Colorectal Neoplasia

Dr. Smita Devani MBChB, MRCP

Consultant Physician and GastroenterologistAga Khan University Hospital, Nairobi

Case History

• BT, 69yr male Caucasian• History of rectal bleeding• No change in bowel habit• Non smoker• FHx - father died of stomach cancer at

85yrs • Examination normal

Case History

Colonoscopy• Caecum reached• 3.5cm sessile polyp found in the

ascending colon - biopsy showed tubulovillous adenoma

• Smaller polyps in the sigmoid colon which were hot biopsied

Case History

• Patient informed of need to do mucosal injection and piecemeal biopsy

• Warned of risk of perforation and possible need for surgery

Case History

Repeat colonoscopy • 6mls of diluted methylene blue and

normal saline injected to raise the polyp and piecemeal polypectomy done

• Histopathology showed tubulovillous adenoma

Colonoscopy

Colonoscopy

Colorectal Carcinoma (CRC)

• In 2006, > 500,000 deaths worldwide due to CRC*

• Population screening effective in reducing mortality**

*Jemal A, Tiwari RC, Murray T, et al. Cancer statistics 2004. CA Cancer J Clin 2004;54: 8-29.

** Winawer SJ, Zauber AG, Ho MN, et al. The National Polyp Study Workgroup. Prevention of colorectal cancer by colonoscopic polypectomy. N Engl J Med 1993;329: 1977 83.

Colorectal Carcinoma

• Usually a premalignant precursor precedes cancer

• Natural history of cancer progression 5-10 yrs

Colorectal Neoplasia

Colorectal Neoplasia

Colorectal Neoplasia

• Types of polyps• Frank Cancer• Malignant polyps• Villous • Tubulovillous• Adenomatous• Serrated • Hyperplastic

Colorectal Polyps

Tubular adenoma

Adenomatous polyp

Serrated polyp

Colorectal neoplasia

Colorectal Neoplasia

• Malignant polyps• Whole polyps should be surrendered• Check for invasion of stalk

histologically and ultrasound• Tumour differentiation• Vascular or lymphatic invasion• Lymphatic channels not visible under

light microscopy• Immunohistochemistry helpful but not

widely used

Normal

Adenoma(early)

Adenoma(advanced)

Early Cancer

Late Cancer

2-5 yrs

2-4 yrs

Aetiology

familial risk

HNPCC

FAP

Hamartomatouspolyposissyndromessporadic cases

Aetiology

Inherited types• FAP (familial adenomatous polyposis)

- constitute about 1%• HNPCC (Hereditary non polyposis

colorectal carcinoma)- constitute about 5-10%

FAP

• Autosomal dominant• Thousands of polyps• Extracolonic findings eg osteomas,

desmoid tumours, pigmented retinal lesions, periampullary tumours, upper GI tract polyps, brain tumours

FAP

MAP

Attenuated FAPR sided predominance

UGI lesions present

usually in the teens

mean age of CRC 40-45 yrs

FAP

• Deletion of chromosome 5q21 (known as the APC gene) in neoplastic cells (somatic mutation)

• Genetic testing standard of care• DNA testing for APC gene mutations has a

sensitivity of 70% to 90% and a specificity of 100%

FAP

• Flexible sigmoidoscopy from 10 to 12 years of age

• Colonoscopy from 18 to 20 years of age• If adenomas are detected, surgery

considered• Routine OGD surveillance as there is

high risk for potentially precancerous gastric and duodenal adenomas

HNPCC

• Autosomal dominant• Median age of developing cancer is <50yrs• Unusually have proximal bowel cancers• Can have multiple cancers • In women increased association with

endometrial and ovarian cancers

HNPCC

05

10152025303540

Lifetime risk %

Endometrialovariangastric urinary tractrenal cellbiliaryCNSsmall bowel

HNPCC

HNPCC

Sensitivity of Clinical Criteria

Criteria SensitivitySpecificity

Amsterdam 1 54% 62%Amsterdam 2 78% 48%Bethesda 89% 53%

Kievit W, Clinical Genetics 2004: 65;308-316

HNPCC

• In addition to testing for MSI, genetic testing is available for three mismatch repair genes, hMSH2, hMLH1, and hMLH6, which account for about 90% of all HNPCC cases

HNPCC

• Colonoscopy from 20 to 25 yrs of age

• Recommended screening for women includes annual transvaginal ultrasound or endometrial aspiration, beginning at age 25 to 35 years

When To Use Genetic Testing

When inherited syndrome suspected

Syndrome SettingFAP >10 adenomasHNPCC CRC<50, 2 CRC relativesPJ PJ polyps, pigmentJP >5 JPs

Colorectal Carcinoma

Other conditions• Inflammatory bowel disease• Obesity, cigarette smoking increase the

risk

• ?increased fat intake, red meat, fruits and fibre

• Possibly calcium supplements help

• Folate, ASA compounds, HRT,NSAIDs, physical activity

Pathogenesis

• About 30% of pts over >50yrs have colonic polyps

• 5% of these polyps will progress to carcinoma

• Flat polyps more likely to become malignant

Pathogenesis

• Certain amount of genetic instability already present in small adenomas

• Existence of multiple chromosomal instability causes progression

• Cell biologic processes, such as proliferation, differentiation, apoptosis, and invasion

Microsatellite Instability

Normal Small adenoma

Large adenoma Cancer metastasis

APC gene Ras gene TGFβ p53Othermutations

Chromosome or microsatellite instability

Microsatellite Instability

• Microsatellites are genomic regions in which short DNA sequences or a single nucleotide is repeated

• During DNA replication, mutations occur in some owing to misalignment of their repetitive subunits and result in contraction or elongations

• These are usually repaired by mismatch repair proteins

Microsatellite Instability

• However repair is inefficient in tumors with these protein deficiency

• This occurs in >50% of microsatellites in the tissue and is easy to detect

• HNPCC - MSH2 and MLH1 not tested if MSI absent. Not so for MSH6

• Most microsatellites occur in non coding DNA ∴ no effect on protein synthesis

• Some genes have MIS in coding regions and results in altered proteins

Pathogenesis

NSAIDS / ASA• Reduce mortality from colorectal

carcinoma by 40 - 50%1

• Reduce the number and size of the polyps2

• Induce regression of polyps in FAP3

1 Smalley W,Dubois RN.Colorectal cancer and non-steroidal anti- inflammatory drugs.Adv Pharmacol 1997;39:1-20

2 Shiff SJ,et al.Nonsteroidal anti-inflammatory drugs and colorectal cancer:Evolving concepts of their chemopreventive actions.Gastroenterology 1997;113:1992-8.

Polyp Cancer Sequence

DiagnosisFaecal Occult Blood Testing (FOBT)

Risks• missed cancers • 50% of cancers will be +ve FOBT

while in advanced neoplasia ≈ 21%*

• Reduce mortality by 15-33%• false reassurance

*Lieberman et al Veterans Affairs Cooperative Study Group 380. One-time screening for colorectal cancer with combined fecal occult-blood test and examination of the distal colon. N Engl J Med 2001; 345: 555-60

Diagnosis

Faecal immunochemical test (FIT)

• Done annually • No dietary restrictions• Positive test indication for colonoscopy

Diagnosis

0

10

20

30

40

50

60

cancer cancer +HGD

advanced

DNAFOBT

Stool DNA tests

Diagnosis

CT Colonography

Effectiveness• sensitivity good• interobserver variability• evaluation of extracolonic

features• referral to colonoscopy

Diagnosis

Double contrast barium enema

• Every 5 years• Decision based on Patient preferenceCostRadiologist training

Diagnosis

Colonoscopy• best tool for polyp detection

and cancer prevention• 2-12% of polyps >1 cm not found• requires highly qualified

endoscopist

Diagnosis

Complications of Colonoscopy

Serious complications 2-3/1000

• incomplete exams

• missed lesions

• incompletely removed lesions

Current Guidelines for Screening

• Colonoscopy every 10 years

• If adenomatous polyps, family history of CRC or polyps

• Inflammatory bowel disease

Treatment

• Polypectomy• Endomucous resection• NSAIDs for polyps• Chemoradiotherapy for

downgrading tumours

Treatment

• Surgery • Laparoscopy• Open surgery• Surgery for metastases - liver

or lung resection• CEA - guide for recurrence

Treatment

• Palliative• Chemotherapy• Stenting for stenosing tumours• Surgery

• To stop bleeding• Stenosing tumours• Urethral blockage

Low Public Compliance…!