Clinical Pathological Conference Colorectal Cancer

1. Clinical Pathological ConferenceColorectal Cancer Dr. L. Oliveira – Gastroenterology Dr. C. Walsh – Radiology Dr. F. Halwani - Pathology

2. OBJECTIVES • Explain the adenoma – carcinoma sequence and rationale behind colon cancer screening. • Describe the epidemiology, etiology and risk factors for colonic adenocarcinomas. • Outline the clinical presentation, diagnosis and staging of colonic adenocarcinomas. • Discuss the prevention, management and prognosis of colonic adenocarcinomas. • Summarize the options and guidelines for colon cancer screening and surveillance. • Describe, in general, features of the major hereditary gastrointestinal polyposis syndromes including Hereditary Non‐Polyposis Colorectal Cancer (HNPCC), Familial Adenomatous Polyposis (FAP) and Peutz‐Jeghers Syndrome.

3. OBJECTIVES • Identify the best radiological imaging modality to screen for colonic polyps. • Identify the best radiological imaging modality to screen for colon cancer • Identify the best radiological imaging modality to stage colon cancer. • Classify polyps into benign and pre‐malignant categories and according to pathological features. • Identify the morphological features of the different types of colonic polyps. • Identify the morphological features of colonic carcinoma.

4. Pre-Test Questions

5. Question # 1 • All of the following are risk factors for colon cancer except: A. Age B. Hyperplastic polyps C. Family history of colon cancer D. Primary sclerosing cholangitis

6. Question #2 • If an adenomatous polyp is found and removed on colonoscopy, a surveillance colonoscopy should be done… • A. in 10 years • B. in 2 years • C. in 5 years • D. in 1 year

7. Question #3 • All of following polyps are benign (non-neoplastic) except: • A. Hamartomatous polyps • B. Serrated polyps • C. Hyperplastic polyps • D. Inflammatory polyps

8. CASE 1 • 53 yo male referred for weight loss and rectal bleeding • PMHx: healthy • MEDS: none • FAM HX: mother had colon cancer age 56 • HPI: • lost 30lbs in the last 4 months • Decreased appetite • Bowel movements associated with dark blood on and off

9. CASE 1 • P/E: unremarkable • Labs: Hb 110 (115-155g/L) • Ferritin 10 ug/L

10. CASE 1: Colonoscopy

11. CRC : Diagnosis - Colonoscopy • Colonoscopy has advantage that one can biopsy • In 5 % of cases scope can not be passed to cecum • There is a miss rate associated with colonoscopy • 1/1000 perforation rate. • Risks of sedation • Can be pain during procedure • Greater emphasis being paid to screening of populations at risk and average risk patients

12. CRC : Clinical Features • Often asymptomatic and present for a long time before symptoms appear • Symptoms relate to tumour size and location Occult Bleeding ( right sided colon cancer ) Obstructive symptoms /change in bowel pattern ( left sided colon cancer ) Rectal Bleeding ( left sided colon cancer ) Weight Loss Abdominal Pain Altered Bowel Pattern Perforation/Abscess Tenesmus/ Incomplete evacuation

13. CRC : Clinical Features • Cancers of proximal colon tend to grow larger before causing symptoms. May present with occult blood loss and iron deficiency anemia ( fatigue, SOBOE, exertional chest pain) • Cancers of the distal colon tend to have less room to grow and may present with obstruction or rectal bleeding. May have altered bowel pattern, pencil thin stool

14. Colon Cancer : Epidemiology • 4th most common cancer ( after prostate, breast, lung) • 10 % of all new cancers • Average individual : 6 % lifetime risk of CRC • 2-3 times increase risk if a first degree relative is affected • Progressive decline in mortality due to earlier detection and better treatment • 70 % of cases are sporadic. ie no family history, no history of IBD.

15. Colorectal Cancer (CRC) : Epidemiology • 98% Adenocarcinoma. Other ( Lymphoma, Carcinoid, Leiomyosarcoma) • Sporadic : 70% Familial : 25% Inherited : small percentage ( HNPCC, polyposis syndrome) • Risk Factors ?

16. Colorectal Cancer (CRC) : Risk Factors Disease of developed countries Age : 90% of cases after age 50

17. Colorectal Cancer (CRC) : Risk Factors Risk Factors • Environmental factors play a minor role high fat low fibre high red meat low calcium low folate • Adenomatous Polyps

18. Colorectal Cancer (CRC) : Risk Factors • Family History : First degree relative with colorectal cancer • Polyposis Syndromes ex Familial Adenomatous Polyposis ( FAP) Hereditary Non Polyposis Colorectal Cancer (HNPCC) Juvenile Polyposis Syndrome Peutz Jeghers Syndrome • Inflammatory Bowel Disease (IBD) / Primary Sclerosing Cholangitis (PSC) • ASA/NSAID protective

19. Polyps • Discrete mass of tissue protruding into lumen of colon from normally flat mucosa • Generally asymptomatic • Important characteristic is histology Neoplastic Non Neoplastic • Removal of adenomatous polyps prevents CRC • Closer surveillance of patients who have had adenomas removed

20. Polyps Can be characterized by gross appearance Sessile vs pedunculated (on a stalk) Removal of adenomatous polyps prevents CRC

21. Polyps : Classification Non Neoplastic : Benign Hyperplastic – 90% Inflammatory Hamartomatous: Juvenile, Peutz-Jeghers polyps Lymphoid Neoplastic : Characterized by cellular dyplasia Adenomas Tubular, Villous, Tubulovillous, Serrated Malignant polyps

22. Hyperplastic polyp Serrated architecture

23. Hamartomatous polyps:1.Juvenile (retention) polyp • Most common childhood polyp • Usually children < 5 years, may occur in adults • 80% in rectum • Commonly presents with rectal bleeding polyps may autoamputate (10%) due to torsion • Usually sporadic; rarely associated with juvenile polyposis syndrome • Not neoplastic by themselves, but may be associated with dysplasia

24. Juvenile (retention) polyp

25. Hamartomatous polyps:2.Peutz-Jeghers polyp • Hamartomatous polyps that involve the mucosal epithelium, lamina propria, and muscularis mucosa. • May occur singly or multiple in the Peutz-Jeghers syndrome • Syndromic patients have an increased risk of developing GI (2-12%) and extra GI carcinomas ( pancreas, breast, lung, ovary, and uterus) • Solitary polyps do not have malignant potential, occur in colon • Syndromic polyps occur mostly in jejunum intussusceptions

26. Peutz-Jeghers polyp Arborizing MM (looks like a tree)

27. Neoplastic polyps • Polypoid areas of epithelial dysplasia • Adenoma = low grade dysplasia • Risk of invasive colorectal adenocarcinoma in the adenoma depends on size: <1% if < 1 cm vs. 10% if > 2 cm; higher risk if villous component • The risk of cancer is high (40%) in sessile villous adenomas > 4 cm • Risk of subsequent carcinoma is related to presence of 3 or more polyps, location at proximal or transverse colon

28. Tubular adenoma Raised lesion, looks like a berry, protruding in the lumen,attached to a stalk

29. Tubular adenoma Head of polyp, covered by dysplastic mucosa-with LGD Stalkofpolyp, covered by normal non dysplastic mucosa

30. VILLOUS ADENOMA Large mass, with a broad, sessile base

31. VILLOUS ADENOMA Long, slender villi, covered by dysplastic mucosa –with LGD

34. Malignant Potential of Adenomatous Polyps Nearly all CRC arises from adenomas, but minority ( 5 % or less) of adenomas progress to cancer Prevalence: 25-30 % of people at age 50 will have adenomas • Size Diminutive polyp ( <5 mm) . Low risk of progression • Histologic Type • Degree of Dysplasia Adenoma with Advanced Pathology ( >1 cm, villous, or high grade dysplasia)

35. Adenoma – Carcinoma Pathway

36. Adenoma – Carcinoma Hypothesis • Accumulation of genetic alterations leads to adenoma progression • On average, felt to be 10 years from initiation of adenoma to • progression to adenocarcinoma • APC gene mutation is the critical first step in adenoma formation. • ( Epithelial cells lose function of both APC alleles ). • In Familial Adenomatous Polyposis (FAP) , one APC gene • is inherited in a mutated form

37. Colon adenocarcinoma Right side carcinoma- can get really large before symptoms, cecum very distensible Left side carcinoma – usually presents with obstruction

38. Invasive Adenocarcinoma

39. Invasive Adenocarcinoma

40. The single most important prognostic indicator : extent of the tumor at the time of diagnosis (TNM stage) T- tumor N - lymph node M - metastasis

41. Pathologic Staging (pTNM)- AJCC 2002 - Primary Tumor (pT) • pTX: Cannot be assessed • pT0: No evidence of primary tumor • pTis: Carcinoma in situ, intraepithelial (no invasion) • pTis: Carcinoma in situ, invasion of lamina propria • pT1: Tumor invades submucosa • pT2: Tumor invades muscularis propria • pT3: Tumor invades through the muscularis propria into the subserosa or the nonperitonealized ericolic or perirectal soft tissues • pT4: Tumor directly invades adjacent structure

42. Can you identify the layers of colon wall? Can you stage depth of invasion (pT)? 1 1

43. Regional Lymph Nodes (pN) • pNX: Cannot be assessed • pN0: No regional lymph node metastasis • pN1: Metastasis in 1 to 3 lymph nodes • pN2: Metastasis in 4 or more lymph nodes

44. Clinical staging of CRC TNM Stage Groupings Astler-Coller Stage Dukes Stage 0 Tis N0 M0 N/A N/A Stage I T1 N0 M0 Stage A A T2 N0 M0 Stage B1 A Stage IIA T3 N0 M0 Stage B2 B Stage IIB T4 N0 M0 Stage B3 B Stage IIIA T1,T2 N1 M0 Stage C1 C Stage IIIB T3,T4 N1 M0 Stage C2,C3 C Stage IIIC Any T N2 M0 Stage C1,C2,C3 C Stage IV Any T Any N M1 Stage D D

45. CRC : Natural history • Start as epithelial lesions • Become invasive, spreading to lymphatics and vascular channels • Rectal cancers tend to progress to involve local structures • Generally , spread to regional and distant lymph nodes, peritoneum, liver via portal circulation and then lung

46. CRC : Staging • Physical, Bloodwork ( liver enzymes, CEA), CXR, CT abdo / pelvis. • CEA not useful for screening. High CEA at diagnosis is a marker of poor prognosis. CEA useful for follow up • Localized — confined to the primary site (TNM stage I or II ) • Lymph node involvement (TNM stage III) • Distant metastases (TNM stage IV) • Rectal cancers generally have a worse prognosis than colon cancers 5 year survival Stage I (T1-2N0) — 93 percent Stage IIA (T3N0) — 85 percent Stage IIB (T4N0) — 72 percent Stage IIIA (T1-2 N1)— 83 percent Stage IIIB (T3-4 N1) — 64 percent Stage IIIC (N2) — 44 percent Stage IV — 8 percent

47. CRC : Treatment Exclude synchronous lesion ( 2 distinct primary tumours. 5 % of cases) Surgery is the treatment of choice where possible Generally, adjuvant chemo for Stage 3 ( and selected patients with stage 2 disease) Chemotherapy for metastatic stage 4 disease Consider adjuvant radiation for rectal cancers to reduce local recurrence

48. CRC : Treatment Palliative stenting for obstructive tumours

49. CRC : Screening Removal of Polyps can prevent colon cancer Early detection improves prognosis Fecal Occult Blood Testing /Fecal Immunochemistry (FIT) every 1-2 years FOBT is inexpensive and non invasive FOBT testing will reduce CRC mortality FOBT is not a good test to detect polyps Many false positives occur. Only 2 % of positive tests due to cancer

50. CRC : Screening Flexible Sigmoidoscopy every 5 years Flexible Sigmoidoscopy and FOBT every 5 years Colonoscopy every 10 years starting at age 50 Radiology CT Colonography DCBE every 5 years