Colorectal cancer is the third most common cancer in both men and women. Colorectal cancer incidence rates have been decreasing for most of the past two decades, which has largely been attributed to increases in the use of colorectal cancer screening tests that allow the detection and removal of colorectal polyps before they progress to cancer. From 2004 to 2008, annual declines in white men were much larger than those in African American men, 2.9% versus 0.8%, respectively; whereas, among women, declines among whites (2.2% per year) and African Americans (1.7% per year) were similar. In contrast to the overall declines, colorectal cancer incidence rates have been increasing by 1.7% per year since 1992 among adults younger than 50 years of age, for whom screening is not recommended for those at average risk.
Diet: the exact mechanism is not well established . However, it has been theorized that reduced fiber content decreased stool bulk and altered composition of the intestinal microbiota increase in the synthesis of toxic oxidative metabolites by bacterial metabolism ( which will remain in contact with colonic mucosa for a longer time as a result of reduced stool bulk )High fat intake increase hepatic synthesis of cholesterol and bile acids , which can be converted into carcinogens by intestinal bacteria
The most imp neoplastic polyps that are precursore to the colonic adenoca are the colonic adenomas. These can be small , pedunculated to large ,sessile. 50% of the adults living in the western world develop colonic adenomas by age 50.Size of the adenomas is the most imp factor that corresponds to the risk of malignancy.Polyps (precancerous growth associated with aging)Irradiationusually for carcinoma of cervix
Rare forms of CRC syndromes:Torre Muir syndrome : Multiple CRC + multiple sebaceous tumor + keratoacanthomas
Involves a series of molecular alterations.Both pathways involve stepwise accumulation of multiple mutations, but the genes involved and the mechanisms by which the mutations accumulate differs.
The Wnt signaling pathway is a network of proteins that passes signals from receptors on the surface of the cell through the cytoplasm and ultimately to the cell's nucleus where the signaling cascade leads to the expression of target genes. It controls cell-cell communication in the embryo and adult Through these signaling pathways, Wnt proteins play a variety of important roles in embryonic development, cell differentiation, and cell polarity generation.
K-RAS mutation , usually in larger polyps
Clear cell ca Accumulation of glycogen results in a clear appearance of the cytoplasm.Micropapillary 20% ;Greater frequency of lymphovascular invasion and lymph node metastases;Poor prognosisBasaloid Similar to its counterpart in the anal canal.Rare in colorectum . Oncocytic Occurs after preoperative chemoradiation or developing from a villous adenoma with oncocytic changes.Glassy cell carcinomasimilar to its counterpart in the uterine cervixAnaplastic Similar to that of its counterpart in many other organs and its behavior is very aggressiveHepatoid Similar to that of its gastric counterpart.
CDX2 is a caudal-type homeobox gene which encodes a transcription factor that plays an important role in the proliferation and differentiation of intestinal epithelial cells. It is found by immunohistochemistry in the overwhelming majority of colorectal carcinomas. it can also be expressed in primary mucin-producing carcinomas of ovary, bladder, and lung, as well as pancreaticobiliary adenocarcinomas.
Villina cytoskeletal protein associated with the axial microfilament bundles of brush border microvilliCathepsinBalysosomal cysteine proteinaseNeuropilin a molecule normally present in the developing nervous systemSRCA 2an ATPase crucial to many cell functionsCadherinalso known as liver-intestine cadherinCalretinincan be expressed by a minority of colorectal adenocarcinomas (especially the undifferentiated oneshuman chorionic gonadotropin (hCG) common in mucinous and poorly differentiated tumors ( high reactivity) Placental alkaline phosphatase (PLAP) ~ 10% of all colorectal carcinomas Estrogen and progesterone receptors are usually absent or are present in a small minority of tumor cells Racemase, a marker for prostatic adenocarcinoma, is expressed in over half of large bowel adenocarcinomas, a potential source of misdiagnosis
EM: Presence of prominent collections of microfilaments running perpendicular to the cell membrane and entering the brush border.This feature, although helpful, is not diagnostic. It can also be found in intestinal-type carcinomas of the stomach, small bowel, gallbladder, and pancreas
the technique employed to obtain the specimen – which involves extensive cleansing of the colon followed by a diagnostic enema with manipulation of the patient – has led to an unenthusiastic response from clinicians.
Recent advances on colo rectal carcinoma1
Recent advances on Colo-rectal
Dr. Samriddhi Karki
1st year Resident
Department of Pathology
Staging and grading
Spread and Metastasis
• Third most common type of cancer and second
most frequent cause of cancer-related death.
• Most curable form of carcinoma of the
• Usually begins as a noncancerous polyp that
can, over time, become a cancerous tumor.
• Males and females are equally affected.
• Mean age : 62 year
• Worldwide distribution
• Highest incidence rates
Other developed countries
• Colorectal Carcinoma (CRC) among
Nepalese young adults accounts for a high
incidence (28%) of all CRC cases.
• Although right sided colonic cancer has
been increasing, rectum is
the commonest site.
Asian Pacific Journal of Cancer Prevention, Vol 13, 2012
Hereditary Non-polyposis colorectal
cancer ( HNPCC)
• Autosomal dominant disorder.
• Cancers at several sites
Features of CRC in HNPCC
Right –sided location
Lack of necrosis
Familial adenomatous polyposis
• Autosomal dominant disorder.
• Numerous ( 100- 1000) colorectal adenomas.
• Mutation of the adenomatous polyposis coli (APC)
• In left untreated colorectal carcinoma ( 100%) ,
before age 30.
• TWO distinct genetic pathways .
1. APC / β- catenin pathway
Associated with WNT signaling pathway and
the chromosomal instability pathway.
2. Microsatellite instability pathway
▫ Associated with defects in DNA mismatch
APC / β- catenin pathway
• APC tumor suppressor gene (5q21)
• Downregulate growth promoting signals
• Component of WNT signaling pathway.
• Catenins proteins found in complexes
with cadherin cell adhesion molecules.
• β-catenin participates in the WNT
signaling pathway as a growth promoting
WNT signaling pathway
• Network of proteins that passes signals from cell
surface receptors to the nucleus through
cytoplasm leading to expression of target genes
(transcription regulator genes- c MYC)
• Major role in controlling cell fate, adhesion, and
cell polarity during embryonic development.
• WNT signaling is also required for self –renewal
of the hematopoetic stem cells.
Chromosomal instability pathway
• Increased rate of chromosome
missegregation in mitosis .
• Due to
– Gain / loss of chromosome ( aneuploidy)
– Gross chromosomal rearrangements (GSM)
• Earliest event involved in CIN is APC gene
mutation ( 80%)
▫ K-RAS mutation
▫ P53 gene mutation
• Late event : DCC (deleted in colonic
carcinoma) gene mutation
• Advanced event : DPC4/ SMAD4 mutation
CIN forms the basis of
MICROSATELLITE INSTABILITY pathway
Why is it more liable to be unstable ?
How this instability leads to colorectal
• Satellite DNA is composed of
tandemly repeating DNA
( non - coding regions)
• Tandem repeats occur in DNA when a
pattern of two or more nucleotides is
Type of DNA repeat
No. of nucleotide repeat
• Microsatellite DNA :
If the number of nucleotide repeat is 1-4
▫ Dinucleotide repeat:
When exactly two nucleotides are repeated.
Such regions in DNA are commonly affected in
• Microsatellites are more prone to get unstable compared
to other neutral regions of DNA
• This instability is due to any errors , most likely error is
▫ Slippage during DNA replication .
• Such error is normally repaired by Mismatch repair
enzymes which are encoded by MisMatch repair genes.
Defect in MMR gene
Reduced capacity of cells to repair specific types
of DNA damage
Increased rate of mutation accumulation in
• As majority of microsatellites are located in
the non-coding region, these mutations are
• Some microsatellites which are present in
the coding region of the gene are involved in
the regulation of cell growth , like those
▫ Type II TGF-ß receptor
▫ Proapoptotic protein BAX
Defect in MMR genes
• Mutation HNPCC
• CpG island Hypermethylation in
MMR genes Sporadic CCR
CpG Island Hypermethylation
What is CpG?
Terms like : CpG site and CpG Island?
What is methylation?
What is hypermethylation ?
How hypermethylation leads to carcinoma?
• CpG sites:
▫ Regions of DNA where a cytosine occurs next
to a guanine.
▫ DNA methylation occurs at these sites by an
enzyme called DNA methyltransferases.
• In humans, 80 to 90% of all CpGs are
• This methylation results in the conversion of
the cytosine to 5-methylcytosine.
• The remaining 10% nonmethylated CpGs are grouped
in a cluster forming CpG
island , and is usually located
in the promoter regions
towards 5’ end.
• The unique property of CpG
island is that it is unmethylated
in the germ line.
• Methylation of CpG island
within the promoters of genes
silencing of tumor
suppressor genes Cancer
• MSI can be detected by PCR amplification of
microsatellite loci in DNA extracted from CRC
• Newer tests: Nucleic acid flourescence labelling,
laser scanning , flourescence PCR amplification .
• To identify the risk for hereditary cancer and
predict the outcome of CRC.
• To detect MLH1 and MSH2 germline mutations .
The Bethesda Guidelines
MSI testing is recommended in people with any of the following
1. Cancer in families that meet Amsterdam criteria.
2. Two HNPCC- related cancers
3. A first degree relative with CRC and/or HNPCC- related
extracolonic cancer and/or colorectal adenoma diagnosed
4. Right-sided CRC with an undifferentiated pattern on HPE.
5. Signet-ring cell type CRC diagnosed under 45yr.
6. Adenomas diagnosed under 40 yr.
• Asymptomatic for years.
• Left sided colonic carcinomas
▫ occult bleeding
▫ changes in bowel habit
▫ crampy left lower quadrant discomfort
• Right sided colonic carcinomas
▫ iron deficiency anemia
(Anemia in females may arise from gynecologic causes, but it is a clinical
maxim that iron deficiency anemia in an older man means gastrointestinal
cancer until proved otherwise)
• 50% rectosigmoid area (involvement of
the proximal colon is increasing)
• Right-sided tumors more common in the
▫ patients with diverticular disease
A. PROXIMAL COLON
▫ Bulky mass, well-defined/ rolled margins and a
sharp dividing line with the normal bowel.
▫ Less elevated surface and is centrally ulcerated
• These tumors rarely cause obstruction
B. DISTAL COLON
• Annular lesions producing “napkin – ring”
constrictions and luminal narrowing .
• These tumors can cause obstruction.
Tall columnar carcinomas looks similar.
• •All colorectalcells resembling dysplastic epithelium
as in adenomas.
• Almost all – ADENOCARCINOMAS
•secreting variable amounts of mucin.
Inflammatory infiltrations (lymphocytes, plasma cells,
eosinophils, histiocytes ) are prominent at the edge of
• Ranges from well-differentiated to
undifferentiated, frankly anaplastic
Poorly differentiated tumors might form few GLANDS.
• Rarely, the tumor stroma may exhibit metaplastic
• 15 % of all CRCs
• Common in rectum.
• Microscopically :
more than 50%
• High association
• Worse prognosis.
Signet ring adenocarcinoma
• Microscopically :
more than 50%
• About one third
cases are associated
• Worst prognosis.
Common in proximal colon .
Occurs in elderly.
Microscopic : Sheets of malignant cells with
vesicular nuclei , prominent nucleoli,
abundant pink cytoplasm.
• Invariably associated with MSI .
• Favourable prognosis .
• 7.5% of all CRCs.
• Common in proximal colon.
• Derived from serrated
▫ serrated, mucinous or trabecular pattern of
▫ abundant eosinophilic cytoplasm
▫ chromatin condensation
▫ preserved polarity, and
▫ no necrosis.
• Common in proximal colon.
• Usually associated with glandular elements
• Occasionally , seen in a pure form (squamous
• Evidence for human papilloma virus 16
involvement in the pathogenesis of some rectal
• Can occur focally in CRCs.
• hCG can be demonstrated
immunohistochemically in such tumor cells.
• Occasionally the entire tumor has the
appearance of a choriocarcinoma.
• This phenomenon should be distinguished from
conventional adenocarcinomas( where hCG
positivity is more common )
• Conventional adenocarcinoma of large bowel express are
MUC1 and MUC3.
• Mucinous carcinoma express MUC2.
• CRCs invariably positive for cytokeratin (CK) positivity for
CK20 and negativity for CK7
• Positive for CEA.
• Positive for CDX2, in majority of CRCs.
• Tumor-associated glycoprotein (TAG-72) is present in 100 %
of invasive colorectal carcinoma.
• CRCs , especially poorly differentiated show loss of blood
group isoantigens and of HLA A, B, and C expression.
Human chorionic gonadotropin (hCG)
Placental alkaline phosphatase (PLAP) ~10%
Estrogen and progesterone receptors
Electron microscopic features
• There is a need of POSITIVE BIOPSY before
radical surgery for CRC.
• In large lesions, several biopsies should be taken
form diverse areas.
• Biopsy from center only granulation tissue
• Biopsy from the very periphery only
hyperplastic colonic epithelium
• Its an accurate way of diagnosing CRC.
• Little practical value.
• Low-lying rectal lesions can be easily sampled.
• Brush cytology can also be performed via the
• It is a sensitive technique, perhaps even more so
than endoscopic biopsy, but it has not yet found
Various screening modalities
• Virtual colonography
• Fecal occult blood test
• Double contrast barium enema
• Digital rectal examination
Staging and Grading
• In 1937, Dukes proposed staging for rectal
• In 1954, Astler and Coller proposed different
• American Joint committee on Cancer(AJCC)
• The Union Internationale Countre Le Cancer
Dukes’ Stage A
• The tumor involve the
wall of the bowel only.
• Treatment is surgery
to remove the tumor
and some surrounding
Dukes’ Stage B
• The cancer extend through
the wall has not spread to the
• Colon cancer is treated with
surgery and, in some cases,
chemotherapy after surgery.
• Rectal cancer is treated with
surgery, radiation therapy,
Dukes’ Stage C
• The cancer has spread to
the regional lymph nodes
(lymph nodes near the
colon and rectum)
▫ C1: regional L.N
▫ C2: mesenteric B.V.
• Colon cancersurgery and
radiation therapy, and
Dukes’ Stage D
• Spread outside of the
colon or rectum to other
areas of the body
• Treatment : chemotherapy.
• Surgery to remove the
colon or rectal tumor may
or may not be done
• Additional surgery to
remove metastases may
also be done in carefully
Astler and Coller Staging
• Stage A
▫ Limited to mucosa
• Stage B1
▫ Involving the muscularis externa but not penetrating it
• Stage B2
▫ Penetrating through the muscularis externa
• Stage C1
▫ Confined to the bowel wall but with nodal metastasis
• Stage C2
▫ Penetrating through the wall and with nodal metastsis
TNM Staging of Colon Cancer
T0 = none evident
Tis = in situ (limited to mucosa)
T1 = invasion of lamina propria or submucosa
T2 = invasion of muscularis propria
T3 = invasion through muscularis propria into subserosa or nonperitonealized perimuscular tissue
T4 = invasion of other organs or structures
Lymph Nodes (N)
0 = none evident
1 = 1 to 3 positive pericolic nodes
2 = 4 or more positive pericolic nodes
3 = any positive node along a named blood vessel
Distant Metastases (M)
0 = none evident
1 = any distant metastasis
5-Year Survival Rates
T1 = 97%
T2 = 90%
T3 = 78%
T4 = 63%
Any T; N1; M0 = 66%
Any T; N2; M0 = 37%
Any T; N3; M0 = data not available
Any M1 = 4%
Microscopically, colorectal carcinoma
can be graded into
▫ I – well differentiated
▫ II- moderately differentiated
▫ III- poorly differentiated
Spread and Metastasis
▫Regional lymph nodes
Lymph node metastasis
• More common in the tumors showing
▫ poorly differentiated areas
▫ highly infiltrative pattern of growth.
• Minimum number of nodes recovered from a
surgical specimen of colorectal carcinoma
should be 14 or 15.
• More common in the tumors showing
evidence of blood vessel invasion.
• Other relatively common
metastatic sites include
• The 5-year survival rate after curative resection
for CRC ranges between 40% and 60% .
• Local recurrence and/or regional lymph node
metastases occur in over 90% of the failure cases.
• Over two-thirds of the recurrences are evident
within the first 2 years and 91% by 5 years.
• The prognosis of colorectal carcinoma is related
to a number of clinical and pathologic parameters.
• Category I
▫ Well supported by the literature, generally used in
patient management and of sufficient importance to
modify TNM stage groups.
• Category IIA
▫ Extensively studied biologically and/or clinically.
Prognostic value for therapy, sufficient to be noted in
• Category IIB
▫ Well studied but not sufficiently established for
Category I or IIA
• Category III
▫ Not yet established to meet criteria for Category I or II
• Category IV
▫ Studied and shows no consistent prognostic
(R - P)