Medicine Grand Rounds

March 9, 2005

Yoshi Makino, M.D.

USC Department of Internal Medicine Andrew Stolz, M.D.

Faculty Moderator

Case Presentation

Patient F.B. is a 64 year old African American male, referred from an outside M.D. for OB(+) stool and anemia. Patient was scheduled for colonoscopy based on the above indications.

PSH: none PMH: – HTN – hyperlipidemia

Case Presentation

SH: – EtOH: 1-2 beers/day, 6-pack on weekends x 40 years – Tobacco: ¾ ppd x 40 years – Drugs: Marijuana in youth; without h/o IVDA ROS: – Denies h/o BRBPR, melena, stool caliber changes, nor weight loss. Without h/o GERD or other upper GI complaints.

Case Presentation

Allergies: NKDA Medications – Pravachol 40 mg PO daily – HCTZ 25 mg PO daily – Atenolol/Chlorthalidone 50 mg / 25 mg PO daily – Quinapril 40 mg PO daily – Norvasc 10 mg PO daily – Cardura 2 mg PO daily – EC ASA 81 mg PO daily – Darvocet or Tylenol 500 mg prn pain/HA

Laboratories

5.3

13.0

39.1

278 140 3.8

103 20 14 0.8

78 MCV RDW Ferr TIBC Fe %Sat 81.6

17.6

191 55 Alk P TProt Alb TBili DBili 129 7.9

4.3

0.5

0.1

AST ALT 29 18

Colonoscopy

Poor prep Anus: small IH Sigmoid: 2 cm flat polyp, s/p bx Transverse colon: one diminutive polyp and a 1.5 cm sessile polyp, s/p bx Ascending colon: multiple 2-9mm sessile polyp, s/p bx

Biopsy Results

8 of 11 polyps biopsied showed tubular adenoma Of these 8 polyps, 2 also showed areas of focal increased glandular complexity and high grade dysplasia

Colonoscopy Images

Colonoscopy Images

Family History

Colon CA; Age 70’s Colon CA; Age 68 “Bone” CA; Age 64 Colon CA; dx age 46; Presently 66 Multiple adenomatous polyps @ age 42, now 46

Familial Colorectal Cancers

Objectives

Overview Types of familial colorectal cancers – Clinical Features – Diagnostic Criteria – Genetics Genetic Testing Surveillance Management/Treatment

Colon Cancer Overview

Annual Statistics – 150,000 new cases diagnosed – 56,000 deaths Second leading cause of cancer deaths Lifetime incidence rate of 5% Most cases occurring after age 50

Lifetime Risk of CRC

General Population Prior History of CRC 3.5 - 6% 15% Family History 15% Colorectal Adenomas 15-25% HNPCC Ulcerative colitis FAP 80% 50-90% 100% Pucciarelli. 21st ICLAM Congress. Venice, April 2004.

Familial Colorectal Cancers

Familial clustering studies suggest 20%-30% of colon cancers may have a genetic cause Johns LE et al. Am J Gasteoenterol 2001;96:2992-3003.

The causative genes have been identified in only <5% of cases

UC HNPCC FAP AFAP

Cao et al. AJG 2002;97(7)1822-1827

Familial Adenomatous Polyposis

Familial Adenomatous Polyposis (FAP) was first described by Lockhart-Mummery in 1925 as a disease with clear dominant inheritance Adenomatous Polyposis Coli (APC: 5q21) gene identified by Kinzer and Groden in 1991 Courtesy of Florida State University and Pucciarelli 2004

Clinical Features of FAP

Greater than 100 colonic adenomatous polyps, frequently exceeding 1000 polyps Polyps can develop throughout the colon and rectum 90% of patient will have duodenal and periampullary polyps 100% lifetime risk for colorectal carcinoma Polyps appear at a mean age of 16 years, and colon cancer develops at a mean of 39 years, and invariably by 50 years

Extracolonic Manifestations

High association with gastric fundic polyps Extracolonic cancers include: – duodenal and periampullary tumors (5-10%) – pancreatic (2%) – thyroid (2%) – Gastric (0.5%) Osteomas, desmoid tumors and soft tissue tumors of the skin Congenital hypertrophy of the retinal pigment epithelium (CHRPE) Hernegger et al. Dis Colon Rectum. 2002 Jan;45(1):127-136.

Gastric Fundic Gland Polyps

Fundic gland polyps account for 50% of all gastric polyps and are observed in 0.8-1.9% of all patients undergoing EGD Studies estimate 52-88% of FAP patients have gastric fundic glands polyps Lifetime risk of gastric cancer is estimated to be 0.6% Burt. Gastro 2003;125:1462-1469.

Gastric Fundic Gland Polyps

FAP AFAP Burt. Gastro 2003;125:1462-1469.

CHRPE

Edward S. Harkness Eye Institute, Columbia University

Clinical Criteria for FAP

Clinical diagnosis of FAP can be made if… – Presence of >100 colon adenomas – Multiple adenomas, with both of the following criteria a first-degree relative is diagnosed with FAP the patient is on the affected side of the family Groden et al. Cell 1991;66:589 –600 However, genetic testing is now standard of care for those meeting the above criteria Giardiello FM. JAMA 1997;278:1278 –1281

Attenuated FAP

In 1990, Lynch et al described two families with “right-sided colonic flat adenomas” with more polyps than HNPCC but fewer than FAP Lynch also observed later age of onset of colon cancer, and a paucity of rectal adenomas Lynch et al. Cancer. 1990 Sep 1;66(5):909-15.

Initially called “hereditary flat adenoma syndrome”, later called attenuated FAP

Clinical Features of AFAP

Less than 100 adenomas, typically morphologically flat Polyps primarily located proximal to the splenic flexure, sparing the rectum Diagnosed at mean age of 44 years, and cancers at a mean of 56 years Extracolonic malignancies similar to FAP, but CHRPE, desmoid tumors and, osteomas are not seen Hernegger et al. Dis Colon Rectum. 2002 Jan;45(1):127-136.

Clinical Criteria for AFAP

Leppert et al suggest a set of diagnostic criteria for the disease – A positive family history of colorectal cancer with… at least one of the following criteria CRC at any age > 5 colorectal adenomas 2-4 adenomas and multiple gastric fundic polyps Leppert et al. N Engl J Med 1990; 322:9.

Later studies suggest a fourth criteria – Number of colorectal adenomas must be < 100 Knudsen et al. Familial Cancer. 2003;2:43-55.

The Genetics of FAP and AFAP

Primary defect is in the adenomatous polyposis coli (APC) gene, located on 5q21 APC gene is a classic tumor suppressor gene, primarily down-regulating intercellular and progression tumor suppressor activity β-catenin activity and ultimately slowing cell cycle entry “Dominant negative model” suggests that the mutated gene product forms dimers with the wild-type protein, causing lowered or abolished 30% of FAP/AFAP cases are due to

de novo

mutations of the APC gene Burt. Gastro. 2000;119:837-853

APC, β-catenin and E-cadherin

Fearnhead et al. Hum Mol Gen. 2001;10(7):721-733.

APC Gene Mutations

Fearnhead et al. Hum Mol Gen. 2001;10(7):721-733.

APC Mutation Phenotypes

Colored = distinct protein domains / Boxed = areas of mutation Fearnhead et al. Hum Mol Gen. 2001;10(7):721-733.

Extreme Phenotypic Variability

Burt et al. Gastro. 2004;127:444-451.

HNPCC / Lynch Syndrome

Hereditary Nonpolyposis Colorectal Cancer was first described in 1913 by Warthin, and formally characterized as an autosomal dominant condition by Lynch et al. in 1966 Lynch et al. Arch Intern Med 1966;117:206 –212.

Mismatch Repair (MMR) gene defects identified by 3 independent groups in 1993 Ionov et al. Nature 1993. / Thibodeau et al. Science 1993.

Peltomaki et al. Science 1993

Clinical Features of HNPCC

Sporadic colonic polyps (<10 polyps) Despite the name “non-polyposis,” accelerated transformation of flat polyps  carcinoma is suspected 70-80% lifetime risk for colorectal carcinoma, at a mean age of 44 years

Extracolonic Manifestations

Numerous extracolonic cancers including – Endometrium (43%) – Stomach (19%) – Biliary tract (18%) – Urinary tract (10%) – Ovary (9%) – Brain (1%) – Small bowel (rare) Specific MMR mutations are associated with varying rates of the above cancers –

MSH2

mutations have higher incidences of cancer than

MLH1

mutations –

MSH6

mutations have highest rate of endometrial cancers Grady. Gastro. 2003;124:1574 –1594

Clinical Criteria for HNPCC

Amsterdam criteria (All criteria must be met) – One member diagnosed with colorectal cancer before age 50 years – Two affected generations – Three affected relatives, one of them a first-degree relative of the other two – FAP should be excluded – Tumors should be verified by pathologic examination Amsterdam II and Bethesda criteria are more lenient, however there is no consensus on which criteria should be used for genetic testing Grady. Gastro. 2003;124:1574 –1594

The Genetics of HNPCC

A defect in one of several MMR genes has been associated with HNPCC –

MLH1 (59%)

– –

MSH2 (38%)

MSH6

(1.3%),

PMS2 EXO1

,

MLH3

(0.8%),

PMS1

(0.4%),

TGFBR2

, MMR genes are vital in the repair of microsatellites (short, repeated DNA sequences) Microsatellite instabilities (MSI) are expansion or contraction of these repeated sequences

MSI and MMR

Yangming et al. AJG. 2002;97(7):1822-1827.

Summary of Familial CRCs

Inheritance Incidence Gene Defect Colonic Polyps Lifetime CRC Risk Average age of CRC

FAP

Dominant 1:10,000 APC Always > 100, often >1000 Near 100% 39

AFAP

Dominant

HNPCC

Dominant 1:100,000 1:2,000 APC / MYH ?

49 MMR genes 10 - 100, usually proximal Few, sporadic 70-80% > 80% 44 Adapted from Grady. Gastro. 2003;124:1574 –1594

Overview of Genetic Testing

Should be offered to patients… – With strong family history – Where test results can be adequately interpreted – If results would influence screening and management ASCO Statement. J Clin Onc 1996;14:1730-1736.

Patients should at least meet the clinical criteria for the disease in question A genetic counselor should be involved to provide both pretest and post-test counseling

Who to Test for FAP

Clinical criteria for FAP met – >100 colon adenomas, or – Multiple adenomas in first degree relative of a known FAP case, on the affected side of family First-degree relatives of a person with a known APC mutation, regardless of polyp status A person with multiple adenomas who is a relative of a person with a known APC mutation Grady. Gastro. 2003;124:1574 –1594.

Who to Test for AFAP

Clinical criteria for AFAP met – Greater than 5 to 10 and less than 100 colorectal adenomas – 2-4 adenomas and multiple gastric fundic polyps First-degree relatives of a person with a known APC mutation, regardless of polyp status A person with multiple adenomas who is a relative of a person with a known APC mutation Grady. Gastro. 2003;124:1574 –1594.

Genetic Testing in AFAP/FAP

Testing involves direct DNA sequencing of APC gene – 95% mutation detection rate – Most expensive (~$800/test) Other tests are less expensive but also less sensitive – Confirmation strand electrophoresis with protein truncation (80-90%) – Protein truncation alone (80%) – Linkage analysis Detection rate dependent on accuracy of family tree Cannot be performed if only one member is affected (25% of FAP cases are de novo) Grady. Gastro. 2003;124:1574 –1594.

Who to Test for HNPCC

Amsterdam criteria met – Greater than 5 to 10 and less than 100 colorectal adenomas – 2-4 adenomas and multiple gastric fundic polyps First-degree relatives of a person with a known MMR mutation Complex algorithm using Bethesda criteria and other predictors (e.g. CRC case at <35 years of age) has also been proposed Grady. Gastro. 2003;124:1574 –1594.

Genetic Testing in HNPCC

Direct DNA sequencing of

MSH2

,

MLH1

, +/-

MSH6

is highest yielding approach – >95% of HNPCC cases

MSH2

and

MLH1

– Extremely expensive ($800-$3000)

MSI Testing

95% of HNPCC tumors have MSI 13% of all CRC have MSI 1%-6% of CRC are associated with HNPCC MSI testing can be conducted for $300-$500 Serves as a useful screening test prior to full

MSH2, MLH1

testing Pucciarelli. 21st ICLAM Congress. Venice, April 2004.

Summary of Costs

FAP/AFAP – APC Full Sequence:

$800

– Single site mutation analysis:

$200

HNPCC – MLH/MSH2 Full Sequence:

$800-$3000

– MSI Testing:

$300-500

Pricing from American Gastroenterology Association 2001.

Surveillance for FAP

Surveillance may initially be by sigmoidoscopy – Annually, starting at age 10-12 Annual colonoscopy from mid-teens until age 30 – Every 3-5 years past age 30 EGD starting at 30 years, every 1-3 years, depending on polyp status in duodenum Consider AFP and liver imaging from infancy to age 5 Grady. Gastro. 2003;124:1574 –1594.

Surveillance for AFAP

Surveillance must be by colonoscopy – Due to lesions proximal to splenic flexure – Contrasts with screening by flexible sigmoidoscopy in classic FAP Colonoscopy starting at 10 –17 years, annually EGD starting at 30 years, every 1 –3 years, depending on polyp status in duodenum Grady. Gastro. 2003;124:1574 –1594.

Surveillance for HNPCC

Surveillance must be by colonoscopy, as lesions are usually located in ascending colon Colonoscopy starting at age 25 – May be conducted every 2-3 years Annual colonoscopy after age 40 until age 75 ** EGD starting at 30 to 50 years, every 2 years, until age 75 All above studies should be conducted 5 years earlier than youngest affected person in family Grady. Gastro. 2003;124:1574 –1594.

Distinguishing Flat Polyps

Eisen et al. Gastrointest Endosc 2002;55:687-94.

High-resolution Chromoendoscopy

Hyperplastic Polyp Adenomatous Polyp

“Pit” pattern “Grooves” Eisen et al. Gastrointest Endosc 2002;55:687-94.

High-resolution Chromoendoscopy

Conventional dyes (e.g. 0.9% indigo carmine) or florescent dyes used in conjunction with a high resolution endoscope (410k – 850k pixels vs standard scopes 100k – 200k pixels) Hyperplastic polyps – a characteristic “pit” pattern of orderly arranged circular “dots,” morphologically similar to surrounding normal mucosa.

Adenomatous Polyps – surface “grooves” occasionally with a sulcus-like appearance In a recent multicenter trial by Eisen et al., chromoendoscopy had a sensitivity of 82% and specificity of 82% in distinguishing the above polyps Eisen et al. Gastrointest Endosc 2002;55:687-94.

2D Axial Image Acquisition

http://itswww.epfl.ch/~cuisenai/endoscopy.shtml

3D Virtual Reconstruction

http://itswww.epfl.ch/~cuisenai/endoscopy.shtml

FAP in Virtual Colonoscopy

Clinical Application of 3D Virtual Colonoscopy

myweb.hinet.net/ home7/r2207759/

Management of FAP/AFAP

100% lifetime risk of CRC in FAP Exact risk of CRC in AFAP remains unknown (general consensus is roughly 60-80%) Disease progression from adenoma to carcinoma is not accelerated Colonoscopy – In AFAP, there is a sufficiently low number of colonic polyps to make polypectomy practical Burt et all. Gastro. 2004;127:444-451 .

EGD – Best treatment of gastric fundic gland polyps is presently unknown Burt. Gastro 2003;125:1462-1469.

When to Perform Colectomy?

In FAP patients, The American Society of Colon and Rectal Surgeons recommends colectomy between ages 15 to 18 Church and Simmang. Dis Colon Rectum, August 2003.

No clear consensus exists for AFAP – 15 year delay in onset of disease would suggest colectomy at age 30 – In a series of 120 patient with AFAP by Burt et al., first CRC was at a mean age of 58 years (range of ages 29 to 81), with 12 patients over the age of 60 with intact colons Burt et all. Gastro. 2004;127:444-451.

Type of Surgery

Three main surgical options – Colectomy and ileorectal anastomosis (IRA), – Proctocolectomy with ileostomy (TPC) – Proctocolectomy with ileal pouch-anal anastomosis (IPAA) As AFAP almost always spares the rectum, present consensus is for IRA, with subsequent surveillance by flexible sigmoidoscopy annually B ülow et al. Gastro. 2000;119:1454–1460.

Church and Simmang. Dis Colon Rectum, August 2003.

Pharmacologic Therapy

Treatment with sulindac and celecoxib may also reduce polyp burden Giardiello et al. N Engl J Med 1993;328:1313-1316.

Steinbach et al. N Engl J Med 2000;342:1946 –52.

In 1999, FDA approves celecoxib as a treatment for patients with FAP – Dosage: celecoxib 400 mg PO BID – “To reduce the number of adenomatous colorectal polyps in familial adenomatous polyposis (FAP), as an adjunct to usual care (e.g., endoscopic surveillance, surgery).” FDA Application NDA 21-156 & 20-998/S007

Celecoxib and FAP

Steinbach et al. N Engl J Med 2000;342:1946 –52.

Management of HNPCC

Life time risk of colon cancer is >80% Disease progression from adenoma to carcinoma is accelerated Burt. Gastro 2003;125:1462-1469.

Given high prevalence of extracolonic malignancies, consider – Pap smears, transvaginal ultrasound, endometrial aspiration biopsy every 1-2 years – Urinalysis, urine cytology, and if abnormal, ultrasound +/- cystoscopy every 1-2 years

Surgical Management of HNPCC

If colorectal cancer found, subtotal colectomy with ileorectal anastamosis is recommended, as metachronous lesions are common Prophylactic colectomy is recommended, but no consensus exists on timing Procotocolectomy should be considered in

MSH2

mutation, given higher rates of rectal involvement Kouraklis et al. Dig Dis Sci. 2005 Feb;50(2):336-44.

CRC Survival Rates in HNPCC

5 year survival rates for patients with HNPCC CRC is significantly better than for sporadic cases of CRC Sankila et al. in 1996 followed 175 patients with genetically proven HNPCC CRC, compared to 14,086 patients with sporadic CRC – 5 year survival rate in HNPCC: 65% versus sporadic: 44% Sankila et al. Gastro. 110:682-687, 1997.

Conclusions

Genetic and familiar factors may account for up to 30% of colorectal cancers While specific genetic defects are rarely identified (5% of cases), given the high malignant potential (80-100% lifetime risk of CRC), early recognition is vital Many polyps  think FAP Few polyps  think HNPCC (more common), but do not discount AFAP Involve a genetic counselor early, and use genetic testing judiciously

Patient Follow-up

Patient had an EGD on 9/20/2004 to evaluate for gastric fundic gland polyps and periampullary disease – No significant lesions found Patient underwent genetic counseling at Norris Comprehensive Cancer Center on 9/24/2004 Ultimately, the proband (the sister) underwent genetic testing via the Kaiser Permanente system

MLH1 mutation found

Acknowledgements

Dr. Andrew Stolz Rebecca Zemetra Roche Pharmaceuticals This presentation is available at: http://www.makino.net/gastro

Oh no! Is that a short call?

Questions?

I have

two

questions.

Hmm.. it’s almost 8 o’clock

Genetic Testing and Counseling

Dr. Andrew Stolz

Associate Professor of Medicine USC Department of Internal Medicine Division of Gastrointestinal and Liver Diseases

Risk - Benefits for Genetic Testing

+

 Non-invasive test  Preventive treatment  Highly predictive

-

 Fails to identify all cases  Social implication  Psychological implications

Genetic Testing Strategy for BRC1/2

Pre-Test counseling session Pt declines BRCA 1/2 + Reinforce medical management Counsel as needed.

-

Post genetic testing session Discuss option for medical management

-

Coping strategy for family members Nature Cancer Rev 4:153, 2004

Potential Outcomes of Genetic Testing

Result in index case Result in at-risk family member Interpretation of result in at-risk family member

Significant mutation found Significant mutation found Same mutation found Positive No mutation found Negative No mutation found Do not test Not informative Variant of unknown significance found Do not test Not informative

Screening Recommendation for APC Patients

Annual screening for hepatoblastoma up to age 5 Sigmoidoscopy every one to two years after age 10 Colonoscopy once polyps are detected.

Annual colonoscopy if colectomy is delayed more than a year after polyps emerge.

Esophagogastroduodenoscopy (EGD) beginning when colonic polyposis is detected or by age 25.

Small bowel X-ray (small bowel enteroclysis or abdominal and pelvic CT with orally administered contrast) when duodenal adenomas are detected or prior to colectomy, Attention to extraintestinal manifestations, usually for cosmetic concerns.

Annual physical examination including palpation of the thyroid.

Screening Recommendation for HNPCC Patients

Colon cancer.

Colonoscopy every one to two years beginning between age 20-25 years or ten years before the earliest age of diagnosis in the family.

Gynecological cancer.

can be considered.

Endometrial cancer and ovarian cancer surveillance is less well established than that for colon cancer. In addition to an annual Pap smear and pelvic examination, annual transvaginal ultrasound examination, endometrial biopsy, and CA 125 blood test beginning between 25-30 years of age

Stomach and duodenum.

lesions.

Upper endoscopy surveillance is available to for gastric and duodenal cancers. However, one study suggested no benefit from this because of the lack of identifiable precursor

References

Al Tassan et al. Inherited variants of MYH associated with somatic G:C- >T:A mutations in colorectal tumors. Nat Genet. 2002 Feb;30(2):227-32.

Bülow et al. Ileorectal anastomosis is appropriate for a subset of patients with familial adenomatous polyposis. Gastroenterology. 2000 Dec;119(6):1454-60.

Burt et al. Genetic testing and phenotype in a large kindred with attenuated familial adenomatous polyposis. Gastroenterology. 2004 Aug;127(2):444-51.

Burt. Gastric fundic gland polyps. Gastroenterology. 2003 Nov;125(5):1462 9. Cao et al. Challenge in the differentiation between attenuated familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer: case report with review of the literature. Am J Gastroenterol. 2002 Jul;97(7):1822-7. Church and Simmang. Practice parameters for the treatment of patients with dominantly inherited colorectal cancer (familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer). Dis Colon Rectum. 2003 Aug;46(8):1001-12.

References

Eisen et al. High-resolution chromoendoscopy for classifying colonic polyps: a multicenter study. Gastrointest Endosc. 2002 May;55(6):687-94.

Fearnhead et al. The ABC of APC. Hum Mol Genet. 2001 Apr;10(7):721-33. Giardiello et al. Primary chemoprevention of familial adenomatous polyposis with sulindac. N Engl J Med. 2002 Apr 4;346(14):1054-9.

Giardiello et al. Treatment of colonic and rectal adenomas with sulindac in familial adenomatous polyposis. N Engl J Med. 1993 May 6;328(18):1313-6. Grady. Genetic testing for high-risk colon cancer patients. Gastroenterology. 2003 May;124(6):1574-94.

Hawk et al. Colorectal cancer chemoprevention--an overview of the science. Gastroenterology. 2004 May;126(5):1423-47.

Hernegger et al. Attenuated familial adenomatous polyposis: an evolving and poorly understood entity. Dis Colon Rectum. 2002 Jan;45(1):127-34; discussion 134-6. Jones et al. Biallelic germline mutations in MYH predispose to multiple colorectal adenoma and somatic G:C-->T:A mutations. Hum Mol Genet. 2002 Nov 1;11(23):2961-7.

References

Knudsen et al. Attenuated familial adenomatous polyposis (AFAP). A review of the literature. Fam Cancer. 2003;2(1):43-55. Kouraklis G, Misiakos EP. Hereditary nonpolyposis colorectal cancer (Lynch syndrome): criteria for identification and management.

Dig Dis Sci. 2005 Feb;50(2):336-44.

Leppert et al. Genetic analysis of an inherited predisposition to colon cancer in a family with a variable number of adenomatous polyps. N Engl J Med. 1990 Mar 29;322(13):904-8.

Lynch et al. Phenotypic variation in colorectal adenoma/cancer expression in two families. Hereditary flat adenoma syndrome. Cancer. 1990 Sep 1;66(5):909-15.

Spirio et al. Alleles of the APC gene: an attenuated form of familial polyposis. Cell. 1993 Dec 3;75(5):951-7.

Steinbach et al. The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. N Engl J Med. 2000 Jun 29;342(26):1946 52. Wang et al. MYH mutations in patients with attenuated and classic polyposis and with young-onset colorectal cancer without polyps. Gastroenterology. 2004 Jul;127(1):9-16.

Acknowledgements

Dr. Andrew Stolz Rebecca Zemetra Roche Pharmaceuticals This presentation is available at: http://www.makino.net/gastro