recent advances on colo rectal carcinoma1
TRANSCRIPT
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Recent advances on Colo-rectal carcinoma
Dr. Samriddhi Karki1st year Resident
Department of Pathology
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• Introduction • Epidemiology • Etiology• MOLECULAR PATHOGENESIS• Clinical features• Morphology• Diagnostic modalities• Staging and grading• Spread and Metastasis• Treatment• Prognosis
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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
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EPIDEMIOLOGY•Worldwide distribution
•Highest incidence rates in ▫United States▫Canada▫Australia▫New Zeaand▫Denmark ▫Sweden, and ▫Other developed countries
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•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
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ETIOLOGY1. Dietary factors2. Obesity 3. Smoking4. Inflammatory bowel disease
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5. Polyps
6. Pelvic Irradiation
7. Genetic factors▫Hereditary non-polyposis colorectal cancer (HNPCC) -
Lynch syndrome▫Familial adenomatous polyposis (FAP)
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Hereditary Non-polyposis colorectal cancer ( HNPCC)
•Autosomal dominant disorder.
•Cancers at several sites ▫Colorectum▫Endometrium ▫Stomach ▫Ovary ▫Uterus ▫Brain ▫Small bowel ▫Hepatobiliary▫Skin
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Features of CRC in HNPCC•Young age•Right –sided location•Mucinous features•Poor differentiation •Lymphocytic infiltration •Lack of necrosis
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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.
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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
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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.
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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.
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Chromosomal instability pathway(CIN)
• Increased rate of chromosome missegregation in mitosis .
• Due to – Gain / loss of chromosome ( aneuploidy)– Gross chromosomal rearrangements (GSM)
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•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)
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CIN forms the basis of Adenoma -Carcinoma
Sequence
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Adenoma-carcinoma sequence
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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 ?
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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
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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
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•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.
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• 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.
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Defect in MMR gene
Reduced capacity of cells to repair specific types of DNA damage
Increased rate of mutation accumulation in microsatellite DNA
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Mismatch repair genes•MSH2 (2p21) , MSH3, MSH4, MSH5, MSH6•MLH1(3p21.3), MLH2, MLH3•PMS1, PMS2
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•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
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Defect in MMR genes •Mutation HNPCC•CpG island Hypermethylation in MMR genes Sporadic CCR
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CpG Island Hypermethylation •What is CpG?•Terms like : CpG site and CpG Island?•What is methylation?•What is hypermethylation ?•How hypermethylation leads to
carcinoma?
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•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.
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• 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
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Microsatellite instability
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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 .
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The Bethesda GuidelinesMSI 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.
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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)
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MORPHOLOGY•50% rectosigmoid area (involvement of the proximal colon is increasing)
•Right-sided tumors more common in the▫elderly▫blacks▫patients with diverticular disease
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GROSSA. 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
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B. DISTAL COLON
•Annular lesions producing “napkin – ring” constrictions and luminal narrowing .
•These tumors can cause obstruction.
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MICROSCOPIC
•All colorectal carcinomas looks similar.
•Almost all – ADENOCARCINOMAS secreting variable amounts of mucin.
•Ranges from well-differentiated to undifferentiated, frankly anaplastic masses.
• Tall columnar cells resembling dysplastic epithelium as in adenomas.
• Inflammatory infiltrations (lymphocytes, plasma cells, eosinophils, histiocytes ) are prominent at the edge of the tumor.
• Poorly differentiated tumors might form few GLANDS.
• Rarely, the tumor stroma may exhibit metaplastic bone formation
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Well - differentiated Poorly differentiated
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Other microscopic
variants
Mucinous
Signet Ring
Medullary
Serrated
Squamous differentiati
onTrophoblastic
differentiation Hepatoid
Basaloid
Neuro-endocrine
Glassy cell
Oncocytic
Micro-papillary
Anaplastic
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Mucinous adenocarcinoma•15 % of all CRCs•Common in
rectum.•Microscopically :
more than 50% extracellular mucin
•High association with MSI
•Worse prognosis.
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Signet ring adenocarcinoma•Rare•Microscopically :
more than 50% intracellular mucin
•About one third cases are associated with MSI
•Worst prognosis.
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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 .
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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.
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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 .
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Trophoblastic differentiation•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 )
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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.
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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
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Electron microscopic features
Prominent microfilamen
ts
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Diagnostic modalities
CYTOLOGY BIOPSY
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Biopsy
•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
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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.
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Various screening modalities
•Colonoscopy
•Virtual colonography
•Sigmoidoscopy
•Fecal occult blood test
•Double contrast barium enema
•Digital rectal examination
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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)
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Dukes’ Stage A
• The tumor involve the wall of the bowel only.
• Treatment is surgery to remove the tumor and some surrounding lymph nodes
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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
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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
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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
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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 and with nodal metastsis
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• TNM Staging of Colon Cancer
• Tumor (T)• 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%
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Microscopically, colorectal carcinoma can be graded into
▫I – well differentiated▫II- moderately differentiated ▫III- poorly differentiated
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Spread and Metastasis•Common sites ▫Regional lymph nodes ▫Liver
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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.
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Liver metastases •More common in the tumors showing
evidence of blood vessel invasion.
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•Other relatively common metastatic sites include ▫peritoneum▫lung▫ovaries.
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TREATMENT
•Chemotherapy•Radiotherapy•Photodynamic therapy•Radical surgery•Gene therapy
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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.
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•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 pathology report
•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
significance
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Prognosis
AgeP
SexM-P
CEA seum levels P
Tumor location +/-
Tumor multiplicity
(S) Local extent
P
Tumor size +/-
Tumor edge NP-P
Obstruction P
Perforation P Category
I
Category III
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PROGNOSIS
Tumor margins/
inflm rxn G
Tumor budding
P
Vascular invasion P
Pericolonic tumor
deposits P
Perineurial invasion
P
Surgical Margins (R -
P)
Tumor thickness +/-
Microscopic tumor type (Mu/S/A -P,
Me -G)
Acinar morphology P
Presence of neuroendocrine cells +/-
Category IIA
Category IIA
Category IIB
III
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PROGNOSIS
Tumor angiogenesis
P
Mucin related antigens P
Fascin P
HLA-DR expression
G
pRB and P16P
hCG expression
+/-
BCL2 protein expression G
DNA ploidy +/-
Cell proliferation
+/-
Claudin-1Loss- P
III
IIB
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PROGNOSIS
Loss of chr 18q
P
TGF-B1 mutations
G
Oncogene & TSG
expression P53 –PMSI-G
LN involveme
ntP
Pattern of LN rxnCMI- G
Staging
Microscopic grade
Category I
Category IIACategory IIB
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THANK YOU