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Colorectal Carcinoma Recent Advances.
1. Recent advances on Colo-rectal
carcinoma
Dr. Evith Pereira
Moderator – Dr. Hoogar M.B
2. Recent advances in Histopathology
Volume 19, Micheal Sheaf, Colin
Berry. Chapter 15.
3. INTRODUCTION
• Third most common type of cancer and second
most frequent cause of cancer-related death.
• Most curable form of carcinoma of the
gastrointestinal tract.
• Usually begins as a noncancerous polyp that can,
over time, become a cancerous tumor.
• Males and females are equally affected.
• Mean age : 62 year
4. EPIDEMIOLOGY
• Worldwide distribution
• Highest incidence rates in
▫ United States
▫ Canada
▫ Australia
▫ New Zealand
▫ Denmark
▫ Sweden, and
▫ Other developed countries
6. REDUCED FIBER CONTENT
DECREASED STOOL BULK
INCREASED FECAL TRANSIT TIME
ALTERED BACTERIAL FLORA
TOXIC OXIDATIVE BIPRODUCTS OF CARBOHYDRATE
LONGER EXPOSURE OF MUCOSA TO BIPRODUCTS
REFINED DIETS WITH LESS Vit A ,C, E
DECREASED RADICAL SCAVENGER ACTIVITY
HIGH CHOLESTEROL
INTAKE IN RED MEAT
INCREASED SYNTHESIS
OF BILE ACIDS
CONVERTED INTO
POTENTIAL CARCINOGENS
INCREASED MALIGANT POTENTIAL OF COLONIC MUCOSA
6
1
4
2
3
9. Hereditary Non-polyposis colorectal cancer
( HNPCC)
• Autosomal dominant disorder.
• Molecular defect - DNA mismatch repair
• Target genes – MSH 2, MLH 1 on chr 2p16, p21
• Cancers at several sites
▫ Colorectum
▫ Endometrium
▫ Stomach
▫ Ovary
▫ Uterus
▫ Brain
▫ Small bowel
▫ Hepatobiliary
▫ Skin
10. Features of CRC in HNPCC
• Young age
• Right –sided location
• Mucinous features
• Poor differentiation
• Lymphocytic infiltration
• Lack of necrosis
11.
12.
13. Familial adenomatous polyposis (FAP)
• Autosomal dominant disorder.
• Numerous ( 100- 1000) colorectal adenomas.
• Mutation of the adenomatous polyposis coli (APC)
gene.
• In left untreated colorectal carcinoma ( 100%) ,
before age 30.
14. MOLECULAR PATHOGENESIS
• 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 repair
15. APC / β- catenin pathway
• APC tumor suppressor gene (5q21)
• Downregulate growth promoting signals (β-
catenin)
• 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 signals.
16. 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.
17.
18. Chromosomal instability pathway
(CIN)
• Increased rate of chromosome mis-
segregation in mitosis
• Due to
– Gain / loss of chromosome ( aneuploidy)
– Gross chromosomal rearrangements (GSM)
19. • 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
(18q21)
22. MICROSATELLITE INSTABILITY pathway
(MSI )
1. Satellite DNA?
2. Microsatellite DNA?
3. Why is it more liable to be unstable ?
4. How this instability leads to colorectal carcinoma ?
23. Satellite DNA
• 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
repeated.
A-T-T-C-G-A-T-T-C-G-A-T-T-C-G
24. Type of DNA repeat No. of nucleotide repeat
1. Satellite 5-200
2. Minisatellite
a. Hypervariable 10-60
b. Telomeric 6
3. Microsatellite 1-4
a. Monomorpic
b. Polymorphic
25. •Microsatellite DNA :
If the number of nucleotide repeat is 1-4
▫ Dinucleotide repeat:
When exactly two nucleotides are repeated.
Eg: ACACACAC
Such regions in DNA are commonly affected in
HNPCC.
26. • Microsatellites are more prone to get unstable compared to
other neutral regions of DNA
• This instability is due to many 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.
27. Defect in MMR gene
Reduced capacity of cells to repair specific types of
DNA damage
Increased rate of mutational accumulation in
microsatellite DNA
29. • As majority of microsatellites are located in the
non-coding region, these mutations are
generally silent.
• Some microsatellites which are present in the
coding region of the gene are involved in the
regulation of cell growth , like those encoding
▫ Type II TGF-ß receptor
▫ Proapoptotic protein BAX
30. Defect in MMR genes
• Mutation HNPCC
• CpG island Hypermethylation in MMR
genes Sporadic CCR
31. CpG Island Hypermethylation
• What is CpG?
• Terms like : CpG site and CpG Island?
• What is methylation?
• What is hypermethylation ?
• How hypermethylation leads to carcinoma?
32. • 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
methylated.
• This methylation results in the conversion of the
cytosine to 5-methylcytosine.
33. • The remaining 10% non-
methylated 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
36. MSI testing
• MSI can be detected by PCR amplification of
microsatellite loci in DNA extracted from CRC
specimens .
• 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 .
37. The Bethesda Guidelines
MSI testing is recommended in people with any of the following
features :
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 under
40yr.
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.
38. CLINICAL FEATURES
• Asymptomatic for years.
• Left sided colonic carcinomas
▫ occult bleeding
▫ changes in bowel habit
▫ crampy left lower quadrant discomfort
• Right sided colonic carcinomas
▫ fatigue
▫ weakness
▫ 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)
39. MORPHOLOGY
• 50% rectosigmoid area (involvement of the
proximal colon is increasing)
• Right-sided tumors more common in the
▫ elderly
▫ blacks
▫ patients with diverticular disease
40. GROSS
A. PROXIMAL COLON
• Polypoid:
▫ Bulky mass, well-defined/ rolled margins and a sharp
dividing line with the normal bowel.
• Ulcerative:
▫ Less elevated surface and is centrally ulcerated
• These tumors rarely cause obstruction
41.
42. B. DISTAL COLON
• Annular lesions producing “napkin – ring”
constrictions and luminal narrowing .
• These tumors can cause obstruction.
46. Mucinous adenocarcinoma
• 15 % of all CRCs
• Common in rectum.
• Microscopically :
more than 50%
extracellular mucin
• High association with
MSI
• Worse prognosis.
47. Signet ring adenocarcinoma
• Rare
• Microscopically : more
than 50%
intracellular mucin
• About one third cases
are associated with
MSI
• Worst prognosis.
48. Medullary carcinoma
• Rare.
• 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 .
49. Serrated adenocarcinoma
• 7.5% of all CRCs.
• Common in proximal colon.
• Derived from serrated
adenoma.
• Microscopic:
▫ serrated, mucinous or trabecular pattern of growth
▫ abundant eosinophilic cytoplasm
▫ chromatin condensation
▫ preserved polarity, and
▫ no necrosis.
50. Squamous differentiation
• Common in proximal colon.
• Usually associated with glandular elements
(adenosquamous carcinoma)
• Occasionally , seen in a pure form (squamous cell
carcinoma).
• Evidence for human papilloma virus 16
involvement in the pathogenesis of some rectal
cases .
51. Immunohistochemical features
• 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.
52. Other markers
• Villin
• Cathepsin B
• Neurolipin-1
• SRCA2
• Cadherin-17
• Calretinin
• Human chorionic gonadotropin (hCG)
• Placental alkaline phosphatase (PLAP) ~10%
• Estrogen and progesterone receptors
• Racemase
54. Biopsy
• There is a need of POSITIVE BIOPSY before radical
surgery for CRC.
• In large lesions, several biopsies should be taken from
diverse areas.
• Biopsy from center only granulation tissue
• Biopsy from the very periphery only hyperplastic
colonic epithelium
55. Cytology
• 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
fiberoptic scope.
• It is a sensitive technique, perhaps even more so than
endoscopic biopsy, but it has not yet found
widespread acceptance.
56. Various screening modalities
• Colonoscopy
• Sigmoidoscopy
• Fecal occult blood test
• Double contrast barium enema
• Digital rectal examination
57. Staging and Grading
• In 1937, Dukes proposed staging for rectal
carcinoma .
• In 1954, Astler and Coller proposed different
staging system.
• American Joint committee on Cancer(AJCC)
• The Union Internationale Countre Le Cancer
(UJCC)
58. Dukes’ Stage A
• The tumor involve the
wall of the bowel only.
• Treatment is surgery to
remove the tumor and
some surrounding lymph
nodes
59. Dukes’ Stage B
• The cancer extend through the
wall has not spread to the
lymph nodes.
• Colon cancer is treated with
surgery and, in some cases,
chemotherapy after surgery.
• Rectal cancer is treated with
surgery, radiation therapy, and
chemotherapy
60. 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. ligature
• Colon cancersurgery and
chemotherapy
• Rectalcancersurgery,
radiation therapy, and
chemotherapy
61. 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 selected
patients
62. Astler and Coller Staging
System
• 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 with nodal metastsis
65. 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.
68. PROGNOSIS
• 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.
70. • Development of CRC is a complex process involving
combination of environmental and genetic factors.
• Most carcinomas arise because of epithelial
hyperproliferation
• It seems more genes are involved in the
carcinogenic pathway will be found to clarify
additional aspects of CRC
• Presumed genes include p16 loss, a putative
modifier of FAP located at 1p35 and other loci of
allelic loss at as 3p22 (E-cadherin) and 16q22 (B-
catenin).
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)
Irradiation usually 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 prognosis
Basaloid 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 carcinoma similar to its counterpart in the uterine cervix
Anaplastic Similar to that of its counterpart in many other organs and its behavior is very aggressive
Hepatoid 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.
Villin a cytoskeletal protein associated with the axial microfilament bundles of brush border microvilli
Cathepsin Ba lysosomal cysteine proteinase
Neuropilin a molecule normally present in the developing nervous system
SRCA 2an ATPase crucial to many cell functions
Cadherin also known as liver-intestine cadherin
Calretinincan be expressed by a minority of colorectal adenocarcinomas (especially the undifferentiated ones
human 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
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.
