4th Year MBBS,

Jinnah Medical College, Peshawar

COLORECTAL CARCINOMA

Lecture By:
Dr. Shahid Hasnain Siddiqui
Assistant Professor Pathology
COLORECTAL CARCINOMA
• Colorectal adenocarcinoma stands as the most prevalent malignancy
within the gastrointestinal tract.

• It significantly impacting morbidity and mortality rates worldwide.

• By contrast, the small intestine, which accounts for 75% of the overall
length of the gastrointestinal tract, is an uncommon site for benign
and malignant tumors.
EPIDEMIOLOGY
• Colorectal cancer comprises 98% of all malignant tumors of the large
intestine.

• It is the commonest form of visceral cancer accounting for deaths from

cancer in the United States, next only to lung cancer.

• The incidence of carcinoma of the large intestine rises with age;

average age of patients is about 60 years.

• It is now recommended that screening for colorectal cancer begins at

the age of 45 years.
EPIDEMIOLOGY
• Cancer in the rectum is more common in males than females in the
ratio of 2:1.

• Aspirin and other NSAIDs appear to have a protective effect.

• It is suspected that this effect is mediated by inhibition of the enzyme

cyclooxygenase-2 (COX-2), that is known to promote epithelial
proliferation, particularly in response to injury.

• COX-2 is highly expressed in 90% of colorectal carcinomas and 40%

to 90% of adenomas.
ETIOLOGY
GEOGRAPHIC VARIATIONS

• Colorectal cancer incidence vary globally, with higher rates in North

America and Northern Europe compared to Africa and Asia.

• The disease is often associated with affluent societies due to high

socioeconomic status.

• In Japan, rectal cancer rates are similar to the US while colon cancer
rates are lower.
ETIOLOGY
DIETARY FACTORS

• Following dietary habits are strongly linked to an increased risk of

developing colorectal cancer.

o Low intake of vegetable fiber.

o High consumption of fatty foods.
o Overeating refined carbohydrates.
ETIOLOGY
ADENOMA-CARCINOMA SEQUENCE

• Strong evidence suggest that colonic adenocarcinoma evolves from

preexisting adenomas, referred to as adenoma-carcinoma sequence.

• In a case with early invasive cancer, the surrounding tissue often

shows preceding changes of evolution from adenoma 
hyperplasia  dysplasia  carcinoma in situ  invasive
carcinoma.

• The risk of adenocarcinoma colon declines with endoscopic removal

of all identified adenomas.
ETIOLOGY
ADENOMA-CARCINOMA SEQUENCE

• The risk of malignancy increases with the following adenoma-related

factors:

a) Size of adenomas: large size increases the risk.

b) Number of adenomas: familial polyposis coli syndrome

almost certainly evolves into malignancy.

c) Type of adenomas: greater villous component is associated

with higher prevalence.
Morphologic and molecular changes in the adenoma- carcinoma sequence.
ETIOLOGY
HEREDITARY NON-POLYPOSIS COLONIC CANCER
(HNPCC OR LYNCH SYNDROME)

• HNPCC is associated with colorectal cancer without evidence of

familial polyposis coli, with only few precursors that tend to be
sessile serrated adenomas.

• In HNPCC, colorectal cancer is seen in at least two generations of

first-degree relatives, occurs at a relatively early age (< 50 years).

• It is due to germline mutations in mismatch repair genes, MSH2 or

MLH1, resulting in DNA instability.
ETIOLOGY
OTHER FACTORS

• Presence of certain pre-existing diseases and some other factors

increase the risk of developing colorectal cancer subsequently, e.g:

i) Inflammatory bowel disease (especially ulcerative colitis).

ii) Diverticular disease for long duration.

iii) Role of tobacco smoking in development of colorectal

cancer in younger patients.
PATHOGENESIS
• At least two distinct genetic pathways have been implicated in
colorectal carcinogenesis:

• The APC/ β-catenin pathway, and

• The microsatellite instability pathway (MSI)

APC/ β-Catenin Pathway
• The classic adenoma-carcinoma sequence, typically involves mutation
of the APC tumor suppressor early in the neoplastic process.

• For adenomas to develop, both copies of the APC gene must be

functionally inactivated, either by mutation or epigenetic silencing.

• With loss of APC function, β-catenin accumulates and translocates to

the nucleus, where it interacts with Wnt targets.
APC/ β-Catenin Pathway
• Nuclear localization of β-catenin and its subsequent action, activates
the transcription of MYC and cyclin D1, thereby promoting
proliferation.

• Other mutations involving KRAS, SMAD2 & SMAD4, and the

tumor suppressor gene TP53, as well as activation of telomerase, lead
to the emergence of a full-blown cancer.
 APC

APC

↓
↑ MYC & Cyclin D1 + ↑KRAS, ↓SMAD4 & ↓TP53
Microsatellite Instability Pathway (MSI)

• Defects in DNA mismatch repair genes result in microsatellite

instability.

• This permit accumulation of mutations in numerous genes, especially

those involved in cell survival and proliferation, promoting tumor
progression.

• These genes include type II TGF-b receptor (TGF RII), BAX,

Insulin-like growth factor 2 receptor (IGF2R), transcription factor-4
(TCF-4).
Microsatellite Instability Pathway (MSI)
• In a subset of colon cancers with microsatellite instability, mutations in
DNA mismatch repair genes are absent.

• Instead, in these tumors MLH1 promoter region is hypermethylated,

thereby reducing MLH1 expression and repair function.

• These features define the CpG island, (cytosine followed by a guanine

linked by a phosphodiester bond), hypermethylation phenotype
(CIMP).

• Activating mutations in the BRAF oncogene are common in these

cancers, whereas KRAS and TP53 are not typically mutated.
Morphologic and molecular changes in the mismatch repair pathway of colon carcinogenesis.
MORPHOLOGY
MORPHOLOGY (GROSS)
o Right-sided colonic growths tend to be large, cauliflower-like,
soft and friable masses projecting into the lumen (fungating
polypoid carcinoma).

o Left-sided colonic growths, have napkin-ring configuration i.e.

they encircle the bowel wall circumferentially forming annular
lesions, causing constriction and luminal narrowing.

o Left sided growths have central ulceration on the surface with

slightly elevated margins (carcinomatous ulcers).
 Napkin-Ring
Configuration
MORPHOLOGY
• These differences in right and left colonic growths are probably due to
the liquid nature of the contents in the ascending colon leaving space
for luminal growth on right side.

• In contrast, the more solid nature of contents in the left colon may not
permit as much space for luminal growth compared to the right side &
hence allows for the spread of growth within the bowel wall.

• However, early lesion in left as well as right colon are small, button-
like areas of elevation.
Gross appearance of colorectal
carcinoma.

A. Right-sided growth—
Fungating polypoid carcinoma
showing cauliflower-like growth
projecting into the lumen.

B. Left-sided growth— Napkin-

ring configuration with spread of
growth into the bowel wall.
This cancer is more
exophytic in its growth
pattern.
Carcinomatous ulcers –
Central ulceration on the
surface with slightly
elevated margins
 An opened colon shows a
typical circular carcinoma
with elevated, heaped-up
edges and central
ulceration.
MICROSCOPY
• The general microscopic characteristics of right- and left-sided
colonic adenocarcinomas are similar.

• About 95% of colorectal carcinomas are adenocarcinomas of varying

grades of differentiation.

• Histologic grades of differentiation may range from well-

differentiated, to moderately-differentiated and poorly-differentiated.

• Most tumors are composed of tall columnar cells that resemble

dysplastic epithelium found in adenomas.
MICROSCOPY
• Invasive component of these tumors elicits a strong desmoplastic
response, that is responsible for their characteristic firm consistency.

• Some poorly differentiated tumors form few glands.

• Others produce abundant mucin that accumulates within the intestinal

wall and are called mucinous carcinomas.

• Tumors may also be composed of signet ring cells similar to those in

gastric cancer, and are associated with a poor prognosis.
 Well Differentiated
Colonic Adenocarcinoma

₋ Showing infiltrative glands

exhibiting intestinal type
features
 Moderately Differentiated
Adenocarcinoma of Colon

₋ There is still a glandular

configuration, but the glands are
irregular and very crowded.

₋ Many of them have lumens containing

bluish mucin.
 Poorly Differentiated
Adenocarcinoma

₋ Sheets of atypical cells without

gland formation, infiltrating the
wall of the colon.
 Poorly Differentiated
Adenocarcinoma

₋ Tumor cells infiltrating the wall

of the colon, with
lymphovascular invasion.
CLINICAL FEATURES
• Cecal and right-sided colon cancers typically manifest with fatigue &
weakness from iron deficiency anemia, prompting clinical attention.

• This presentation underscores the common clinical notion that GI

cancer should be considered as the initial cause of unexplained iron
deficiency anemia in older males or postmenopausal females.
CLINICAL FEATURES
• On the other hand, left-sided colorectal adenocarcinomas may show
signs of:

• Occult bleeding

• Alterations in bowel habits

• Cramping, or discomfort in the left lower quadrant.

• Features of both right & left sided colonic tumors include loss of weight
(cachexia) & loss of appetite (anorexia)
STAGING AND PROGNOSIS
• HISTOLOGIC GRADE OF TUMOR.

o Histologic grades of differentiation also determines prognosis.

o Poorly differentiated and mucinous types are linked to a less

favorable prognosis.

o Advanced stage, lymphovascular and perineural invasion are

also associated with poor prognosis.
STAGING AND PROGNOSIS
• The depth of invasion and lymph node involvement are key
prognostic factors shaping the TNM staging system.

• DEPTH OF INVASION.

o Tumors limited to the mucosa have 5-year survival rates

approaching 100%.

o Invasion into the submucosa or muscularis propria reduces 5-year

survival to 95% and 70% - 90%, respectively.
STAGING AND PROGNOSIS
• LYMPH NODE METASTASES.

o The presence of lymph node metastases also reduces survival.

o As a result, most cases with lymph node metastases receive

radiation or chemotherapy.

o In some cases, these treatments may be administered prior to

primary tumor resection, a process termed neoadjuvant therapy.

o Molecular characterization of the tumor can help guide the

specific therapeutic approach.
STAGING AND PROGNOSIS
• DISTANT METASTASES.

o Distant metastasis to lung, liver, or other sites limits survival.

o Only 15% patients with metastases live five years post-diagnosis.

o Regardless of stage, some patients with small numbers of mets do

well for years after resection of distant tumor nodules.

o Tumors that exhibit MSI are often responsive to immune

checkpoint inhibitor therapies.
TREATMENT
• Surgical resection is generally required unless tumor is small and
confined to a polyp.

• Neoadjuvant therapy often given for rectal carcinomas.

 THANK YOU!
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