A seminar on colon cancer including topics of Epidemiology, Aetiology, Molecular Biology, Pathology, Clinical presentation, Screening, Diagnosis and Staging.

1. COLON CANCER
Presenter : Dr. Shivaji Sharma
Moderator: Dr. Pavan T. Sugoor

2. POINTS OF DISCUSSION
• Epidemiology
• Aetiology
• Molecular Biology
• Pathology
• Clinical presentation
• Screening
• Diagnosis
• Staging

3. EPIDEMIOLOGY

4. • Colon cancer, along with rectal cancer cancer is the most common
malignancy in the gastrointestinal tract worldwide.
• Third most commonly detected cancer and third common cause of cancer
related mortality in the United States.
• In India, the incidence, and thus the mortality is lower as compared to the
West.

5.  GEOGRAPHICAL VARIATION
• Worldwide, colon cancer shows large geographical differences in
incidence and mortality.
• As per Globocan 2018 records:

6. • Globocan India 2018 shows the following data

7.  BURDEN OF DISEASE IN INDIA
• As per the National Cancer Registry Programme of the PBCRs: 2012-2016,

9.  DATA FROM KIDWAI:
Year Total
Registered
cases(SoG)
Colon cancer
cases
Male Female
2013 8555 116 (1.3%) 66 50
2014 9068 111 (1.22%) 55 56
2015 8976 125 (1.39 %) 74 51
2016 9050 135 (1.49%) 86 49
2017 9295 148 (1.59%) 91 57
0
20
40
60
80
100
120
140
160
2013 2014 2015 2016 2017
Females
Males

10. • Migrants from low-incident areas to high-incident areas assume the
incidence of the host country within one generation.
• Race and ethnicity may also have a role to play:
– An inherited adenomatosis polyposis coli (APC) gene mutation confers
a higher risk within certain Ashkenazi Jewish families.
– Mutations in the DNA mismatch repair genes may be more common
among African Americans.
 SOCIOECONOMIC FACTORS
• Generally, cancer incidence and mortality rates have been higher in
economically advantaged countries.
• This may be related to consumption of a high fat and high red meat diet,
lack of physical activity with resulting obesity.

11.  EFFECT OF AGE
• Age impacts CC incidence greater than any other demographic factor.
• The median age at onset is 72 years for colon cancer. Except in the setting
of hereditary forms of colon cancer, this disease rarely occurs before age
40.
• After age 50, there is a rapid increase in the rate of disease as the incidence
is more than 14 times higher in adults 50 years and older.
• This is represented by 91% of new cases and 94% of deaths occurring in
patients older than 50.

12. AETIOLOGY

13. • Non – hereditary causes:
 Sporadic causes:
 No family history or an inherited
predisposition - accounts for
approximately 65 -85% of all colorectal
cancers - affects patients commonly
older than 50 years.
 Familial causes:
 Second most common (10% - 20%) -
colon cancer develops too frequently to
be considered a sporadic colon cancer,
but the pattern is not consistent with the
known inherited syndromes.
• Hereditary causes:
 Least common and associated with known
inherited genetic mutations - HNPCC is the
most commonly inherited cause of colorectal
cancer, followed by FAP.

14.  EXTRINSIC FACTORS
a) Diet:
– Total calorie intake and obesity–
• Obesity and total caloric intake are independent risk factors .
- Meat, fat and protein -
• In 2015, the World Health Organization declared red meat and processed meat as
probable carcinogens.
• Ingestion of red meat but not white meat is associated with an increased CC risk.
- Fiber
• Total dietary fiber intake was traditionally taken to be inversely associated factors.
• More recent prospective trials, however, have questioned the benefit of dietary fiber.
- Vegetables and fruits
• A protective effect of vegetables and fruits against colon cancer has been observed
with raw, green, and cruciferous vegetables.
- Dietary Inflammatory Index:
• This is a literature review–based score that emphasizes the specific impact of certain foods
on inflammation.

15. • It comprises 45 food parameters with varying effects on specific inflammatory
mediators such as interleukin (IL)-1, IL-4, IL-6, IL-10, tumor necrosis factor α
(TNF-α), and C-reactive protein (CRP).
• A number of recent studies have demonstrated an association of proximal colon
cancer risk with elevated DII score.
b) Lifestyle :
- Physical activity
• Regular physical activity has been shown in several studies to decrease the
risk.
• Physical activity after the diagnosis of stages I to III colon cancer may reduce
the risk of cancer-related mortality and the amount of aerobic exercise
correlates with a reduced risk of recurrence following resection of stage III
colon cancer.
- Cigarette Smoking
• The risk of colon cancer and adenomatous polyps is increased modestly among
long-term smokers compared with non-smokers.

16. - Alcohol intake
• An increased risk of CC development has also been linked to moderate
alcohol consumption (30 g or approximately 2 drinks/day).
• Interference with folate metabolism through acetaldehyde is suspected.
- Diabetes mellitus
• Diabetes was associated with increased risk of colon cancer with even higher
risk for those patients on insulin therapy.
- Cholecystectomy and bile acids:
• Bile acids can induce hyperproliferation of the intestinal mucosa.
• Cholecystectomy, which alters the enterohepatic cycle of bile acids, has been
associated with a moderately increased risk of proximal colon cancers.

17. c). Drugs and medication:
- NSAIDS:
• Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) interfere
with the development of colonic neoplasms by blocking the cyclooxygenase
(COX)-dependent prostaglandin pathway.
• Lower dose aspirin (75 to 300 mg per day) taken for 5 years or more was
associated with a reduced 20-year incidence and mortality due to colon cancer,
more so in right sided colon cancers..
• COX inhibition may delay the onset and number of adenomatous polyps in
FAP, but it is not yet clear whether it is able to prevent the cancers overall or
reduce their respective risk.
• Similar trials with aspirin in Lynch syndrome report a significantly decreased
incidence of colon cancer as well as a trend toward reduction in extra-colonic
Lynch syndrome–associated cancers.

18. - Vitamins, calcium and micronutrients:
• Folate and methionine have been found to have a definite role in chemoprevention of
colon cancer.
• Calcium has been implicated as having a protective effect against colonic adenomas
and colon cancer due to its ability to bind injurious bile acids.
• Magnesium intake demonstrated a modest risk reduction.
• Vitamin D intake and blood 25(OH)D levels were found to be inversely associated
with the risk of colon cancer. However, the role of vitamin D is not fully established.
• Vitamins with antioxidant properties including beta-carotene, vitamins A, C, E, and
selenium demonstrate no protective effect when these vitamins are derived from
food sources, but a daily multivitamin supplement showed a relative risk reduction
for colon cancer with its use.
• In postmenopausal women, a correlation was found between dietary heme iron and
an increased risk of proximal colon cancer, whereas intake of dietary zinc reduced
the risk of both proximal and distal colon cancer.

19. - Bisphosphonates:
• Bisphosphonates have been shown to have various antiproliferative,
antiangiogenic, proapoptotic, and antiadhesive effects for both proximal and
distal colon cancers.
c). Role of micro – organisms:
- Human papilloma virus:
• An association between the two was first reported in 1990, and since then, a
growing number of studies have detected the virus in colon adenocarcinoma
specimens with Damin et al. reporting a high prevalence of human
papillomavirus (31.9%) in affected patients.
- Escherichia coli:
• The colonic mucosa-adherent or mucosa-internalized strains might play a
role in carcinogenesis by inducing chronic inflammation.
• Bonnet et al. found an increased prevalence of these pathogenic strains in
colonic tissue from cancer patients versus controls.

20. d). Inflammatory Bowel Disease:
• Ulcerative colitis is a clear risk factor for colon cancer.
• The risk varies inversely with the age of onset of the colitis and directly
with the extent of colonic involvement and duration of active disease.
• The cumulative risk is 2% at 10 years, 8% at 20 years, and 18% at 30 years.
• Patients with colorectal Crohn’s disease are at 1.5 to 2 times increased risk
for colorectal cancer. The risk is less than that of those with ulcerative
colitis.

21. MOLECULAR BIOLOGY

22.  ADENOMA  CARCINOMA SEQUENCE (FEARON
VOGELSTEIN MODEL)
• Vogelstein and colleagues in 1988
pioneered a genetic model for
colorectal tumorigenesis that since
has been known as the adenoma-
carcinoma sequence.
• The Fearon-Vogelstein adenoma-
carcinoma multistep model of
colorectal involves damage to
proto-oncogenes and tumor
suppressor genes.
• Cancers result from the stepwise
accumulation of multiple somatic
mutations. Therefore, many CCs
remain asymptomatic for years
before diagnosis.

23. • Mutations that activate the Wnt signaling pathway seem to be necessary
initiating events.

24.  PATHWAYS OF MOLECULAR TUMORIGENESIS
1. Chromosomal instability pathway (CIN)
2. Mismatch repair pathway (MMR)
3. CIMP+ pathway (part of the serrated pathway)

25. CIN PATHWAY
MSI PATHWAY

26.  CHROMOSOMAL INSTABILITY (CIN)
• A chromosomal instability (CIN), results when the chromosomes are not
divided symmetrically during mitosis such that 1 daughter cell receives both
copies and the other cell receives none, which is described as loss of
heterozygosity (LOH) of the chromosomes.
• Encompasses 80% to 85% of all colon cancer.
• CC caused by CIN usually have poor prognosis.
• These cancers are characterized by gross chromosomal abnormalities :
 Aneuploid karyotype
 Large chromosome segment deletion & duplication
 Increased nuclear DNA content.
• APC mutation (>90%) , 18q allelic loss (~80%) [DCC , SMAD2 & SMAD4] ,
TP53 mutation (~70%) , KRAS mutation (~50%).
• Some tumors harbour BRAF mutation as an alternative to KRAS mutation.

27.  MICROSATELLITE INSTABILITY PATHWAY
• Around 15% of sporadic CCs & almost all CCs in HNPCC patients
develop along MSI pathway
• Occurs as a result of replication errors in repetitive short polymorphisms
due to failure of enzymes that monitor newly formed DNA and correct
replication errors {called DNA mismatch repair (MMR)}.
• This leads to repetitive short segment nucleotide sequences or
microsatellites. This phenomenon is described as microsatellite instability
(MSI).
• Microsatellites are short sequences of 1 to 6 nucleotide base pairs which
are repeated dozens to hundred times throughout the genome.
• Collectively designated as MSI-hi tumours.

28. • There are 4 important MMR genes : hMLH1, hMSH2, hMSH6, hPMS2,
loss of function mutation in any one of which may lead to MSI – hi
tumours.
• 90% in hMLH1, hMSH2

29. MSI-Hi tumours are usually:
 Right sided
 Mucinous or occasionally Medullary adenocarcinoma
 Peritumoral lymphocyte infiltrate
 Expansile growth
 Better stage specific prognosis

30.  CpG ISLAND METHYLATOR PHENOTYPE(CIMP+)
PATHWAY
• CpG island are usually found in the regions close to promoters.
• Methylation of cytosine residues in these CpG islands leads to change in
chromosomal structure, inhibits gene expression (including tumor suppressor
genes) and resultant loss of function.
• Tumors with CIMP often have MSI-H due to methylation of MLH1 MMR
gene ; however >50% of CIMP cancers are microsatellite stable.
• CIMP status clusters with MSI status & mutations in KRAS, BRAF & TP53
 Tumors with frequent MSI-H & BRAF : CIMP 1
 Tumors with KRAS mutation but microsatellite stable : CIMP2
 Tumors with TP53 mutation but microsatellite stable :CIMP3

32. CONSENSUS MOLECULAR SUBTYPES (CMS)
CLASSIFICATION OF COLON CANCER
• Gene expression–based subtyping is widely accepted as a relevant source
of disease stratification.
• Consensus molecular subgroups (CMS) based on gene-expression analysis
have gained attention since being published by Guinney et al. in 2015.
• Using gene-expression data from six different cohorts, four different types
of colorectal cancer have been defined:
 CMS1 defined by an upregulation of immune genes is highly
associated with microsatellite instability (MSI-hi).
 CMS2 reflects the canonical pathway of carcinogenesis as defined by
the adenoma-carcinoma sequence. Genetically chromosomal instable
tumors are associated with mutations in APC, p53, and RAS.

33.  CMS3 is defined by metabolic dysregulation with higher activity in
glutaminolysis and lipidogenesis
 CMS4 is defined by an activated tissue growth factor (TGF)-β pathway
and by epithelial–mesenchymal transition (EMT) making it in general
more chemo-resistant.

34. • The CMS groups are considered a robust classification system based on
molecular biology currently available for CRC with clear biological
interpretability-and the basis for future clinical stratification and subtype-
based targeted interventions.

35.  CANCER STEM CELL MODEL
• There is increasing evidence that not all cells within a tumor have the same
capacity for proliferation and tumorigenesis.
• Instead, tumor growth is driven by a subset of the population, termed
cancer stem cells.
• Arise from normal stem cells that have lost their regulation of self-renewal.
• Multiple signaling pathways are used to regulate stemness, including the
Wnt, BMP, and Hedgehog pathways - aberrations in these signals can
disrupt the normal crypt-villus axis.
• This has implications for future therapeutic treatment as current
radiotherapy and chemotherapy target all rapidly dividing cells
nonspecifically.
• If all cancer stem cells within the tumor are not destroyed, this could lead
to disease relapse and metastasis.
• Treatments that specifically target the cancer stem cell population will
allow more complete treatment of the disease and prevent relapse.

36. PATHOLOGY

37. • Majority of colon tumours are of epithelial origin and arise from the
mucosal surface, where they become visible descriptively as a polyp.
• The word polyp is derived from Latin an Greek words meaning “many
feet” and is defined as a mass that protrudes into the lumen of the bowel.
• Polyp is a descriptive clinical term for any mucosal elevation - further
categorized along several dimensions, including
1. Size

38. 2. Character of their attachment to the bowel wall (eg, sessile or
pedunculated) - main clinical relevance of this distinction lies in the
ease of endoscopic removal; the way in which a polyp is attached to the
wal of the colon does not accurately predict the presence versus absence o
an invasive malignancy.
3. Cellular architecture (eg, adenomas, hyperplastic, hamartomas,
inflammatory) and histologic appearance (eg, tubulous, tubulovillous,
villous)
4. Progression from benign to malignant behavior (eg, benign, dysplastic,
cancer)

39. 1. Adenomatous polyp:
• Adenomas are the most common type of colorectal
polyps and are found in 23% to 58% of adults, and
their incidence increases with age.
• There are three histologic subtypes of adenoma:
 Tubular (85% to 91%) - consist of at least 80%
dysplastic tubules that are packed tightly and
extend into normal-appearing lamina propria;
 Villous (5% to 10%) – Villous adenomas have
at least 80% villous fronds that are made of a
core lamina propria surrounded by adenomatous
epithelium;
 Tubulovillous (1%) - Tubulovillous adenomas
are those polyps that have more than 20%
tubular components and less than 80% villous
components;

40. • The distribution of adenomas in the colon is: cecum, 5%; ascending colon,
7%; hepatic flexure, 4%; transverse colon, 16%; splenic flexure, 6%;
descending colon, 19%; sigmoid colon, 40%; and rectum, 3%.
• Cellular proliferation in adenomas differs from normal colonic epithelium
in that it is not confined to the base of the crypts.
• Risk of malignancy in adenomatous polyps depends on the size and
architecture.

41. • The Haggitt classification, which defines 4 levels within the polyp, has evolved as a
useful tool to describe the degree of cancer invasion into a pedunculated or sessile
adenomatous polyp.
• In Haggitt levels 1, 2, and 3, the risk of lymph node metastasis is less than 1%;
level 4 invasion of the stalk carries a higher risk of 12% to 25% of having lymph
node metastases.

42. • A similar classification was developed in 1993 by Kudo et. al, who for
prognostic purposes suggested to divide the submucosal invasion of sessile
malignant lesions into 3 levels [Sm1 (lymphatic spread 0%), Sm2 (10%), and
Sm3(25%)].

43. 2. Hyperplastic polyp:
• They arise from faulty epithelial maturation and a failure of apoptosis.
• Usually, they are less than 5 mm in size and most occur in the recto-sigmoid.
• Generally considered to be non-malignant, though adenomatous changes can
occur.
3. Serrated polyps:
• Varying degrees of atypia and dysplasia are found.
• May turn neoplastic when it appears as a part of Serrated Polyposis syndrome.
4. Hamartomatous polyps:
• Localized overgrowths of normal, mature intestinal epithelial cells.
• Sporadic hamartomatous polyps do not have any malignant potential unless they
contain adenomatous components.

44. 5. Inflammatory polyps:
• Also known as pseudo-polyps, arise from mucosal ulceration and repair
and occur most commonly in the setting of IBD.
• Because of their etiology, they nearly always occur in multiples.
• Do not turn malignant per se, but may coexist along with malignancy in the
setting of long standing IBD.

45.  HEREDITARY AND NON – HERDITARY COLON CANCER
SYNDROMES:
Colon cancer
Hereditary
Adenomatous
polyposis
syndrome
FAP (1%)
HNPCC (5%)
Hamartomatous
polyposis
syndrome
Peutz Jeughers
Juvenile
polyposis
Cowdens
B-R-R
C-C
Non - Hereditary
Sporadic (60%) Familial (25-30%)

46.  FAMILIAL ADENOMATOUS POLYPOSIS SYNDROME
• Constitutes 1% of all CC incidence - autosomal dominant inheritance with near-
complete penetrance
• Attributed to a truncating mutation in the germline adenomatous polyposis coli
(APC) gene on chromosome 5q21 – however, up to 20% of patients with FAP
have new mutations without a family history.
• Two hit hypothesis - Inherit a mutated copy of the APC gene: during life -
acquire inactivation of the remaining APC gene copy, which accelerates the
progression to CC.
• Characterized by greater than 100 and often several thousand adenomatous
intestinal polyps that start to develop in the late teens and early twenties and
turn into cancer by age 40 to 45.
• Mutations in the extreme 5′ or 3′ ends of APC exons cause a variant syndrome,
attenuated APC, in which few polyps or CCs develop late in life, more in the
proxial colon, and occur due to mutation in the 5’ or 3’ end of the FAP gene.

47. • Variants of the polyposis syndrome
 Gardner’s syndrome (ie, epidermoid cysts, desmoid tumours,
osteomas {skull, mandible & tibia}, thyroid neoplasms, and CHRPE)
 Turcot syndrome (ie, brain tumors –glioblastoma/ medulloblastoma).
• Extracolonic manifestations include
 benign conditions – CHRPE (most common extra-colonic
manifestation), mandibular osteomas, supernumerary teeth, epidermal
cysts, adrenal cortical adenomas, desmoid tumors
 malignant conditions—thyroid tumors, gastric and small intestinal
polyps with a 5% to 10% risk of duodenal or ampullary
adenocarcinoma, and brain tumors (medulloblastoma / GBM).
• Nearly all FAP patients develop duodenal adenomas - severe in 10% -
account for the group’s second highest cancer - periampullary
adenocarcinoma developing in 3% to 10% carcinoma arising in the
duodenum after colectomy is the main cause of cancer-related deaths in
FAP patients.

48. • Patients with Spigelman IV polyposis have a high risk of harboring or
developing duodenal cancer (reported as high as 36%), and surgical
resection should be considered in these patients.
• Operative intervention should be individualized, and alternatives include
local excision, ampullectomy, pancreas-sparing duodenectomy, and
pancreaticoduodenectomy.

49. • Nonadenomatous fundic gastric polyps develop in
approximately 10% to 30% of patients with FAP but
usually do not have a malignant potential.
• Up to 30% develop desmoid tumors intra-
abdominally (80%) or on the abdominal wall,
extremities, and trunk - Even though they do not
necessarily carry features of a malignant lesion,
desmoids are lethal in 10% - third most frequent
cause for mortality of FAP patients, mainly due to
the intra-abdominal variants due to small bowel and
ureteral obstructions.
 HEREDITARY NON – POLYPOSIS COLON
CANCER
• Inherited autosomal dominant disease that accounts
for 3% to 5% of all colon cancers – also known as
Lynch Syndrome
• Despite its name, these cancers typically arise from
colonic polyps, but a diffuse polyposis is not
present.

50. • It has a strong family history and the penetrance is high and resulting in an
80% to 85% lifetime risk of colon cancer.
• Compared with patients with sporadic colon cancer, patients with HNPCC;
 have cancers that are more right sided (60% to 70% occur proximal to the
splenic flexure),
 occur earlier (at about 45 years of age),
 have a lower stage,
 poorly differentiated, contain an excess of mucin, and signet cell features
 have better survival, and
 have an increased rate of metachronous and synchronous tumors (20%).
• Can be divided into two phenotypical expressions:
 Lynch I - characterized by cancer of the proximal colon occurring at a
relatively young age.
 Lynch II - at risk for colorectal and extracolonic cancers, including cancers of
endometrial (43%), ovarian (9%), gastric (30-70%), small intestinal,
pancreatic, and ureteral and renal pelvic (6%) origin.

51. • To facilitate the clinical diagnosis of HNPCC, the International
Collaborative Group on HNPCC (ICG-HNPCC) proposed the Amsterdam
Criteria in 1990
• Linkage studies in HNPCC families fulfilling Amsterdam Criteria I led to
discovery of the first 2 human MMR genes — hMSH2 and hMLH1
accounting for 45% to 86% of all classic HNPCC families.
• Several other MMR genes have been identified in conjunction with
HNPCC and include hPMS1, hPMS2, and hMSH6.
• Higher risk for hMSH2 mutation carriers to develop extracolonic cancers,
in particular endometrial cancer.

52. • Wijnen et.al reported that endometrial cancer represents the most
common clinical manifestation of HNPCC among female hMSH6
mutation carriers and that colorectal cancer cannot be considered an
obligate requisite to define HNPCC.
• The ICG-HNPCC therefore revised the criteria in 1999 (Amsterdam
Criteria II), which now include extra-colonic manifestations as part of the
family history.
• The mainstay of the diagnosis of Lynch syndrome is a detailed family
history - however, 20% of newly discovered cases of HNPCC are caused
by spontaneous germline mutations, so a family history may not accurately
reflect the genetic nature of the syndrome.

53. • Colorectal cancer, or a Lynch syndrome–related cancer, arising in a person younger
than 50 years should raise suspicion for this syndrome and genetic counseling and
testing should be offered.
• The Bethesda criteria were created in 1997 to determine which patients with colon
and extracolonic tumors should have MSI testing – revised criteria were issued in
2004.
• Associated with 60% to 94% sensitivity for identifying individuals with HNPCC
even though these individuals may not conform to the Amsterdam criteria.

54. • If either Amsterdam or Bethesda criteria are fulfilled, genetic testing is
done:
• Whereas these preliminary screening tests have traditionally only been
applied to patients who meet the Amsterdam or Bethesda criteria for high-
risk family history, there has been a strong push recently toward expanding
this testing to all cases of CC.
• The proponents of this “universal screening” approach argue that HNPCC
is underdiagnosed, with a significant number of cases being missed by
selective testing.
• In as many as 50% of patients with a family history that clearly
demonstrates Lynch syndrome–type transmission of cancer, DNA testing
will fail to identify the causative gene – however, that is not a criteria to
exclude the diagnosis of Lynch Syndrome.

55.  MUTYH ASSOCIATED POLYPOSIS
• Autosomal recessive condition caused by biallelic mutations in the
MUTYH gene which is a base excision repair gene.
• Associated with an increased risk of colon cancer and the early
development of multiple adenomatous polyps.
• Colonic and extracolonic manifestations can be present.
• Colonic phenotype –
 Usually develop 10 to 100 colorectal polyps; predominantly adenomas
but multiple hyperplastic and/or sessile serrated polyps may occur with
an approximate lifetime risk of CC of 70% to 75% at an average age of
48 years.
• Extra – colonic phenotype -
 increased risk of duodenal cancer; other extracolonic findings include
gastric polyps, endometrial cancer, breast cancer, ovarian cancer,
bladder cancer, thyroid cancer, sebaceous gland adenomas, lipomas,
CHRPE, osteomas, desmoid tumors, and epidermoid cysts.

56.  HAMARTOMATOUS POYPOSIS SYNDROMES:
• These are rare syndromes, mostly affecting the paediatric and adolescent
population, and represent <1% of CCs annually.
1. Juvenile Polyposis Syndrome:
• Most common hamartomatous syndrome - autosomal dominant - onset is
approximately 18 years – congenital birth defects in 15% of patients.
• Criteria include
 3 or more hamartomatous polyps of the colon,
 Hamartomatous polyps outside the colon, or
 any number of polyps in a member of a family with a known history of
juvenile polyps.
• Mutations that have been identified include a mutation in the SMAD-4
tumor suppressor gene or in the BMPR1-A gene
• Patients have a life time risk of 30% to 50% - colon carcinoma, a 13.7% -
gastric cancer, 10% to 20% - upper GI tract, a 3.4% - duodenal, and a 3.4%
- pancreatic cancer.

57. 2. Peutz Jegher’s Syndrome:
• Second most common hamartomatous syndrome,
occurring as an autosomal dominant condition with
variable penetrance.
• Carries a mutation of the serine threonine kinase
gene - STK11/LKB1
• Associated with hamartomatous polyps of the
gastrointestinal tract (<100) and cutaneous melanin
deposition.
• The most common location of Peutz-Jeghers polyps is
in the upper gastrointestinal tract, specifically the upper
jejunum – colonic polyps are seen in 50% cases.
• A characteristic feature is the melanin depositions -
seen most frequently in the perioral region (vermillion
border – 95% cases) or buccal mucosa - also nostrils,
eyes, genital region and on the hands and the feet -
occurs in infancy but fades by late adolescence or
adulthood.

58. • Patients have risks of developing malignancy in the polyps or other associated
malignancies: breast (lifetime risk of 54%), colon and rectum (20%-39%),
pancreas (30%-36%), stomach (5%), small bowel esophagus, uterus, ovary,
testicle, and lung.
3. Cowden’s Syndrome:
• Autosomal dominant condition with nearly complete penetrance by age 20 that
is caused by germline mutations in the PTEN tumor suppressor gene.
• 80% of patients present with trichilemmoma, a benign tumor of the hair shaft,
40% with macrocephaly; only 35% of patients have gastrointestinal polyposis,
but no increased risk of invasive gastrointestinal malignancy has been reported
to date.
• The main concern for malignancy is a projected lifetime risk of 10% for thyroid
cancer and of 30% to 50% for breast cancer.

59. 4. Bannayan Riley Ruvalcaba Syndrome:
• Rare autosomal dominant polyposis syndrome due to mutation in the PTEN
gene characterized by hamartomatous polyps of the gastrointestinal tract
macrocephaly, mental retardation and delayed psychomotor development,
• No increased risk of colorectal carcinoma, other gastrointestinal
malignancies, or extraintestinal malignancy has been documented in these
patients.
5. Cronkite Canada Syndrome –
• Very rare polyposis syndrome with no evidence of inheritance developing
gastrointestinal hamartomas in adulthood - located predominantly in the
duodenum, additional segments of the small bowel and the stomach.
• The polyps can develop adenomatous changes and there is a 10% risk of
developing adenocarcinoma.

60.  SUMMARY OF THE HEREDITARY SYNDROMES

62. CLINICAL PRESENTATION

63. • Clinical presentation depends on the location and
gross morphology (annular / ulcerative /
proliferating) of the disease.
• Chang in bowel habit is most frequent complaint
of the patient with colorectal cancer.
• May also present with loss of appetite and
weight, easy fatiguability, abdominal discomfort
and mass per abdomen.
• 20% of cases present as an acute intestinal
obstruction.
• Right sided growth (ulcero-proliferative)
commonly presents with anaemia and palpable
mass in the right iliac fossa.

64. • Left sided growth (annular or stenosing)
presents with colicky pain, altered bowel
habits (alternating constipation and
diarrhoea), palpable lump, distension of
abdomen due to sub acute/chronic
obstruction.
• Bladder symptoms may warn of colo-
vesical fistula.
• Closed loop obstruction can occur in
transverse colon growth (stricture type
causing block) with competent ileocaecal
valve. Enormously dilated right sided
colon is prone for stercoral ulcer,
perforation and faecal peritonitis.
• Metastatic disease may present ,
depending on the site of metastasis as
hepatomegaly, ascites, rectovesical
secondaries and palpable left
supraclavicular lymph nodes.

65. SCREENING

66. • The vast majority of CCs arise via the classic adenoma-to-carcinoma
pathway so that the identification and timely removal of premalignant
lesions can prevent progression to carcinoma.
• The goals of screening are
 detection of early cancers and
 prevention of cancer by finding and removing adenomas.
• Screening should be initiated at age 50 for patients with average CC risk.
• African Americans are more likely to be develop CC than other populations
and tend to present at a younger age; so screening should be initiated at age
45 years in this population.

67. • Current guidelines for CC screening and surveillance as recommended by
the US Multi-Society Task Force are outlined:

70. • Screening recommendations as per NCCN guidelines are as follows:

73. • Screening for gynecologic cancers in HNPCC may include
 regular gynecologic examination,
 transvaginal ultrasound, and
 endometrial aspiration biopsy starting at age 25.
• Recommendations for urologic cancer screening include urinalysis once or
twice per year, even though there are no data to support the efficacy of this
approach.

74. DIAGNOSIS

75. • In addition to a thorough history and clinical examination, the following
investigations helps to diagnose and stage the disease:
1. Colonoscopy:
• Most accurate and versatile diagnostic test since it can localize and biopsy
lesions throughout the large bowel and detect synchronous neoplasms.
• Methods for tissue sampling include punch biopsies, brushings, and
polypectomy.
• For lesions that are completely removed endoscopically, tattooing is
important for subsequent localization if an invasive neoplasm is found, and
additional local therapy is needed. Tattoos are typically placed adjacent to
or a few centimeters distal to the lesion
• Limitations:
– 20% of polyps are missed in the initial examination. Moreover, flat and
depressed lesions are hard to identify.

76. – Incomplete colonoscopy —in symptomatic patients are approximately
12%. Reasons include
 the inability of the colonoscope to reach the tumor or to visualize
the mucosa proximal to the tumor for technical reasons (eg,
partially or completely obstructing cancer, tortuous colon and poor
preparation) and
 patient intolerance of the examination.
• Newer techniques are available that help identify lesions that would
otherwise be missed:
a. Chromoendoscopy:
 involves the use of dyes or compounds (eg, methylene blue, indigo
carmine and gentian violet) that highlight differences on mucosal
surfaces, which increases the detection of neoplastic polyps compared
with conventional colonoscopy.

77.  A meta-analysis (Brown SR et. al) and systematic review (van den Broek
FJ et.al) compared chromoendoscopy with conventional endoscopy and
confirmed a sensitivity of 92% vs 94%, respectively, and a specificity of
82% vs 85%, respectively, in predicting neoplasia.
b. Narrow Band Imaging (NBI):
 The use of bandwidth filters increases the blue spectrum intensity of the
light used. This lower wavelength is more readily absorbed by
hemoglobin and is less able to penetrate surfaces, thereby enhancing the
visualization of superficial capillaries.
 Because tumors are angiogenic, the vascular network is more prominent
and has a higher density in neoplastic tissue than normal mucosa.

78.  Studies that have compared NBI versus chromoendoscopy (Su MY et.al,
Chiu HM et.al) demonstrate equivalent adenoma detection rates and
similar abilities in differentiating between neoplastic and non-neoplastic
lesions.
c. Other novel technologies include:
 FICE (Fujinon intelligent color enhancement).
 Autofluorescence imaging.
2. Flexible Sigmoidoscopy:
• Rapid and require only minimal bowel preparation (enema).
• However, they do not provide complete information about the rest of the colon,
and therefore, a complementary study is indicated before surgery.
• Furthermore, the flexible sigmoidoscope is notorious for giving inaccurate
measurements of the level of the tumor

79. 3. Contrast Enema:
• Contrast enemas are an especially valuable adjunct
to colonoscopy in patients with near-obstructing
colonic lesions.
• They have the advantage of more accurately
visualizing the anatomic position of a colonic lesion
• Ideally, a barium-air double-contrast technique will
be used; however, in a more acute setting,
particularly if there is suspicion of a colonic
perforation, administration of barium is
contraindicated (risk of barium peritonitis), and
instead, a water-soluble contrast material (eg,
Gastrografin) should be used.
• The typical aspect of a colon cancer is a fixed
filling defect with destruction of the mucosal
pattern in an annular configuration (“apple core”),

80. 4. CT Colonography:
• CT colonography (also called virtual colonoscopy or CT
colography) provides a computer simulated endoluminal
perspective of the air-filled distended colon.
• CT colonography has been evaluated in patients with
incomplete colonoscopy. In this setting, CT
colonography is highly sensitive for the detection of CC
and can provide a radiographic diagnosis.
• The disadvantage is that a tissue diagnosis is not
possible.
• In a study by Regge D et.al, CT colonography had a
sensitivity of 85% for lesions 6 mm or larger.
• The diagnostic performance of CT colonography was
directly compared with colonoscopy in the SIGGAR
trial in which 1610 patients with symptoms suggestive
of CC were randomly assigned to colonoscopy or CT
colonography. Detection rates for CC and large polyps
were 11 percent for both procedures

81. 5.Guiac based Faecal Occult Blood Test (gFOBT):
• It is based on use of Guaiac acid which detects peroxidase and changes
colour in presence of haemoglobin in stool.
• Requires three stool samples; will detect bleeding from anywhere in the
GIT; may react with non-human haeme; may miss tumours that bleed in
small amounts or intermittently (sensitivity – 37 – 79%).
• Fecal immunochemical test (FIT): the FIT uses an antibody against
human globin – the protein part of hemoglobin; specific for human
hemoglobin; single stool sample is sufficient (Sensitivity – 79%; specificity
- 94%).
• Stool DNA tests- the DNA mutations in cells passed in stool from the
colorectal tumors may be detected. Some tests are being approved and are
in use, though their clinical efficacy has not been proved.

82. 6. The PillCam Colon Capsule;
• The PillCam COLON video capsule is equipped
with two miniature color video cameras and
measures 12 mm X 33 mm. It is designed to be
ingested by the patient and transmits images for
approximately 10 hours to a recording device worn
by the patient. Data are transferred from the device
to a computer.
• It could be considered in a patient with an
incomplete colonoscopy who lacks obstruction.
• The risks of PillCam capsule endoscopy include
capsule retention (>15 days), aspiration and skin
irritation.

83. 7. Serum tumour marker – CEA
• CEA is a cell surface glycoprotein that is shed into the blood.
• Sensitivity of CEA for diagnosis of CC is ~ 46% while the specificity is 89%.
Moreover, non – cancer related causes (gastritis, peptic ulcer disease,
diverticulitis, liver disease, chronic obstructive pulmonary disease, diabetes,
tobacco smoking) can also cause its elevation.
• Serum levels of CEA have prognostic utility in patients with newly-diagnosed
CC. Patients with preoperative serum CEA >5 ng/mL have a worse prognosis,
stage for stage, than those with lower levels.
• Elevated preoperative CEA levels that do not normalize following surgical
resection imply the presence of persistent disease and the need for further
evaluation. A rising CEA level after surgical resection implies recurrent disease
and should prompt follow-up radiologic imaging.
• CEA is cleared from the blood only by cells in the liver and lung; therefore, it is
an important marker for the presence of subclinical hepatic or pulmonary
metastases, even before such lesions are detectable by current imaging
modalities

84.  INVESTIGATIONS FOR STAGING OF
DISEASE
1. CT Scan:
• In patients with newly-diagnosed CC, preoperative chest, abdominal and pelvic
CT scans can demonstrate regional tumor extension, regional lymphatic and
distant metastases, and tumor-related complications.
• The sensitivity of CT for detecting distant metastasis is higher (75 to 87%)
than for detecting nodal involvement (45 to 73%) or the depth of transmural
invasion (approximately 50%).
2. Hepatic MRI:
• Contrast-enhanced magnetic resonance imaging (MRI) of the liver can identify
more hepatic lesions than are visualized by CT, and is particularly valuable in
patients with background fatty liver changes.
• However, use of triple-phase imaging has improved sensitivity of CT for
detection of liver metastases.
• Liver MRI is generally reserved for patients who have suspicious but not
definitive findings on CT scan, particularly if better definition of hepatic
disease burden is needed to make decisions about potential hepatic resection.

85. 3. PET Scan:
• Positron emission tomography (PET) scans do not appear to add significant
information to CT scans for routine preoperative staging of CC. However, it
may be used in the following settings:
– Localizing sites of disease recurrence in patients who have a rising serum
carcinoembryonic antigen (CEA) level and non-diagnostic conventional
imaging evaluation.
– In patients with isolated CC liver metastases, use of PET reduces the
number of nontherapeutic laparotomies. However, the benefit of a PET
scan is to detect extra-hepatic metastases in patients considered liver
resection candidates.
4. Staging Laparoscopy:
• In a study by Klaus Thaler et.al on the role of DL and IOUS in colorectal
cancers with isolated hepatic metastasis on 152 patients, staging
laparoscopy/IOUS identified surgically untreatable disease in 25% because
of peritoneal metastases, nodal involvement, diffuse hepatic disease, no
identifiable disease, and untreatable disease, and significantly altered the
procedure performed in 23% of patients relative to the pre-operative plan.

86. STAGING

87. • The AJCC TNM staging (8th Edition in 2017) is the most commonly used
staging system.

90. • Difference with the 7th Edition:

91. • Other Staging methods:
– Historical classifications like Duke’s staging (1930) and Modified
Astler Coller’s Classification (1954) of the Duke’s system are of
historical significance and have largely been abandoned.

92. TAKE HOME MESSAGE
• The incidence of colon cancer in India is comparatively low as compared to the
west, being higher in the North Eastern region.
• Most commonly sporadic, with red meat, sedentary lifestyle and tobacco being
contributory factors.
• Results from the stepwise mutation of a number of genes, thus taking a
relatively long time to manifest.
• For the same reason, screening can lead to early detection and reduction in
incidence and mortality.
• FOBT as a screening tool, though not specific, reduces mortality from CC.
• Colonoscopy and CECT is used for diagnosis and staging; pre-op CEA has a
prognostic role; the role of PET-CT and laparoscopy for staging is yet to be
fully established.
• TNM staging helps prognosticate the disease – older staging methods are of
historical significance.