mutant CRCs (Canon etal. 2019).
It is likely that the presence of BRAF
V600E
mutation also
confers resistance to anti-EGFR therapy. However, this can
be rescued through triplet therapy with BRAF (encorafenib),
EGFR (cetuximab) and MEK (binimetinib) inhibitors,
which have been shown to increase overall survival compared to standard treatment (Kopetz etal. 2019). Therefore,
most modern guidelines also recommend testing metastatic
CRC for BRAFV
600E
mutation (Loughrey et al. 2022;
Pietrantonio etal. 2015).
A number of studies investigating other possible biomarkers in colorectal cancer are underway and other tests
will inevitably emerge in the near future. For example, HER2
activation (which leads to MAPK phosphorylation and
subsequent resistance to EGFR inhibition) appears to be a
possible druggable target, with combination therapy of
trastuzumab plus lapatinib or trastuzumab and pertuzumab
(Meric-Bernstam et al. 2019; Sartore-Bianchi et al. 2016).
Table 7 summarizes current and emerging biomarkers and
their clinical significance.
164 2 COLORECTAL AND ANAL CANCER
https://t.me/medicina_free
New diagnosis of CRC
Te st for mismatch repair deficiency
PCR-based MSI test
MSH1
abnormal
test
positive
MSI (MSI-L
or MSI-H)
BRAF
V600E
MSS
No further testing No further testing
IHC panel for MLH1, MSH2,
MSH6, and PMS2
MSH2, MSH6,
or PMS2
abnormal
All 4 genes
normal
negative
positive
MSH1 promoter
hypermethylation test
negative
Confirm Lynch syndrome by genetic testing of germile DNA
Figure14 Flowchart of molecular testing algorithm suggested by NICE.
Table 7 Suggested markers for routine testing and their possible significance (in addition to prognostication).
Marker Test Present and possible future significance
Microsatellite instability (MSI) PCR • PD1 blockade
Mismatch repair (MMR) status IHC • Screening for Lynch syndrome
NGS • PD1 blockade
KRAS, HRAS, NRAS PCR • Resistance to anti-EGFR therapy
V600E
BRAF
PIK3CA* NGS • Aspirin as adjuvant therapy
HER2* IHC
NTRK fusion* NGS • TRK inhibition
MET amplification* NGS • Resistance to anti-EGFR therapy
Consensus molecular subtyping* Transcriptional profiling • Targeted cetuximab (in CMS2) or bevacizumab (in CMS1)
* emerging biomarkers with current limited evidence.
NGS
IHC
NGS
NGS
• KRAS-specific inhibitors
• BRAF-specific inhibitors
• HER2 blockade
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