Colorectal Cancer (CRC)Colorectal Cancer (CRC)

One of the most common cancers in the worldOne of the most common cancers in the world

US:US: 4th most common cancer (after lung, 4th most common cancer (after lung, prostate, and breast prostate, and breast

cancers)cancers) 2nd most common cause of cancer 2nd most common cause of cancer deathdeath (after lung cancer)(after lung cancer)

2001:2001: 130,000 new cases of CRC130,000 new cases of CRC 56,500 deaths 56,500 deaths

caused by CRCcaused by CRC

Anatomic Location of CRCAnatomic Location of CRC

CecumCecum 14 %14 %

Ascending colonAscending colon 10 %10 %

Transverse colonTransverse colon12 %12 %

Descending colonDescending colon7 %7 %

Sigmoid colonSigmoid colon 25 %25 %

Rectosigmoid junct.9 Rectosigmoid junct.9 %%

RectumRectum 23 %23 %

Symptoms associated with CRCSymptoms associated with CRC

Colon cancers result from a series of pathologic changes that Colon cancers result from a series of pathologic changes that transform normal epithelium into invasive carcinoma. Specific transform normal epithelium into invasive carcinoma. Specific genetic events, shown by vertical arrows, accompany this genetic events, shown by vertical arrows, accompany this multistep process. multistep process.

WHO Classification of CRCWHO Classification of CRC

Adenocarcinoma in situ / severe dysplasiaAdenocarcinoma in situ / severe dysplasiaAdenocarcinomaAdenocarcinomaMucinous (colloid) adenocarcinoma (>50% Mucinous (colloid) adenocarcinoma (>50% mucinous)mucinous)Signet ring cell carcinoma (>50% signet ring Signet ring cell carcinoma (>50% signet ring cells)cells)Squamous cell (epidermoid) carcinomaSquamous cell (epidermoid) carcinomaAdenosquamous carcinomaAdenosquamous carcinomaSmall-cell (oat cell) carcinomaSmall-cell (oat cell) carcinomaMedullary carcinomaMedullary carcinomaUndifferentiated CarcinomaUndifferentiated Carcinoma

Risk factors for CRCRisk factors for CRC

AgeAge

Adenomas, PolypsAdenomas, Polyps

Sedentary lifestyle, Diet, ObesitySedentary lifestyle, Diet, Obesity

Family History of CRCFamily History of CRC

Inflammatory Bowel Disease (IBD)Inflammatory Bowel Disease (IBD)

Hereditary Syndromes (familial Hereditary Syndromes (familial adenomatous polyposis (FAP))adenomatous polyposis (FAP))

Development of CRCDevelopment of CRC

Result of interplay between environmental and Result of interplay between environmental and genetic factorsgenetic factors

Central environmental factors: Central environmental factors:

Diet and lifestyleDiet and lifestyle

35% of all cancers are attributable to diet 35% of all cancers are attributable to diet

50%-75% of CRC in the US may be preventable 50%-75% of CRC in the US may be preventable through dietary modificationsthrough dietary modifications

Dietary factors implicated in Dietary factors implicated in colorectal carcinogenesiscolorectal carcinogenesis

Increased riskIncreased risk

consumption of red consumption of red meatmeat

animal and saturated animal and saturated fatfat

refined carbohydratesrefined carbohydrates

alcoholalcohol

Dietary factors implicated in Dietary factors implicated in colorectal carcinogenesiscolorectal carcinogenesis

Decreased riskDecreased risk

dietary fiberdietary fiber

vegetablesvegetables

fruitsfruits

antioxidant vitaminsantioxidant vitamins

calciumcalcium

folate (B Vitamin)folate (B Vitamin)

Specimen containing an invasive colorectal carcinoma and Specimen containing an invasive colorectal carcinoma and two adenomatous polyps.two adenomatous polyps.

Multiple adenomatous polyps of the cecum are seen here in a Multiple adenomatous polyps of the cecum are seen here in a case of familial polyposiscase of familial polyposis..

Familial polyposis in which mucosal surface of the colon is a carpet Familial polyposis in which mucosal surface of the colon is a carpet of small adenomatous polyps. Even though they are small , there is of small adenomatous polyps. Even though they are small , there is a 100% risk over time for development of adenocarcinoma, for a 100% risk over time for development of adenocarcinoma, for which total colectomy is recommendedwhich total colectomy is recommended

Adenocarcinoma of the rectosigmoid region . Heaped up margin of Adenocarcinoma of the rectosigmoid region . Heaped up margin of tumor at each side with a central area of ulceration. Normal mucosa at tumor at each side with a central area of ulceration. Normal mucosa at the right. The tumor encircles the colon and infiltrates into the wall. the right. The tumor encircles the colon and infiltrates into the wall. Staging is based upon the degree of invasion into and through the wall.Staging is based upon the degree of invasion into and through the wall.

Adenocarcinoma of the cecum demonstrates an exophytic growth Adenocarcinoma of the cecum demonstrates an exophytic growth pattern.pattern.

The barium enema instills the radiopaque barium sulfate into the colon, The barium enema instills the radiopaque barium sulfate into the colon, producing a contrast with the wall of the colon that highlights any masses producing a contrast with the wall of the colon that highlights any masses present. In this case, the classic "apple core” lesion is present, representing an present. In this case, the classic "apple core” lesion is present, representing an encircling adenocarcinoma that constricts the lumen.encircling adenocarcinoma that constricts the lumen.

Staging of CRCStaging of CRCTNM systemTNM system

Primary tumor (T) Primary tumor (T)

Regional lymph nodes (N)Regional lymph nodes (N)

Distant metastasis (M)Distant metastasis (M)

*Note: Tis includes cancer cells confined within the glandular basement membrane *Note: Tis includes cancer cells confined within the glandular basement membrane (intraepithelial) or lamina propria (intramucosal) with no extension through the (intraepithelial) or lamina propria (intramucosal) with no extension through the muscularis mucosae into the submucosa. muscularis mucosae into the submucosa.

**Note: Direct invasion in T4 includes invasion of other segments of the colorectum **Note: Direct invasion in T4 includes invasion of other segments of the colorectum by way of the serosa; for example, invasion of the sigmoid colon by a carcinoma by way of the serosa; for example, invasion of the sigmoid colon by a carcinoma of the cecum. of the cecum.

Dukes staging systemDukes staging system

AA MucosaMucosa 80%80%

BB Into or through M. propriaInto or through M. propria50%50%

C1C1 Into M. propria, + LN !Into M. propria, + LN !40%40%

C2C2 Through M. propria, + LN!Through M. propria, + LN!12%12%

DD distant metastatic spread <5%distant metastatic spread <5%

Sites of metastasisSites of metastasis

Liver

Lung

Brain

Bone

Via blood

Lymph nodes

Abdominal wall

Nerves

Vessels

Via lymphatics Per continuitatem

TherapyTherapy

Surgical resection the only curative Surgical resection the only curative treatmenttreatment

Likelihood of cure is greater when disease Likelihood of cure is greater when disease is detected at an early stageis detected at an early stage

Early detection and screening is of pivotalEarly detection and screening is of pivotal

importanceimportance

Surgery is the mainstay of treatment of RCSurgery is the mainstay of treatment of RC

After surgical resection, local failure is commonAfter surgical resection, local failure is common

Local recurrence after conventional surgery:Local recurrence after conventional surgery:

15%-45% (average of 28%)15%-45% (average of 28%)

Radiotherapy significantly reduces the number Radiotherapy significantly reduces the number of local recurrences in rectal cancers, its use in of local recurrences in rectal cancers, its use in colon cancer is not routine due to the sensitivity colon cancer is not routine due to the sensitivity of the bowels to radiation. of the bowels to radiation.

Radiotherapy in the management Radiotherapy in the management of Rectal Cancerof Rectal Cancer

In at least 28 randomised trials the value of In at least 28 randomised trials the value of either preoperative or postoperative RT has either preoperative or postoperative RT has been testedbeen tested

Preoperative RT (30+Gy): 57% relative Preoperative RT (30+Gy): 57% relative reduction of local failurereduction of local failurePostoperative RT (35+Gy): 33% relative Postoperative RT (35+Gy): 33% relative reductionreduction

Colorectal Cancer Collaborative Group. Lancet Colorectal Cancer Collaborative Group. Lancet 2001;358:12912001;358:1291

Gamma C. JAMA 2000;284:1008Gamma C. JAMA 2000;284:1008

Adjuvant Therapy of Rectal Adjuvant Therapy of Rectal CancerCancer

1990 US NIH Consensus Conference1990 US NIH Consensus Conference

Postoperative chemoradiotherapy = Postoperative chemoradiotherapy = standard of care for RC Stage II,IIIstandard of care for RC Stage II,III

The consensus statement was based The consensus statement was based upon the results of three randomised trialsupon the results of three randomised trials

ESMO RecommendationsESMO Recommendations

Resectable casesResectable cases

Surgical procedure: TMESurgical procedure: TME

Preoperative RT: recommendedPreoperative RT: recommended

Postoperative chemoradiotherapy: T3,4 or Postoperative chemoradiotherapy: T3,4 or N+N+

Non-resectable cases: local recurrencesNon-resectable cases: local recurrences

Preoperative RT with or without CT Preoperative RT with or without CT

Predicting risk of recurrence in Predicting risk of recurrence in Rectal CarcinomaRectal Carcinoma

Surgery-relatedSurgery-related-Low anterior resection-Low anterior resection-Excision of the -Excision of the mesorectummesorectum-Extend of -Extend of lymphadenectomylymphadenectomy-postoperative -postoperative anastomoticanastomotic

leakageleakage-Tumor perforation-Tumor perforation

Tumor-relatedTumor-related-Anatomic location-Anatomic location-Histologic type-Histologic type-Tumor grade-Tumor grade-Pathologic stage-Pathologic stage-radial resection -radial resection

marginmargin-neural, venous, -neural, venous,

lymphatic invasionlymphatic invasion

Incidence of local failure in RCIncidence of local failure in RC

T1-2,No,MoT1-2,No,Mo <10% <10%

T3,No,MoT3,No,Mo 15-35%15-35%

T1,N1,MoT1,N1,Mo 15-35%15-35%

T3-4,N1-2,MoT3-4,N1-2,Mo 45-65%45-65%

Total Mesorectal Excision Total Mesorectal Excision (TME)(TME)

Local recurrence rates after surgical Local recurrence rates after surgical resection of RC have decreased from resection of RC have decreased from about 30% to < 10%about 30% to < 10%

1. Radio(chemo)therapy1. Radio(chemo)therapy

2. Importance of circumferential margin 2. Importance of circumferential margin (TME)(TME)

ScreeningScreening

What is screening?What is screening?

A public health service in which members of a A public health service in which members of a defined population are examined to identify those defined population are examined to identify those individuals who would benefit from treatmentindividuals who would benefit from treatment

To benefit: To benefit: to reduce the risk of a disease or its to reduce the risk of a disease or its complications complications

Types of ScreeningTypes of Screening

Fecal occult blood test (FOBT)Fecal occult blood test (FOBT)Chemical test for blood in a stool sample. Chemical test for blood in a stool sample. Annual screening by FOBT reduces Annual screening by FOBT reduces colorectal cancer deaths by 33%colorectal cancer deaths by 33%

Flexible sigmoidoscopy can detect about Flexible sigmoidoscopy can detect about 65%–75% of polyps and 40%–65% of 65%–75% of polyps and 40%–65% of colorectal cancers. colorectal cancers. Rectum and sigmoid colon are visually Rectum and sigmoid colon are visually inspectedinspected

Current Screening GuidelinesCurrent Screening Guidelines

Regular screening for all adults aged 50 years Regular screening for all adults aged 50 years or older is recommended or older is recommended

FOBT every yearFOBT every year

Flexible sigmoidoscopy every 5 yearsFlexible sigmoidoscopy every 5 years

Total colon examination by colonoscopy every Total colon examination by colonoscopy every 10 years or by barium enema every 5–10 10 years or by barium enema every 5–10 yearsyears

NORMAL COLONIC MUCOSANORMAL COLONIC MUCOSA

Concept of differentiation is demonstrated by this small Concept of differentiation is demonstrated by this small adenomatous polyp of the colon. Note the difference in staining adenomatous polyp of the colon. Note the difference in staining quality between the epithelial cells of the adenoma at the top and quality between the epithelial cells of the adenoma at the top and the normal glandular epithelium of the colonic mucosa below.the normal glandular epithelium of the colonic mucosa below.

At high magnification,normalal epithelium at the left contrasts with the At high magnification,normalal epithelium at the left contrasts with the atypical epithelium of the adenomatous polyp at the right. Nuclei are atypical epithelium of the adenomatous polyp at the right. Nuclei are darker and more irregularly sized and closer together in the darker and more irregularly sized and closer together in the adenomatous polyp than in the normal mucosa.adenomatous polyp than in the normal mucosa.

Poorly differentiated neoplasm, it is difficult to tell the cell of origin. Poorly differentiated neoplasm, it is difficult to tell the cell of origin. It is probably a carcinoma because of the polygonal nature of the It is probably a carcinoma because of the polygonal nature of the cells. Note that nucleoli are numerous and large in this neoplasm.cells. Note that nucleoli are numerous and large in this neoplasm.

CK staining reaction for carcinomas helps to distinguish carcinoma from CK staining reaction for carcinomas helps to distinguish carcinoma from sarcomas and lymphomas. Immunoperoxidase staining is helpful to determine sarcomas and lymphomas. Immunoperoxidase staining is helpful to determine the cell type of a neoplasm when the degree of differentiation, or morphology the cell type of a neoplasm when the degree of differentiation, or morphology alone, does not allow an exact classification.alone, does not allow an exact classification.

Changes resulting in colon cancerChanges resulting in colon cancer

Molecular Biology & PathologyMolecular Biology & Pathology

CRCs arise from a series of histopathological and molecular CRCs arise from a series of histopathological and molecular changes that transform normal epithelial cellschanges that transform normal epithelial cells

Intermediate step is the adenomatous polypIntermediate step is the adenomatous polyp

Adenoma-Carcinoma-Sequence (Vogelstein & Kinzler)Adenoma-Carcinoma-Sequence (Vogelstein & Kinzler)

Polyps occur universally in FAP, but FAP accounts for only Polyps occur universally in FAP, but FAP accounts for only 1% of CRCs1% of CRCs

Adenomatous Polyps in general population:Adenomatous Polyps in general population:33% at age 5033% at age 5070% at age 7070% at age 70

SummarySummary

CRC is a leading cause of deathCRC is a leading cause of death

Early stages are detectableEarly stages are detectable

Screening can prevent CRC Screening can prevent CRC

REFERENCESREFERENCES

Katie Couric: Katie Couric: http://http://www.nccra.com/about/videos.htmwww.nccra.com/about/videos.htm

http://http://en.wikipedia.org/wiki/File:Colon_cancer.jpen.wikipedia.org/wiki/File:Colon_cancer.jpgg

http://http://ehumanbiofield.wikispaces.com/colon+canehumanbiofield.wikispaces.com/colon+cancer+class+work+EATcer+class+work+EAT